A morphologic study of unexplained hepatitis following halothane anesthesia. A survey of postoperative jaundice throughout the United Kingdom allowed the detailed analysis of 76 patients with unexplained hepatitis following halothane anesthesia ("halothane hepatitis"). In 16 patients liver biopsy specimens were examined by light and/or electron microscopy to determine whether the liver morphology could aid the differentiation between "halothane" and "acute viral" hepatitis. The mitochondrial changes often claimed to be characteristic of holothane hepatitis were unremarkable in our patients. Since lipid vacuolation and a predominantly centrilobular distribution of necrosis are not classically described in fatal viral hepatitis, the presence of these features in some of our fatal cases was of some diagnostic interest. In general, however, the results of light and electron microscopy in patients with unexplained postoperative hepatitis is considered to have little differential diagnositc value.


Autofluorescent particles of human uterine muscle cells. Smooth muscle tissue collected from the uterine fundus of 24 patients undergoing hysterectomy was examined for chromolipoid pigments by histochemical and electron microscopic techniques. Certain cytoplasmic particles were found, mainly in smooth muscle cells, which exhibited characteristic autofluorescence, sudanophilia, and acid phosphatase activity but did not correspond to any typical pigment described previously. These particles were present in all subjects and they tended to increase in number with age. Chemical tests on tissue lipid extracts failed to prove that vitamin A was responsible for the fluorescence. The ultrastructural appearance of the particles somewhat variable, but most particles were rounded and of low electron density, with a lucent central space and dense bodies, probably lysosomes, at the periphery. The whole complex was enclosed by a single trilaminar membrane.


Reversible papillary hyperplasia of the rat urinary bladder. A rapid reproducible method for the production of ulcers and reversible regenerative hyperplasia of the urinary bladder of rats is described. This method does not involve administration of a toxic chemical or retention of a foreign body. Ulceration was produced by means of applying a steel rod, 5 mm in diameter, frozen at -78 C, to the serosal surface of the bladder for 2 seconds, twice, with a 5-second interval between each application. Sequential histologic observations showed that ulcers were accompanied by necrosis of the entire thickness of the bladder at the site of freezing with extensive acute inflammation. Regenerative hyperplasia was evident at the edge of the ulcer by the second day, with greatest severity at 5 days when papillary and nodular hyperplasia were present. At 15 days the bladders were normal or had only minimal hyperplasia. The labeling index by autoradiography was highest in the mildly hyperplastic area near the ulcer at 2 days and remained relatively high through 5 days. The hyperplastic epithelium surrounding the ulcer observed by scanning electron microscopy had numerous degenerative cells on the surface, and small epithelial cells with numerous short, uniform microvilli on their luminal surface were also observed. The numerous short, uniform microvilli on their luminal surface were also observed. The microvilli had a symmetric luminal membrane, as observed on trasmission electron microscopy. More peripherally the cells had microridges only or microvilli and microridges on their luminal surface. Neither pleomorphic microvili nor a structured glycocalyx fuzz on microvilli was observed during the process of regenerative hyperplasia, distinguishing it from neoplastic bladder proliferations.


Effect of cycloheximide on glucagon-induced autophagy. Quantitative examinations on hepatocytes in the rat. By means of fine structural evaluation, a highly significant inhibitory effect of cycloheximide (20 mg/kg) on glucagon-induced autophagy is demonstrated in rat hepatocytes, which also presumably affects physiologic autophagic activities. Contrary to other investigators, we think in vivo global inhibition experiments using cycloheximide as an inhibitor of protein synthesis do not provide substantial information on the origin of the segregating membranes.


The results of pancreatography during pancreatic carcinogenesis. Systematic histologic-pancreatographic examination of the pancreas during pancreatic ductal carcinogenesis revealed both specific and nonspecific diagnostic criteria. Ductal changes due to hyperplasia of ductal epithelium were recognized as distention rather than narrowing. This condition, however, occurred in limited numbers during advanced ductal alteration and was found to be an insignificant criterion. The most reliable tumor marker was complete ductal obstruction: ductal deterioration (displacement, deformity) occurred in 63% of the tumor cases, a pooling effect occurred in 44%, and a filling defect occurred in 42%. In both histologic and pancreatographic studies was found the "chain of lakes" caused by ductular proliferation or adenomas both of which seem to represent precursor stages of adenocarcinomas. Some neoplasms escaped diagnosis, due to either their small size, anatomic location, or specific histologic patterns. The data indicated that pancreatography per se as an early detection tool is unreliable.


Studies on "end-stage" kidneys. II. Embryonal hyperplasia of Bowman's capsular epithelium. Clusters of deeply staining "embryonal-type" epithelial cells surround hyaline glomeruli in some patients with end-stage renal disease treated with dialysis. The kidneys of 40 patients, dialyzed for 2 months to 2 years, were studied with a variety of histologic and histochemical staining techniques. In 4 of these cases such "embryonal-type" cell clusters, arising from the parietal epithelium of Bowman's capsule and here termed "embryonal hyperplasia of Bowman's capsule epithelium" (EHBCE), are identified. In 6 additional cases there are similar cells in a tubular pattern, resembling the adenomatoid or pseudotubule structures of chronic, cresentic glomerulonephritis. The largest lesions are often found in groups within localized areas of cortex, giving their distribution a "field" effect. In such cases they have the appearance of new growths, suggesting the induction of a less differentiated cell type in these diseased adult tissues.


Platelet dysfunction induced by parenteral carbenicillin and ticarcillin. Studies of the dose-response relationship and mechanism of action in dogs. Sequential studies of platelet function were performed in dogs receiving continuous intravenous carbenicillin (CARB) or ticarcillin (TIC). Dose- and time-dependent platelet dysfunction was uniformly observed during the administration of CARB or TIC, 250 to 1000 mg/kg/24 hr. ADP-induced primary and secondary platelet aggregation was markedly inhibited within 24 to 48 hours in dogs receiving 750 or 1000 mg/kg/24 hr, but maximum impairment of aggregation did not occur until 3 to 5 days in dogs receiving 250 or 500 mg/kg/24 hr. Platelet glass bead column retention was abnormal in all dogs studied, and platelet factor 3 availability was impaired in 91%. Collagen-induced platelet aggregation was consistently impaired and the bleeding time was prolonged only during the infusion of greater than or equal to 750 mg/kg/24 hr. Plasma fibrinogen concentrations and thrombin times remained normal. CARB and TIC infusions resulted in inhibition of 14C-serotonin release and slightly decreased platelet ADP, while serotonin, ATP, and ultrastructure remained unchanged. The mutual correction of abnormal platelet aggregation by mixing CARB or TIC platelets with aspirin-treated platelets suggested that CARB and TIC inhibited the platelet release reaction by a mechanism other than inhibition of platelet cyclo-oxygenase. The platelet inhibitory properties of CARB and TIC demonstrated in this study suggest that they may be useful antithrombotic agents.


Effects of whole-body irradiation on neonatally thymectomized mice. Incidence of benign and malignant tumors. The individual and combined effects of neonatal thymectomy and whole-body irradiation on the prevalence of benign and malignant tumors in germ-free female mice of the Charles Rivers line were studied to determine if a portion of the tumorigenic effects of irradiation can be attributed to injury of the thymic-dependent component of the immune response. Neonatal thymectomy increased a) the incidence of benign and malignant tumors and b) the prevalence of multiple primary neoplasms in an individual mouse. Whole-body exposure to 700 rad at 6 weeks of age further increased th incidence of tumors, but the relative magnitude of this increase was less pronounced than in sham-operated controls. Thus, the cumulative effects of thymectomy plus irradiation are less pronounced than the sum of the individual effects. One of several possible explanations for this observation is that a portion of the carcinogenic effects of whole-body irradiation is mediated by suppression of the thymic-dependent component of the immune response.


Endothelial proliferation in inflammation. II. Autoradiographic studies in x-irradiated leukopenic rats after thermal injury to the skin. The effect of leukocyte depletion on endothelial proliferation in the microvasculature of skin sites of acute inflammation was studied. Leukocytes were suppressed by 800 rad of whole-body irradiation 2 or 4 days prior to producing necrotizing thermal injuries (60 C, 20 seconds) on a shielded area of skin. Endothelial proliferation was assayed 3 days after thermal injury by quantitating the labeling index after injection of 3H-thymidine. Circulating mononuclear cells were depressed to 1.3% of pre-irradiation levels by 2 days and remained at similar levels at 5 days. Lesions developing over this interval were devoid of mononuclear infiltrate, although neutrophils emigrated as usual. Three-day lesions without mononuclear infiltrate had a mean endothelial-labeling index of 8.97%, and this was not significantly different control controls (9.42%). Lesions induced at 4 days, when circulating neutrophils were also suppressed, had reduced infiltration of neutrophils, but endothelial-labeling indexes were similar to those of controls. The results indicate that infiltration by monocytes is not a necessary stimulus for endothelial proliferation of new vessel growth in sites of nonimmunologic acute inflammation.


Immunopathology of the renal vascular lesion of progressive systemic sclerosis (scleroderma). Patients with progressive systemic sclerosis (PSS, scleroderma) exhibit a variety of immunologic abnormalities. To verify whether the renal vascular lesions of such patients might be mediated by an immunologic mechanism, kidney tissues of 16 patients with PSS were investigated by means of fluorescence, light, and electron microscopy; elution of tissue-bound antibody; and fixation of heterologous (guinea pig) complement. Controls consisted of 12 nonsclerodermatous patients with similar levels of hypertension with no evidence of associated immunologic abnormalities. Diffuse vascular deposits of immunoglobulins (predominantly IgM) and/or complement (predominantly Clq) were found in all 16 patients with PSS. These deposits were bound to the intima of intralobular and arcuate arteries which, by light microscopy, often exhibited typical fibromucinous alterations. Elution of antibody and heterologous complement fixation studies suggested that such reactants may represent the interaction of complement-fixing antibody and antigen. Electron microscopies studies demonstrated abundant fibrillar and ground substance material in the arterial intima but features of deposited (circulating) immune complexes were not found. By contrast, in the hypertensive (control) group, deposits of immunoglobulin (s) and/or complement were rare and, when present, were mostly confined to the arterioles. As judged by the results of elution and heterologous complement fixation, these arteriolar deposits appeared to represent trapped rather than specifically bound serum proteins. The possible signficance of these findings are discussed in relation to immunologic mechanisms which might be implicated in the pathogenesis of the renal vascular disease of PSS.


Immune synovitis in rabbits. Effects of differing schedules for intra-articular challenge with antigen. The effects of varying intra-articular (ia) doses of bovine serum albumin (BSA) antigen on immune synovitis in rabbits have been investigated. Chronic synovitis, characterized by mononuclear cell infiltration in synovial tissues, was induced by a single ia challenge with BSA in sensitized rabbits. However, cartilage and bone erosions and pannus formation were rarely observed. By varying the number and magnitude of the BSA challenges, lesions with different characteristics were observed at different times of analysis of joint pathology. In 3- to 10-week studies, multiple ia challenges with BSA produced lesions characterized by severe cartilage and bone changes; polymorphonuclear leukocyte (PMN) exudates; and mononuclear cells and, sometimes, PMNs in synovial tissues. Substantial increases in knee widths and synovial tissue weights also observed. By increasing the frequency of ia injections, more severe changes were produced more rapidly, so that within a 3-week period, the animals also experienced pain and were unable to fully extend their antigen-challenged knees. Some of the lesions observed in immune synovis resembled those in rheumatoid arthritis (RA). However, the presence of large numbers of PMNs in synovial tissue under certain conditions suggests some possible differences between the pathogenesis of experimental synovitis and RA.


Lymphocyte migratory pathways in adjuvant disease. I. Distribution of 51Cr-labeled thoracic duct lymph-borne. Evidence for selective extravasation of thoracic duct lymph-borne cells, derived from rats with adjuvant disease, within joints of normal or adjuvant arthritic recipients was sough by adoptive transfer of radiolabeled cells. Control studies were carried out in parallel using thoracic ducts cells from normal donors. No increased homing of lymph-borne cells to inflamed portions of the limbs was detected when cells from adjuvant arthritic donors were compared with those of normal controls. Inflammatory changes, ie, adjuvant-induced disease, in the recipient produced a significant nonspecific enhancement of extravasation; cells from normal and adjuvant arthritic donors responded equally well. One difference in migratory behavior between lymph-borne cells from adjuvant arthritic and normal animals was the increased ability of the former to localize within certain lymph nodes. A possible association between this traffic and the development of chronic inflammatory processes within joints is discussed.


Renal lesions induced induced by tilorone and an analog. Ultrastructure and acid phosphatase study. Tilorone, 2,7-bis-(diethylaminoethoxy)-fluoren-9-one hydrochloride, an interferon inducer, has been shown to cause hydropic degeneration in choroid plexus and distal convoluted tubules of kidney. Ultrastructural and histochemical studies of the renal lesion produced by tilorone and one of its analogs revealed striking accumulation of vacuoles and/or acid-phosphatase-positive lemellar bodies retricted to glomeruli, ascending limb of Henle's loop, and distal convoluted tubules.


Children's concepts of healing: cognitive development and locus of control factors. This study of young children's understanding of the process of healing indicates that both level of cognitive development and locus of control are relevant factors. The importance of the children's locus of control orienation to their understanding was found to depend upon the interaction of the cognitive level and the complexity of the concept considered.


Temporal integration and children's understanding of social information of television. Recent studies are reviewed that suggest that preschool and young grade-school children often have incomplete or distorted impressions of social portrayals on television. It is suggested that cognitive-processing factors in understanding television dramas may put these younger viewers at special risk for deleterious effects of television viewing.


Television and children: issues involved in corrective action. Economic, legal, and political/moral factors affecting the state of children's programming on television are reviewed, and their effects on the effort to encourage "pro-social" programming are considered. It is suggested that the leadership of child-care professionals is essential in the battle to reduce gratuitous violence, limit questionable advertising, and increase positive programming for children.


The relation of reflection and action.

The relation of reflection and action. This paper maintains that mental health delivery systems must be supplemented by critical analyses of the hidden assumptions that guide policy and technique decisions. It compares the intellectual and clinical impact of B.F. Skinner with that of R.D. Laing, and considers the significance of Skinner's generally less preferred theoretical position having gained more widespread practical application, in the form of token economies, than has Laing's Kingsley Hall concept.


Anger, disability, and demands in the family. Parents' tendency to perceive children with behavior problems as "disabled" frequently represents a projection of helplessness, and can be interpreted as a defense against anger. Shared family presumptions regarding the disabling effects of "anger" may lead to revision of behavioral goals or preclude adoption of effective problem-solving tactics. Implications for therapy are offered.


Sexual abuse of children: a clinical spectrum. This paper suggests that incest has been underestimated as a significant determinant of emotional disturbance, and that misuse of sexuality between parents and children can have detrimental consequences that parallel those resulting from other forms of child abuse. The spectrum of parent-child sexuality is classified into ten categories as a guide to the diagnosis, management, and prognosis of sexually abusive behavior.


Common problems of stepparents and their spouses. The half-million adults annually who become stepparents in this country have relatively little guidance available to them from mental health professionals or from the public. This paper examines conflictual situations that frequently interfere with the successful blending and establishment of new stepfamilies.


Preparation for remarriage following divorce: the use of group techniques. The experiences of four series of weekly group meetings with a total of 22 couples, in which at least one partner had children by a previous marriage, are discussed. Major complexitis arose from the permeable boundaries of the second marriage due to continuing ties to the former marriage, and from resultant ambiguity of roles among new partners and their spouses' children. The group experience was found to be beneficial in clarifying roles in the remarriage family.


Mental health interventions in divorce proceedings. The protracted process involved in family disruption provides the opportunity for different types of mental health intervention. In addition to the traditional diagnostic and evaluative services typically requested by the legal system, preventive and therapeutic programs can be developed. Implementation of a program by the UCLA Section on Legal Psychiatry is described.


Psychological problems following recovery from acute life-threatening illness. Counseling of a group of families in which a child had been stricken with a sudden, life-threatening illness is described. Although all children made good medical recoveries, family adjustment problems were marked; incomplete mourning, sense of helplessness and lack of control, and fantasies of death and return on the part of children and of parents were noted. Strategies for helping families cope with this variant of the vulnerable child syndrome are discussed.


Maternal sensitivity to children in problem situations. Sixty mothers and their preschool children were placed in interactions structured to involve a problem situation for the child, the mother, or both. Maternal sensitivity and insensitivity were measured to test a number of parent effectiveness constructs. Results indicate that mothers were more insensitive than sensitive to their children, and that some major assumptions of the parent effectiveness model lack sufficient support to justify its training procedures.


Problem children's adult adjustment predicted from teachers' ratings. Teacher ratings of 187 children seen at a guidance clinic are compared to interview-based ratings of social adjustment nine to fifteen years later. Children described as failing to get along with others are seen to be relatively disturbed at follow-up, and differences are found between teacher-rated behavior patterns relating to later social adjustment for boys and those for girls. It is concluded that teacher ratings can be useful predictors of adjustment, especially if focused on the child's peer relationships.


Effects of sensory-motor training on the language development of retarded preschoolers. Previous research indicates that perceptual-motor training positively influences the development of language in retarded children. In this year-long study, 30 retarded children attending a preschool training center were divided into three equal groups given perceptual-motor training, movement training, or no systematic training. No significant differences were found among the groups on language measures, suggesting that the total remedial environment may be an important factor in the effectiveness of perceptual-motor and of movement training programs.


Coping with pregnancy resolution among never-married women. The Janis-Mann model of decision-making provides the theoretical orientation for empirical analyses of decisions to deliver or abort in matched samples of never-married women. Results focus on four variables: happiness about pregnancy; initial acceptance of delivery or abortion; ease of decision-making; and satisfaction with final choice. Path analyses summarize findings, which are discussed in terms of conflict resolution strategies.


Father-absent and father-present families of disturbed and nondisturbed adolescents. In a study of intact and of father-absent families, male adolescent disturbance in both groups was found to be related to less warm, supportive, and expressive intrafamilial relations; less of a family orientation toward personal growth; and less successful participation in extrafamilial involvement. Disturbance in father-absent boys was not related to negative father-typing by the mother or maternal restrictions, and the findings do not support the assumption of family conditions peculiar to the father-absent home as a factor in adolescent pathology.


Speed-force relations in the motor units of the cat tibialis posterior muscle. The neuro-mechanical properties and speed-force relations of 81 cat tibialis posterior motor units have been studied. Statistically significant correlations were found between alpha-axonal conduction velocity (CV) and average twitch tension (log10 TwT; r = 0.459, p less than 0.001), between CV and twitch contraction time (CT; r = -0.395, p less than 0.001) and between CT and log10 TwT (r = -0.277, p less than 0.02). The present correlations for the intermediate-sized tibialis posterior are stronger than those previously reported for large muscles such as soleus, medial gastrocnemius, plantaris and flexor hallucis longus. However, they are considerably weaker than those reported for the much smaller lumbrical muscles of the cat's foot. These findings support the contention that the spinal mechanisms governing an orderly recruitment of motor units according to the size of their muscle units must be more complex for large than for small muscles, at least in the cat hindlimb.


Provision of rehabilitation services for a rural mountainous region in Colorado. 1. Four alternative methods for provision of rehabilitative services to a rural, mountainous region of Colorado were examined. These concepts were: minicenter, clinic-on-wheels, ambulance taxi, and temporary rest home. 2. From the standpoint of breakeven facts and resource efficiency the minicenter and clinic-on-wheels were similar and superior to the other two. 3. Further comparison between the minicenter and clinic-on-wheels in eight areas revealed that the former had more areas of superiority. Since the items were not weighed, final choice between these two alternatives would have to depend upon the value judgement of the community.


Magnesium-fluoride interrelationships in man II. Effect of magnesium on fluoride metabolism. The effect of magnesium on the fluoride balance was investigated in man by determining metabolic balances of fluoride and magnesium in control studies and during magnesium supplementation. The magnesium intake averaged 264 mg/day in the control studies and 825 in the experimental studies. The studies were carried out during four calcium intakes that ranged from 200 to 2,200 mg/day and during phosphorus intakes ranging from 800 to 2,000 mg/day. The studies were carried out during a fluoride intake of about 4 mg/day that was due to the dietary fluoride content and the intake of water and during a high fluoride intake of 25 mg/day that was due to the addition of sodium fluoride. During the high magnesium intake, both the urinary and fecal magnesium excretions increased and the magnesium balances became more positive. These changes were not associated with any significant changes of either the urinary or fecal fluoride excretions or of the fluoride balances during the different intakes of calcium phosphorus, or fluoride.


Effect of thoracic vagotomy and vagal stimulation on esophageal function. The purpose of this study was to determine the effect of thoracic vagotomy and thoracic vagal stimulation upon esophageal peristalsis and lower esophageal sphincter (LES) function in the opossum. The thoracic portion of the vagus nerve was sectioned in the upper or lower thorax. Bilateral, but not unilateral, thoracic vagotomy above the level of the heart abolished peristalsis and LES relaxation in response to swallowing or cervical vagal electrical stimulation. Thoracic vagotomy at the level of the ventricle or below did not alter either peristalsis or LES relaxation during swallowing or cervical vagal stimulation. Secondary peristalsis and its associated LES relaxation was unaltered by thoracic vagotomy at any level. Electrical stimulation of the distal end of the upper thoracic vagus elicited both peristalsis and LES relaxation. Electrical stimulation of the distal end of the lower thoracic vagus elicited both peristalsis and LES relaxation. Electrical stimulation of the distal end of the lower thoracic vagus, as well as stimulation of the vagal branches to the terminal esophagus, gave only LES relaxation. These studies suggest that: a) the major extrinsic vagal innervation mediating primary peristalsis terminates in the upper portion of the esophagus, whereas the vagal innervation mediating LES relaxation responses are present throughout the length of the esophagus; and b) secondary peristalsis and its associated LES relaxation occurs independent of extrinsic vagal innervation.


A potential artifact in use of a new technique for rapid brain removal. New techniques are are continuously being developed to obtain animal brain tissue that is as close as possible to its in vivo status. The brain-blowing technique provides a swift freezing of brain tissue (within 1 s) in which postmortem changes have been said to be minimal. Higher concentrations of glucose were present in brain samples removed by this method than have previously been found when the brain was frozen in situ, but at the same time the plasma levels of glucose were higher. It is suggested that, although the procedure did not appear to involve any stress, the hyperglycemia was stress related. Modifications of the procedure are described, by which these changes in blood glucose have been minimized.


Histamine receptors in mesenteric circulation of the cat and rat. This study was designed to ascertain the types and functions of histamine receptors in the mesenteric circulation of the cat and rat. Superior mesenteric artery (SMA) flow was measured via an electromagnetic probe in the cat and intestinal submucosal arteriolar diameter by an image-splitting in vivo microscopy technique in the cat and rat. Histamine infusion into the SMA caused dose-dependent decreases in mesenteric vascular resistance. Mepyramine, an H1 receptor antagonist (H1A), inhibited this effect, displacing the histamine dose-response curve to the right. Metiamide, an H2 receptor antagonist (H2A), alone had no effect, but in the presence of H1A caused further displacement of the curve to the right. In both the cat and the rat, histamine superfusion dilated the submucosal arterioles. H1A attenuated this effect. H2A alone had no effect, but in the presence of H1A there was nearly complete inhibition of the histamine effect. In conclusion, both H1 and H2 histamine receptors, both subserving vasodilatation, are present in the mesenteric circulation and the H1 receptor effect predominates.


Cholecystokinin inhibits gastric emptying by acting on both proximal stomach and pylorus. Cholecystokinin is a potent inhibitor of gastric emptying. It is known to both relax the proximal stomach and contract the pyloric sphincter, and either one or both of these actions could mediate inhibition of gastric emptying. We investigated the relative importance of these two actions by studying the effectiveness of the C-terminal octapeptide of cholecystokinin (OP-CCK) to inhibit the emptying of a liquid meal (300 ml saline) before and after operations that either remove or destroy the pyloric mechanism (antrectomy and pyloroplasty), or lead to loss of accommodation of the proximal stomach (vagotomy), and after both vagotomy and antrectomy, and vagotomy and pyloroplasty. The results show that OP-CCK causes dose-related inhibition of gastric emptying in the intact dog. After either pyloroplasty or antrectomy the effectiveness of low but not of high doses of OP-CCK is lost. After vagotomy, OP-CCK at any dose was ineffective. The findings suggest that cholecystokinin inhibits gastric emptying by acting both on the pylorus and on the proximal stomach.


Effects of intestinal bypass surgery on appetite, food intake, and body weight in obese and lean rats. Jejunoileal bypass surgery or sham surgery was performed in female rats made obese with ventromedial hypothalamic (VMH) knife cuts, and in lean control rats. After bypass surgery, the VMH rats underate and lost weight until they reached the body weight of the control sham rats, and they then maintained their weight at control levels. Bypass surgery in lean rats produced much smaller reductions in food intake and body weight. Both bypass groups initially consumed less of a sucrose solution and milk diet during 1 h/day tests, but their intakes returned to near normal levels during the second postoperative month. Reconnection of the intestinal tract in the VMH-bypass rats led to renewed hyperphagia and return to obese body weights. A second experiment revealed that bypass surgery reduces food intake and body weight in genetically obese (fatty) rats, but this effect is not as pronounced as that displayed by VMH rats. These results confirm recent clinical observations that reduced appetite and caloric intake are the major causes of the weight loss produced by intestinal bypass surgery.


Involvement of hepatic metallothioneins in hypozincemia associated with bacterial infection. Hypozincemia was induced in rats by Salmonella typhimurium and live vaccine strain Francisella tularensis (LVS) infections. Hepatic synthesis of zinc-binding proteins (ZBP) was studied in order to elucidate the mechanisms involved in the redistribution of zinc from plasma to liver occurring during infectious illness. ZBP, labeled in vivo with 65Zn, were isolated and identified as metallothioneins based, in part, on their heat stability, dimorphism, and amino acid composition. Cysteine was the major amino acid found in both forms of metallothionein and constituted 28-31% of total residues. The apparent half-life of these proteins as measured by disappearance of 65Zn was determined to be 19 h in a relatively mild infection (LVS) and 38 h in a more severe S. typhimurium infection. Results provide evidence that metallothioneins not only have the previously postulated regulatory role in normal zinc homeostasis but are intimately involved in the zinc redistribution occurring during the acute stage of infectious illness.


Permissive effect of ATP on insulin-stimulated sugar transport by rat soleus muscle. The stimulatory effect of insulin (0.1 U/ml) on D-xylose uptake was progressively lost when rat soleus muscles were preincubated at 37 degrees C under anaerobic conditions for longer than 30 min; after 90 min these muscles were completely insensitive to insulin. This effect was associated with the loss of muscle ATP. When the breakdown of ATP was retarded either by lowering the preincubation temperature or by preincubation with 5 mM glucose, the effect of insulin in anaerobic muscle was correspondingly prolonged. Under certain conditions, externally added ATP promoted an effect of insulin in otherwise insulin-unresponsive muscles. This effect was small in magnitude and was complicated by the degradation of the added ATP in the incubation medium and by the fact that ATP also tended to inhibit insulin-stimulated xylose uptake. These results indicate that there is a relationship between insulin-stimulated sugar transport and muscle ATP levels. This supports the proposal that there may be some ATP-dependent reaction(s) involved in the mechanism whereby insulin promotes the process of muscle sugar transport.


Effect of modified sham feeding on jejunal transport and pancreatic and biliary secretion in man. Because previous evidence suggested that intestinal secretion was under parasympathetic control, we investigated the effect of modified sham feeding on the intestinal transport of water and electrolytes by jejunal perfusion using a triple lumen tube. By measuring the concentration of amylase, protein, and bile acids entering the intestinal test segment, we were also able to obtain data on the influence of sham feeding on pancreatic and biliary secretion. Gastric contents were aspirated throughout the experiment. Although we observed a clear-cut cephalic phase of gastric acid secretion, sham feeding had no effect on jejunal transport of water and electrolytes or on the rate at which bile acids, protein, or amylase were secreted into the duodenum.


Uric acid metabolism in homozygous and heterozygous muscular dystrophic mice. The homozygous muscular dystrophic mice (dydy) were found to have significantly higher plasma uric acid than their heterozygous littermate controls (Dydy), and the Swiss albino mice. Because the rate of uric acid excretion did not compensate for the elevated plasma levels, U/P (urine/plasma) urate was lower in dydy mice. With RNA supplement, plasma and urinary urate were increased in both dydy and Dydy mice; again U/P urate was lower in dydy mice. It appears that the dydy mice to a certain extent are comparable to some gouty subjects, whose hyperuricemia is not accompanied by a corresponding increase in urinary uric acid. There was no difference in converting uric acid to allantoin either on basal diet alone or with RNA supplement. Oxonic acid effectively, though transiently, blocked the uricase activity in both dydy and Dydy mice resulting in hyperuricemia and hyperuricosuria with decreased allantoin. Uric acid content was increased markedly in the kidney without histological evidence of urate deposition, apparently related to the unsustained effect of oxonic acid, which was rapidly excreted.


Spike bursts in rabbit oviduct. I. Effect of ovulation. Electrical activity of rabbit oviducts was recorded in vitro at 18, 24, and 68 h after injection of human chorionic gonadotropin. An array of eight suction electrodes 1-2 mm apart was moved sequentially to cover nearly the whole oviduct. The frequency of spike bursts, pacemaker frequency, percentage of nonpropagating bursts, and probability of propagating in the uterine direction varied steeply within a few millimeters along the oviduct. On the average, spreading was only slightly prouterine. Compared to 18 and 24-h, 68-h oviducts showed higher frequency of activity and longer distances of propagation, particularly in the isthmus. The activity extended to 65.8 and 69.6% of the distance from the fimbriae at 18 and 24 h, respectively, and at 68 h to 70.8% and 84.6% in those oviducts that contained and did not contain ova, respectively. Ova were recovered on the uterine side of the border of activity or in regions in which the percentage of nonpropagating bursts was high or, at 18 and 24 h, in segments containing local regions of inactivity. Apparently, frequency of activity, the degree to which propagation of activity deviates from randomness, and the length of the inactive area regulate the location of ova in the isthmus.


Spike bursts in rabbit oviduct. II. Effects of estrogen and progesterone. Electrical activity of rabbit oviducts was recorded in vitro at 48 h after injection of human chorionic gonadotropin (HCG), 18 or 24 h after HCG with progesterone pretreatment, and 48 or 68 h after HCG with estrogen treatment 24 or 0 h after HCG, respectively. Frequency of spike bursts, pacemaker frequency, percentage of nonpropagating bursts, and probability of propagating in the uterine direction were obtained. Estrogen treatment decreased frequency of activity; at 48 h distance of propagation was increased and activity extended to 72.4% of the length of the oviduct compared to 65.7% in oviducts removed 48 h after HCG without estrogen. Only the ampullary-isthmic junction was active at 68 h after estrogen and HCG injection. Progesterone increased frequency and imposed a uterine bias, and activity extended to 73.6% of the length of the oviduct. These data support the hypothesis that properties of activity in the active area and the location of the active-inactive border regulate the location of ova in the isthmus of the rabbit oviduct.


Renal response of the starling (Sturnus ;ulgaris) to an intravenous salt load. Total kidney GFR's, urine flow, inorganic ion excretion, and single nephron glomerular filtration rates (SNGFRs) were evaluated in anesthetized starlings under control conditions (2.5% mannitol infusion) and in starlings subjected to an osmotic stress induced by the intravenous infusion of 5.8% sodium chloride. Under control conditions the GFR was 2.92 ml/kg per min, urine flow 0.20 ml/kg per min, 63% of filtered sodium was reabsorbed, mean mammalian type (MT) SNGFR was 15.6 nl/min, and mean reptilian type (RT) SNGFR was 7.0 nl/min. During osmotic stress the GFR did not change, urine flow increased to 3 times the control level, the percentage of filtered sodium reabsorbed did not change, both the mean MT SNGFR (24.3 nl/min) and the mean RT SNGFR (10.3 nl/min) were significantly higher than the control levels. During the osmotic stress more MT and fewer RT nephrons were filtering than during control conditions. Under control conditions 98.5% of the sodium excreted by the kidney was associated with uric acid. This percentage decreased as the osmotic stress increased. The starlings tended to excrete the osmotic load imposed by the infusion of NaCl to prevent the plasma osmolality from increasing.


Characteristics of glucose-phlorizin interactions in isolated proximal tubules. Characteristics of phlorizin's interaction with the bidirectional fluxes of glucose were examined using isolated proximal convoluted tubules from the rabbit kidney. Radioisotopic glucose fluxes were determined with artificial perfusates having glucose concentrations of 5-15 mM. Rabbit serum was used as the bath. Phlorizin in intraluminal concentrations of 10(-7) to 10(-4) M progressively reduced the lumen-to-bath flux of glucose without affecting the bath-to-lumen flux. At 10(-4) M phlorizin in the lumen, the lumen-to-bath flux decreased from 92.86 +/- 5.71 to 7.83 +/- 3.04 pmol/mm.min (P less than 0.001), with bath-to-lumen fluxes averaging 4.58 +/- 0.58 pmol/mm-min. Similar changes occurred when phlorizin was added to the bath, although concentrations approximately 10-100 times higher were required. Phlorizin 10(-3) M in the bath also reduced the bath-to-lumen glucose flux from 10.20 +/- 3.07 to 7.16 +/- 2.20 pmol/mm.min (P less than 0.05). Phlorizin transport was passive. The kinetics of phlorizin's inhibition of the lumen-to-bath glucose flux were determined by varying the glucose delivery rate over a range of phlorizin concentrations. Phlorizin reduced the maximal glucose transport rate and increased the delivery rate of glucose at which glucose absorption was half maximal. These data indicate that the interaction of phlorizin with proximal renal glucose transport involves elements of both competitive and noncompetitive inhibition.


Nephron heterogeneity of phosphate reabsorption. Previous micropuncture studies in rats have demonstrated that fractional phosphate delivery (FDP%) from superficial distal nephrons is higher than in urine. To determine whether this apparent reabsorption could be accounted for by a lower FDP% from the deep nephrons, FDP% was determined in free-low micropuncture from deep nephrons (DN) (ascending limb of the loop of Henle in the papilla), superficial nephrons (SN) (distal tubules in the cortex), and urine (duct of Bellini). In six acute thyroparathyroidectomized (TPTX) rats, FDP% in DN was significantly less than SN. The urinary fractional phosphate excretion (FEP%) was significantly less than in the SN, but not significantly different from the DN. In six chronic TPTX rats, FDP% in DN was significantly less than in SN. The urinary FEP% was significantly less than the FDP% in the SN, and significantly less than the FDP% in the DN, evidence which favors phosphate reabsorption in the terminal nephron. We conclude that in TPTX rats, which are conserving phosphate, deep nephrons reabsorb phosphate more avidly than superficial nephrons.


Influence of steady-state PaCO2 on escape from ADH-induced water retention in the dog. The influence of the prevailing PaCO2 on the water-retaining effects of sustained elevations in ADH was assessed by administering vasopressin (5 U in oil, twice daily) and a fixed water intake to dogs with eucapnia (n, 7), chronic hypercapnia (n, 6), and chronic hypocapnia (n, 8). Although water excretion initially fell to a similar extent in all three groups, cumulative water retention by day 4 of vasopressin administration was 77 mg/kg in the hypocapnic group, 46 ml/kg in the eucapnic group, and only 14 ml/kg in the hypercapnic group. These differences were reflected in a marked disparity in the degree of hyposmolality of body fluids, plasma osmolality falling by day 4 to an average value of 223, 237, and 268 mosmol/kg in the hypocapnic, eucapnic, and hypercapnic animals, respectively. In a separate group of dogs, water deprivation and water loading studies revealed that sustained hypercapnia does not affect the maximal concentrating or diluting ability of the kidney. We conclude, therefore, that the striking influence of the prevailing PaCO2 on the water-retaining effects of administered vasopressin cannot be ascribed to an altered responsiveness of the nephron per se, but that this influence reflects an alteration in the ease with which the kidney can escape from the antidiuretic effects of this substance.


Effect of SITS on organic anion transport in the rabbit kidney cortical slice. The effect of SITS (4-acetamido-4'-isothiocyano-2,2'-disulfonic stilbene) on the transport of organic ions in the rabbit kidney cortical slice was studied. SITS at a concentration of 10(-4) to 10(-3) M significantly decreased the slice-to-medium (S/M) concentration ratio of the organic anions p-aminohippurate (PAH), and 2,4,5-trichlorophenoxyacetate, but had no significant effect on that of the organic cation tetraethylammonium. The S/M ratio of PAH decreased to 0.52 +/- 0.03 (SE) in the presence of 10(-3) M SITS. The inhibition of PAH uptake caused by SITS was reversed in the presence of 0.5% bovine serum albumin in the medium. SITS at a concentration of 10(-4) M had no significant effect on the efflux of PAH. However, there was a small increase in PAH efflux at a concentration of 10(-3) M SITS. A Lineweaver-Burk analysis of the data indicates that SITS competitively inhibits PAH uptake and that SITS has a Ki value of 2.3 X 10(-4) M. SITS had no effect on the tissue water content, [14C]inulin space, or intracellular Na and K concentrations. It is suggested that the primary effect of SITS is to inhibit the entry of organic anions from the medium into the cell across the basolateral membrane.


Phenomenological model relating cell shape to water reabsorption in proximal nephron. If the complex pattern of intercellular channels in proximal tubule is determined in part by the forces of large transepithelial water flow, the shape of the cells is an indicator of the type and magnitude of the forces required for water movement and the routes of that flow. To test this thesis, morphologic data and volume flow parameters for rabbit proximal tubule are related generally by a mass balance equation. If the intercellular boundaries are assumed to be highly deformable and to respond to changes in hydrostatic pressure, the solution to that equation is a simple relationship between cell shape and the forces required for water movement. The resulting phenomenological model suggests an important new role for peritubular serum proteins and can be used to compute reasonable values for cell wall hydraulic conductivity, intercellular protein diffusion constant, and a channel fluid osmolality not more than 1% greater than that of luminal fluid. It is concluded that quantitative morphologic studies may serve as a powerful means for evaluating and understanding transport phenomena in the nephron.


Effects of constituent amino acids on tubular handling of microinfused angiotensin II. [14C]angiotensin II ([14C]AII) was microinjected alone or with excess L-isoleucine (IIe) or L-aspartic acid (Asp) into renal tubules of anesthetized rats. Urinary excretion of 14C-labeled material was measured, and the intact peptide and its metabolites were identified and quantified. When isoleucine was administered with [14C]AII, urinary recovery of the 14C-labeled material increased directly with distance of infusion site from glomerulus, and most of the radioactivity in urine was [14C]Ile. The data suggest that isoleucine interfered with reabsorption of [14C]Ile derived from hydrolysis of [14C]AII and less so with the hydrolysis itself. When aspartic acid was administered with [14C]AII into the proximal 5/6 of the proximal convolution, total urinary recovery of the 14C-labeled material was unchanged, but percentage of recovery as [14C]AII increased; with infusion into the distal 1/6 of the proximal convolution, total urinary recovery of the 14C labele increased. The data suggest that aspartic acid interfered with the enzymatic hydrolysis of [14C]AII and reabsorption of isoleucine. In distal tubules the 14C label was almost completely recovered as intact [14C]AII in all protocols. The results show that free amino acids influence proximal tubular handling of small linear peptides in rats.


Volume absorption in the pars recta. II. Hydraulic conductivity coefficient. We evaluated the hydraulic conductivity (Pf, micron s-1) of superficial proximal straight tubules isolated from rabbit kidney. Tubules were perfused with hypotonic (270 mosmol/kg H2O) and bathed with isotonic (290 mosmol/kg H2O) NaCl buffers at 25 degrees C. Due to the tendency of transepithelial osmosis plus solute entry to produce osmotic equilibrium along the perfused length, we observed that the total net volume absorption ('JV, nl min-1) increased from 0.64 to 2.21 when the perfusion rate (VO, nl min-1) was increased from 11 to 45 in a group of tubules with an average length of 0.86 mm. From a 'JV of 2.21 nl min-1 at VO = 45 nl min-1 we computed a minimum Pf of 2,200 micron s-1. And extrapolation of the data to VO leads to infinity gave a Pf value of 5,200-7,600 micron s-1. The same perfusion rate dependence of 'JV in a group of tubules with an average length of 3.29 mm gave quantitatively similar results. A theoretical analysis of radial osmosis occurring simultaneously with axial osmotic equilibration showed that Pf values in the range of 3,000-4,000 micron s-1 accurately predicted the observed relations between VO, 'JV, and tubule length.


Volume absorption in the pars recta. III. Luminal hypotonicity as a driving force for isotonic volume absorption. This paper examines the possibility that osmotic disequilibrium between luminal and bathing solutions may account for isotonic fluid absorption coupled to active Na+ absorption observed when superficial proximal straight tubules isolated from rabbit kidney are perfused and bathed with NaCl solutions in the absence of CO2, HCO3-, and luminal organic solutes. If luminal hypotonicity provides a driving force for isotonic fluid absorption under these conditions, the luminal fluid must be nearly isotonic; and steady-state luminal hypotonicity should develop sufficiently rapidly that the absolute rate of volume absorption ('JV, nl min-1) coupled to active Na+ transport is relatively independent of perfusion rate, so that the normalized rate of fluid absorption (JV, nl min-1 mm-1) is approximately constant. Our theoretical calculations indicate that these expectations are fulfilled. A 0.42-0.56 mM reduction in luminal NaCl concentration adequately accounts for the JV observed under such conditions, because of the high hydraulic conductivity of these tubules; and within the range of tubule lengths normally employed with isolated proximal straight tubules, JV is relatively indepedent of perfusion rate within the generally observed range of experimental error.


Low-grade intravascular coagulation and reticuloendothelial function. The present study evaluated the influence of experimentally produced intravascular coagulation on reticuloendothelial (RE) stability. Intravascular coagulation was initiated by the intraperitoneal injection of bovine thrombin (500 U/100 g body wt) into male rats. RE function was evaluated by the vascular clearance of an 131I-labeled RE test colloid. Thrombin injection resulted in a transient (0.5-2 h) (P less than .05) depression of the phagocytic index (K) with maximal depression at 1 h postthrombin challenge. The phagocytic index was unaltered after injection of saline or heat-inactivated thrombin. Vascular clearance depression was primarily due to a 37% decrease (P less than .001) in hepatic Kupffer cell colloid clearance and was associated with increments in lung (82%) and marrow (100%) colloid localization with no splenic alterations. While intravascular coagulation was associated with decreased hepatic blood flow at 30 min and 120 min, sinusoidal flow was normal during maximum RE impairment at 60 min. The in vivo clearance depression was not reflected as an intrinsic Kupffer cellular deficit when evaluated in an in vitro system. The results indicate a transient RE dysfunction during intravascular coagulation, the mechanism of which remains to be elucidated.


Extent of utilization of the Frank-Starling mechanism in conscious dogs. The extent to which an increase in preload increases left ventricular (LV) end-diastolic (ED) diameter (D) was studied in seven conscious dogs instrumented with ultrasonic D transducers and miniature LV pressure (P) gauges. Preload was elevated by three techniques: 1) volume loading with saline infusion, 2) induction of global myocardial ischemia by constricting the left main coronary artery, and 3) infusion of methoxamine. These three interventions increased LVEDP to over 30 mmHg from a control of 10 +/- 1 mmHg. With volume loading, LVEDD rose by only 1.55 +/- 0.39 mm from a control of 44.08 +/- 1.08 mm; with ischemia LVEDD rose by only .96 +/- .29 mm from a control of 42.55 +/- 2.18 mm, while with methoxamine LVEDD rose by only 1.34 +/- 0.38 mm from a control of 43.89 +/- 2.07 mm. In contrast, in the open-chest, anesthetized dog, LVEDD was greatly reduced and volume expansion resulted in a profound increase in LVEDD. Thus, the Frank-Starling mechanism is not an important controlling mechanism in the normal, reclining, conscious animal, since LVEDD appears to be near maximal at rest and does not increase substantially despite striking increases in LVEDP.


Responses of cerebral arteries and arterioles to acute hypotension and hypertension. The responses of cerebral precapillary vessels to changes in arterial blood pressure were studied in anesthetized cats equipped with cranial windows for the direct observation of the pial microcirculation of the parietal cortex. Vessel responses were found to be size dependent. Between mean arterial pressures of 110 and 160 mmHg autoregulatory adjustments in caliber, e.g., constriction when the pressure rose and dilation when the pressure decreased, occurred only in vessels larger than 200 micron in diameter. Small arterioles, less than 100 micron in diameter, dilated only at pressures equal to or less than 90 mmHg; below 70 mmHg their dilation exceeded that of the larger vessels. When pressure rose to 170- 200 mmHg, small vessels dilated while the larger vessels remained constricted. At very high pressures (greater than 200 mmHg) forced dilation was frequently irreversible and was accompanied by loss of responsiveness to hypocapnia. Measurement of the pressure differences across various segments of the cerebral vascular bed showed that the larger surface cerebral vessels, extending from the circle of Willis to pial arteries 200 micron in diameter, were primarily responsible for the adjustments in flow over most of the pressure range.


Neural control of nutritional and nonnutritional circuits in the dog hindpaw. The neural control of blood flow and volume distribution between parallel nutritional and nonnutritional circuits has been investigated in the vascularly and neurally isolated dog hindpaw. Twelve paws were perfused by controlled pressure and ten paws were perfused by controlled flow via the cranial tibial artery. Venous outflow was measured and collected from the lateral saphenous vein. The superficial and deep fibular nerves and the tibial nerve were cut and individually stimulated, resulting in rates which at least doubled the blood flow resistance. Vascular volume changes were measured by injections of 51Cr-labeled red cells and 131I-labeled albumin. Tissue volume changes were measured by plethysmography. Capillary diffusion capacity was calculated from 86Rb extractions, and capillary filtration coefficients were determined. Superficial fibular nerve and deep fibular nerve stimulations apparently resulted in nonnutritional circuit constriction with resulting blood flow redistribution to nutritional circuits, possibly located in tissues other than the skin, e.g., adipose tissue. Tibial nerve stimulation caused no redistribution of blood flow between the two circuits presumably due to a uniform constriction of arteries and small vessel segments.


Comparison of left ventricular free wall and septal diastolic compliance in the dog. Septal to free wall dimensions are frequently employed for the analysis of diastolic compliance. However, the diastolic properties of these anatomically distinct regions of left ventricle are not well characterized. Regional compliance was studied in eight open-chest anesthetized dogs. Pairs of 2-mm-diameter piezoelectric crystals were implanted in the left ventricular free wall or septum 1.38 +/- 0.06 cm apart at a midwall location 58% +/- 1.9 of the left ventricular endocardial-epicardial or left ventricular endocardial-right ventricular endocardial distance. Left ventricular end-diastolic pressure was increased from an average of 8.1-21.0 mmHg, with a resulting average maximum end-diastolic strain of 11% (end-diastolic (ED) segment length/control ED length). Regional stiffness was assessed at all sites based on the relationship between left ventricular end-diastolic pressure and regional strain. Neither strain nor calculated stiffness coefficients differed significantly among the three sites. Septal transmural pressure (left ventricular end-diastolic pressure--right ventricular end-diastolic pressure) was nearly constant as left ventricular end-diastolic pressure increased during volume infusion and thus did not account for the observed septal strain.


Mechanical responses of isolated dog cerebral arteries to reduction of external K, Na, and Cl. Reduction of the extracellular potassium concentration ([K+]0) caused a significant contraction in helical strips of dog cerebral arteries, but only a slight contraction, or none, in peripheral (coronary, mesenteric, renal, and femoral) arteries. The cerebroarterial contraction was abolished by treatment with ouabain or by substitution of Li+ for Na+, and suppressed by exposure to Ca2+-free media or verapamil. When one-half of the NaCl of the bathing solution was substituted with choline chloride a moderate, sustained contraction was produced in cerebral and peripheral arteries. Ouabain potentiated this contraction, whereas exposure to Ca2+-free media abolished it. Substitution of Na propionate, NaI, or Na acetylglycinate for one-half of the NaCl elicited a marked, transient contraction in only the cerebral arteries. This contractile response was potentiated by ouabain and markedly attenuated by exposure to Ca2+-free media. It may thus be concluded that cerebroarterial contractions induced by a reduction in [K+]0 are due to inhibition of the electrogenic Na+ pump, which results in depolarization of smooth muscle cells. Substitution of Cl- with less permeant anions appears to produce cerebroarterial contraction in association with depolarization of smooth muscle cells.


Progressive postnatal changes in sinus node response to atropine and propranolol. Postnatal development of autonomic control of heart rate was evaluated in the sinus nodes of isolated, perfused right atria obtained from 21 sibling puppies in three different litters between 3 and 11 wk postpartum. Age-related changes in response to autonomic blockade indicated that propranolol administered after atropine had its most profound direct depressive effect on less mature atrial cells. In the youngest sinus nodes the familial antimuscarinic action (increase in sinus rate) of atropine was regularly preceded by a brief period of cholinomimetic action (a marked slowing of sinus rate) in the youngest sinus nodes. These two opposing effects of atropine underwent a developmental change during the 2-mo study. The cholinomimetic action diminished, whereas the antimuscarinic action increased as a function of age.


Diastolic stress-strain relation of nonexcised blood-perfused canine papillary muscle. We studied diastolic stiffness of 10 coronary-perfused twitching papillary muscles of the canine right ventricle. The muscle beat at a regular sinus rhythm of 122 +/- 20 (SD) beats/min at 37 degrees C. They were stretched slowly at a constant rate. Diastolic force increased exponentially with the stretch. Calculating Lagrangian stress (sigma) and strain (epsilon) from diastolic force and length, we found a linear relationship between ln sigma and epsilon within the physiological range of strain (0.025 less than epsilon less than 0.4). This indicates that the diastolic stress-strain relationship of the canine papillary muscle can be approximated by a single exponential curve: sigma = a.exp(b.epsilon). The mean +/- SD of the stiffness constant b was 18.0 +/- 3.2 (dimensionless). Our b values are comparable to those of dogs and human subjects, either indirectly assessed from the ventricular pressure-volume relationship or directly obtained in excised quiescent muscle specimens. Different coronary perfusion pressures (75-125 mmHg) in 10 muscles showed a statistically significant positive correlation to b values.


Increased contractile potential of papillary muscles from exercise-trained rat hearts. Female rats (n = 24) swam 6 h/day, 5 days/wk, for over 6 wk. Training increased both wet and dry weight of ventricles 15% above control. The active length-tension curve for trained left ventricular papillary muscles (LVPM) was elevated, with maximum tension (Tmax) at optimal length 37% higher than that of untrained LVPM. Training did not alter passive length-tension, time-to-peak tension (TPT), or half-relaxation time (1/2RT). The maximum rate of tension development (dT/dt), however, was increased 22% by training. The force-velocity curve of trained LVPM was shifted upward; both estimated Vmax and the minimum isometric load where shortening equals zero were greater than control. Exogenous isoproterenol (5.8 nM) did not affect Tmax but significantly decreased TPT and 1/2RT to the same extent for both groups of muscles. Maximum dT/dt was increased to a greater extent by isoproterenol for trained LVPM. These findings indicate hearts hypertrophied by exercise have an increased contractile potential per unit of myocardial mass.


Hypotensive effect of [Sar1,Thr8]angiotensin II in spontaneously hypertensive sodium-depleted rats. Under inactin anesthesia, intravenous infusion of [Sar1,Thr8]angiotensin II produced a hypotensive effect in young spontaneously hypertensive rats (SHR) treated with furosemide and in mature SH rats fed a low-sodium diet. The angiotensin antagonist also lowered blood pressure of young and mature SH rats receiving a normal diet. Deoxycorticosterone acetate (DOCA) plus saline reversed the hypotensive effect of [Saru,Thr8]angiotensin II in young SH rats, but did not do so in mature SH rats. Plasma renin activity (PRA) was not significantly changed by anesthesia. Furosemide or the low-sodium diet significantly increased PRA in young and mature SH rats. In contrast, DOCA plus saline significantly reduced PRA in both young and mature SH rats. However, there was no correlation between PRA and the action of the angiotensin II antagonist. These data suggest that the renin-angiotensin system is involved in genetic hypertension.


Gonadal hormones and pathogenesis of occlusive arterial thrombosis. Arterial thrombus formation was induced in male and female Wistar rats (3 mo) by inserting a loop-shaped polyethylene cannula into the abdominal aorta. Thrombogenesis was also induced in mature male and female New Zealand rabbits by constriction of the femoral artery and injection of ellagic acid. The criteria for thrombus development in the cannulated rats were: incidence of thrombosis (IT), obstruction time (OT), and thrombus weight (TW). We observed a significant sex difference in all these criteria of thrombogenesis in both rats and rabbits. Pretreatment of either sex with Depo-testosterone shortened OT, increased TW about fivefold in males and threefold in females, and increased mortality rate (MR) more than fourfold in both sexes. Prolonged pretreatment with Depo-testosterone increased in all aspects of thrombogenesis. Depo-estradiol had marginal ameliorating effects in male rats only. Both the antiandrogen Flutamide, and aspirin, significantly decreased the thrombogenic effects of testosterone. Thus, testosterone may be a significant risk factor in experimentally induced thrombogenesis in rats and rabbits.


Role of sodium in strophanthidin toxicity of Purkinje fibers. The action of strophanthidin on the membrane potentials and contractile force of canine Purkinje fibers was studied in vitro. Purkinje fibers were exposed to strophanthidin (10(-6) M) until spontaneous fast discharge occurred. In Tyrode solution, strophanthidin increased and subsequently decreased ("mechanical toxicity") contractile force. The onset of spontaneous rhythms ("electrical toxicity") usually occurred when force was declining. In low-Na Tyrode (-71 mM NaCl), force increased: on exposure to strophanthidin, mechanical toxicity occurred sooner and electrical toxicity later. In low-Na low-Ca Tyrode, electrical toxicity developed sooner than in low-Na Tyrode. In high-Na Tyrode (+27 mM NaCl), force increased, and the time to electrical and mechanical toxicities was decreased. Increasing osmolarity (+54 mosM) with either sucrose or choline chloride increased force and shortened the time to the onset of strophanthidin toxicities. In the presence of arrhythmias, lowering [Na]o decreased transient oscillations and led to disappearance of arrhythmias. It is concluded that Na plays a role in strophanthidin-induced electrical toxicity, whereas Ca appears more important for mechanical toxicity.


Quantitation of collateral and ischemic flows with microspheres and diffusible indicator. Flow to myocardium following coronary occlusion may not originate solely from collateral channels. Some flow might be derived from overlapping coronary arteries which also perfuse tissue within the territory of the obstructed vessel prior to occlusion. Left atrial microsphere injection during perfusion of the left anterior descending (LAD) artery from a special reservoir containing microsphere-free blood and again after LAD occlusion permitted measurement of noncollateral overlap and total ischemic LAD (TIF) flows, respectively, and mathematical derivation of true collateral flow (TCF). Whereas TIF averaged 0.25 +/- 0.03 ml/min per g, TCF was 0.14 +/- 0.03 ml/min per g, only 50.6% of TIF. The remainder of the TIF represented either inadvertant inclusion of normally perfused tissue with the ischemic LAD myocardium or actual overlap of LAD and left circumflex circulations. 86RbCl was injected simultaneously with the microspheres following coronary occlusion. 86Rb and microsphere densities in the whole heart and ischemic area were closely correlated, although microsphere distribution tended to be more heterogeneous. No segment of ischemic myocardium containing 86Rb was free of microspheres. Therefore, the geometry of undeveloped collateral channels is adequate to permit passage of 15-micron particles. Absolute 86Rb flows were consistently less than microsphere flows.


Effect of lanthanum and reduced temperature on 45Ca efflux from rabbit aorta. The ability of lanthanum (La3+) to block calcium efflux from smooth muscle cells of the rabbit aorta has been examined. La3+ promotes the very early phase of 45Ca efflux, which is extracellular in origin, and partially inhibits the latter, cellular portion. Stimulation of 45Ca efflux caused by the release of intracellular 45Ca with either 10(-4) M dinitrophenol or 10 mM caffeine was not reduced by pretreatment with 10 mM La for 40 min, whereas stimulation due to norepinephrine was abolished. It was concluded that during the use of the "La method" for measuring cellular 45Ca there is an underestimation due to unblocked 45Ca loss. This loss can be reduced by processing tissue at 2 degrees C, which inhibits transport processes. The time course of 45Ca uptake and the stimulation of uptake by high K+ are qualitatively but not quantitatively similar if tissues are washed at 37 and 2 degrees C. Tissues washed in La3+ at 2 degrees C for 60 min retain approximately double the cellular 45Ca of those washed at 37 degrees C. This methodology provides an improved correlation between estimates of cellular calcium derived from 45Ca uptake and 45Ca efflux experiments.


A mechanism for minimizing temperature effects on repetitive firing frequency. The magnitudes and time courses of conductance changes in molluscan neurons show marked temperature dependence. Interestingly, though, the relationship between repetitive firing frequency  and stimulus current is not greatly affected by moderated temperature changes (6-8 degrees C). The transient potassium current, IA, is largely reponsible for the interspike voltage trajectory, hence, repetitive interval, in molluscan neurons. It is shown in this study that temperature dependencies of the rate constants and magnitude of the IA system are balanced in such a way that the observed temperature insensitivity of the repetitive response is predicted.


Inhibition of mammary gland lactose secretion by colchicine and vincristine. The possible role of microtubules in milk production was examined in mammary gland slices from lactating guinea pigs. Colchicine, 10(-5)-10(-4) M, depressed lactose secretion within 15 min, maintaining maximal inhibition over 2.5 h, accompanied by retention of lactose within the slices. In colchicine dose-response studies (2 h, 10(-8)-10(-5) M), secretion was depressed 22% by 10(-5) M, whereas tissue lactose increased with dose up to +25% at 10(-5) M. Lactose synthesis was inhibited 3-19% without correlation to colchicine concentration. In another study, incubation with 10(-5) M lumicolchicine yielded one-third less inhibition of secretion than 10(-5) M colchicine with no increase in tissue lactose. Both drugs depressed  synthesis 31%. Lactose secretion showed a negative correlation with 10(-7)-10(-4) M vincristine yielding a maximal 66% inhibition at 10(-4) M, whereas tissue retention showed a linear increase with concentration up to 151% of control at 10(-4) M. Effects on synthesis were sporadic. These data suggest that microtubules have a role in facilitating the transport and/or secretion of lactose and perhaps other milk components.


Pulmonary absorption of drugs in the neonatal rat. To compare the pulmonary absorption of drugs in newborn rats (3-27 days old) with that  in adults, 0.01-0.1 ml of Krebs-Ringer phosphate solution (pH 7.4) containing a drug was administered to anesthetized animals by way of a catheter introduced through a tight-fitting tracheal cannula. After various times, lungs and trachea were removed and assayed for drug that remained. Semilogarithmic plots of percent drug remaining against time yielded a straight line for each compound. The lipid-soluble drugs procaine amide and sulfisoxazole were absorbed at similar rates in newborn and adult rats. In contrast, the lipid-insoluble drugs tetraethylammonium, p-aminohippuric acid, and mannitol were absorbed approximately 2 times more rapidly in younger rats (3-12 days) than in older animals (18 day, 27 day, or adult). The results suggested that the respiratory tract membranes of 3- to 12-day-old rats have a greater porosity than those of older animals.


A bipolar electrode for electromyography of limb muscles of small animals. A bipolar electrode for recording from or stimulating the skinned surface of small, moving muscles is described. The electrode is so light that it clings to the moist surface of the muscle and moves with it, like a piece of confetti. It can be positioned or repositioned instantly and with no damage to the muscle. Because of its small size and bipolar nature, it records from or stimulates a very small volume. It is inexpensive, simple, and requires no special apparatus for its consturction. The electrode is especially suited for muscles in the limbs of small animals, in which movement and small size present special problems.


Oxygen consumption during cimetidine and prostaglandin E2 inhibition of acid secretion. Oxygen consumption was determined during cimetidine and 16,16-dimethyl prostaglandin E2 inhibition of acid secretion in exteriorized segments of the greater curvature of dog stomach. Steady-state acid secretion during histamine infusion correlated well with O2 consumption (r = 0.85, P less than 0.01). Cimetidine and 16,16-dimethyl prostaglandin E2 inhibition of acid secretion produced a reduction of oxygen consumption to resting levels. In contrast, oxygen consumption did not decrease appreciably during thiocyanate inhibition of acid secretion. These observations suggest that the inhibitory action of cimetidine and 16,16-dimethyl prostaglandin E2 precedes, whereas that of thiocyanate is at a point beyond the transfer of energy to the process of acid production.


Vasopressin in cerebrospinal fluid and plasma of man, dog, and rat. Arginine-8-vasopressin (AVP) levels were measured by a sensitive and specific radioimmunoassay (RIA) in plasma and cerebrospinal fluid (CSF) of three species man, dog, and rat (Wistar and the Brattleboro strain). Basal plasma values were 1.7 pg/ml in Wistar rat, and 2.4 pg/ml in dog. Pentobarbitone, used as anesthetic during collection of CSF from dog and rat, caused a significant rise of plasma AVP values in Wistar rats, but not in dogs. After withdrawal of CSF, the plasma AVP levels of Wistar rats were increased to 29.5 +/- 9.5 pg/ml, whereas the CSF levels from the same animals were 11.5 +/- 3.9 pg/ml. The response to the various stimuli was similar in Brattleboro rats, heterozygous for hereditary hypothalamic diabetes insipidus, and in Wistar rats. In Brattleboro rats, homozygous for hereditary hypothalamic diabetes insipidus, AVP was neither detectable in plasma nor in CSF. In dog and man, AVP levels in CSF samples were higher than in simultaneously obtained plasma samples. The possibility that AVP present in CSF, might be released directly from the synthetizing hypothalamic nuclei into the ventricular system is discussed.


Evidence for pyloropancreatic reflux for pancreatic exocrine secretion. In seven dogs provided with innervated pouch of the pyloric antrum, gastric fistula, and chronic pancreatic fistula, the effect of graded antral distenion on pancreatic exocrine secretion was studied. The effect of antral distension was tested both when gastrin release was promoted (alkaline distention) and when gastrin release was blocked (acid distension). These studies were performed both before and after transthoracic truncal vagotomy. Graded alkaline antral distension caused graded rise in protein-rich pancreatic secretion and graded increase in the concentration of serum immunoreactive gastrin. A similar pancreatic response was also seen with graded acid distention although this time no rise in serum gastrin concentration occurred. Pancreatic response to antral distension with either alkali or acid is completely inhibited by pretreatment of the animals with systemic atropine. Truncal vagotomy reduced pancreatic response to alkaline antral distension by 90% but completely abolished pancreatic response to distension of the antrum with acid. These studies provide evidence for a pyloropancreatic reflex mechanism for pancreatic secretion that is cholinergic and requires intact long vagal pathways.


Aldosterone metabolism in isolated perfused rat kidney. The renal metabolism and handling of [1,2-3H]aldosterone ([3H]A) was studied using isolated perfused rat kidney under different perfusion conditions. The metabolite production rate (MPR) and the urinary excretion of [3H]A together with its radiometabolites (UV/P3H) were studied. Among the formed metabolites, no acid-labile conjugate of aldosterone (ALC) was detected. The MPR was not altered in studies using nonfiltering kidney, a result that suggests that the majority of metabolites were formed without requirement of the process of glomerular filtration and tubular uptake of the hormone. High perfusion pressure (high PP) resulted in a striking increase in whole metabolic clearance rate of aldosterone (MCR[3H]A) due mostly to an enhanced urinary excretion of intact aldosterone and, to a lesser degree, to a significant increase in MPR. Factors determining the excretion rate of [3H]A and its metabolites were than investigated under administration of diuretics. Mannitol (44 mM) induced a marked increase in urine volume (UV) accompanied by a significant UV/P3H increase. Meanwhile, 0.1 mM furosemide resulted in an increase only in UV, but not in UV/P3H. These results revealed the UV dependence of aldosterone excretion in certain diuretic conditions.


Studies of glucose transport system of fat cells: effects of insulin and insulin mimickers. The rate of uptake of [U-14C]glucose or 3-O-[14C]methylglucose by isolated fat cells was rapidly measured (within 30 s) by an oil-centrifugation method. Insulin and the chemical agents, H2O2 (0.3 mM), vitamin K5 (48 micron), and spermine (0.3 mM), enhanced the uptake of both sugars. Each agent required a characteristic time period of incubation with the cells to produce maximum activation of transport. Insulin and the chemical agents increased the equilibrium exchange rate of methylglucose by the cells. The increase in rate elicited by the hormone and the reagents resulted primarily from increasing the Vmax of the exchange process. The Kt ranged from 7.5 to 10 mM after treatment of cells with insulin or the other agents. Basal Kt values were more difficult to measure, but in a sugar concentration range of 5-15 mM the values were similar to those found under conditions of stimulated exchange. Overall, these findings suggest that the chemical agents may be useful as probes to study certain aspects of insulin-mediated activation of glucose transport. However, because of the differences in time courses needed for activation, the actual steps that lead to stimulation may differ for the chemical agents and insulin.


Effect of carnitine on branched-chain amino acid oxidation by liver and skeletal muscle. The effect of L-carnitine (0.5-2.0 mM) on the rates of alpha-decarboxylation of 1-14C-labeled branched-chain amino acids by gastrocnemius muscle and liver homogenates of fed rats was investigated. Carnitine increased the rate of alpha-decarboxylation of leucine (125%) and valine (28%) by muscle, but it was without effect on the oxidation of these amino acids by liver. Carnitine increased the rate of alpha-decarboxylation of alpha-ketoisocaproate by both tissues. This effect was more pronounced in muscle (130% increase) than in liver (41% increase). The activity of carnitine acyltransferase, with isovaleryl-CoA as a substrate, was 18 times higher in muscle mitochondria than in liver mitochondria. Both starvation and diabetes increased the rate of alpha-decarboxylation of leucine by muscle without having a remarkable effect on the concentration of carnitine or the activity of carnitine acyltransferase. We conclude that: a) carnitine stimulates decarboxylation of branched-chain amino acids by increasing the conversion of their ketoanalogues into carnitine esters, b) a greater carnitine acyltransferase activity in muscle than in liver may be responsible for the greater carnitine effect in muscle, c) carnitine does not appear responsible for the enhancement of leucine oxidation by muscle of starved and diabetic rats.


Mutual influence of rats having different circadian rhythm of adrenocortical activity. The possibility of a mutual influence between male adult rats having different circadian adrenocortical rhythms was studied under two different lighting conditions. Intact and optic-enucleated rats were housed together in the same cage in various ratios of intact to blinded rats. Twenty-four- or forty-eight-hour patterns of plasma corticosterone levels were determined individually at 4-h intervals. Under diurnal light-dark alternation, the circadian periodicity of the intact rats always synchronized with light, whereas single blinded rats in cages with three intact rats demonstrated free-running rhythms throughout the experimental period of 15 wk. Under constant light the circadian rhythm free-ran in both intact and blinded rats for the first 2 wk. A phase reversal of the rhythm was observed in the intact rats at the end of the 2nd wk, and between 5 and 8 wk after binding in the blinded rats. These results indicate that the circadian adrenocortical rhythms in intact and blinded rats are not entrained to each other, even when the two types of rats live together in the same cage.


Fatty liver in hypervitaminosis A: synthesis and release of hepatic triglycerides. Feeding large doses (30,000 IU/100 g body wt per day) of vitamin A to young rats for 2 days produced fatty liver, caused a stimulation of oxidation and esterification of [1-14C]palmitate by liver slices, and increased the activity of hepatic palmitoyl-CoA synthetase. Under similar conditions, however, release of hepatic triglycerides into the plasma, as judged from the post-Triton triglyceridemia, remained unaffected. It is indicated by the present findings that excessive intake of vitamin A produces fatty liver by stimulating the synthesis of triglycerides in liver without affecting the rate of secretion of hepatic triglycerides. An involvement of altered oxidation of fatty acids in the liver can also be ruled out because in hypervitaminosis A this process is increased rather than decreased as required for fatty liver production.


Hyperglycemic action of synthetic C-terminal fragments of human growth hormone. The synthetic peptides corresponding to amino acids 172-191, 176-191, 177-191, 178-191, 179-191, and 180-191 of human growth hormone (hGH) have been studied for their in vivo effects in normal rats. Four of the peptides (hGH 172-191, 176-191, 177-191, and 178-191) produced a short-lived rise in blood glucose and a more sustained rise in plasma insulin, whereas the other two (hGH 179-191 and 180-191) were inert in the systems tested. A single dose (5 nmol/kg body wt) of the peptides containing the amino acids sequence 178-191 of the hGH molecule significantly reduced insulin sensitivity of the animals in intravenous insulin tolerance tests. The findings also indicate that the biologically active peptides must not only have the minimum of the informational sequence but also that this must be in correct physical configuration.


Measurement of oxygen consumption and locomotor activity in monosodium glutamate-induced obesity. Oxygen consumption and locomotor activity were studied in mice developing obesity after neonatal administration of monosodium glutamate (MSG) and in untreated controls. MSG-treated mice became obese in the absence of increased food intake. Locomotor activity was significantly less in MSG-treated mice 2, 10, and 20 wk after weaning. Oxygen consumption expressed in terms of the Lee index was not significantly different at 2 wk after weaning although at 10 and 20 wk it was significantly lower in MSG-treated mice. Plasma thyroxine was not different between MSG-treated and control mice. It is suggested that diminished energy expenditure is the major factor in the etiology of obesity after neonatal administration of MSG.


Renal potassium excretion in sheep during sodium sulfate, phosphate, and chloride infusion. The renal excretion of potassium by unanesthetized sheep was studied in clearance studies in which water and sodium excretion were elevated by intravenous infusion of isotonic sodium chloride, hypertonic sodium phosphate, or hypertonic sodium sulfate. Aldosterone was infused at 10 microgram/h in some experiments with sodium sulfate. Sodium excretion increased in all experiments, rising at times to equal 25% of the filtered load. Urine flow increased in most experiments. Glomerular filtration rate increased only with infusion of isotonic saline. No consistent change in potassium excretion occurred under any of these loading conditions. This finding contrasts with the increase in potassium excretion commonly seen in man, dogs, and rats intravenously loaded with sodium salts.


Effect of potassium on proximal tubular function. In order to study the effect of potassium on the renal tubule, proximal convoluted tubules were dissected from rabbit kidneys and perfused in vitro. Omitting potassium from both the perfusate and bath caused the rate of fluid absorption and the transtubular potential difference to fall to zero. This effect was due to the absence of potassium in the bathing medium since no change was observed when potassium was omitted from the perfusate only. With 0.5 and 1.0 meq/liter of potassium in the bath, there was still a significant decrease from control in both the potential difference and the rate of fluid absorption. With 2.5 meq/liter of potassium in the bath, the results did not differ from control. In further studies, tubules were perfused with 10 meq/liter of potassium in both perfusate and bath. There was no change in the potential difference of fluid absorption. These results are consistent with the view that active transtubular transport of sodium is linked to the influx of potassium into the cell at the peritubular membrane and that this is probably mediated by sodium-potassium-ATPase. Our results also suggest that the variations of potassium concentration in the physiological range do not affect proximal tubular function.


Apparent escape rate of RIHSA and 51Cr-labeled erythrocytes from the blood of volume-expanded rats. The disappearance rate constant of radioiodinated human serum albumin (RIHSA) and 51Cr-tagged erythrocytes was measured in rats before and after intravenous, isoncotic blood volume expansion (6% bovine albumin; 75 or 33% of blood volume). Before volume expansion the average slope of the semilogarithmically plotted plasma RIHSA activity was -2.068 X 10(-3) +/- 0.146 X 10(-3) (SE) min-1. The slope was not significantly changed when tested by subsequent tracer injections which were made immediately after and 1 h after volume expansion. Preinfusion plasma volume (PV) was constant, but total erythrocyte volume (RCV) increased at a significant rate from 0.0253 +/- 0.0030 to 0.0300 +/- 0.0038 ml/g body wt over the 2-h period. PV was elevated and RCV was unchanged by the infusion, but both decreased significantly thereafter. The observed erythrocyte loss could not be accounted for by sampling or bleeding. Arterial hematocrit remained constant while RCV and PV were decreasing, and it was identical to whole-body hematocrit throughout. It was concluded that 1) isoncotic albumin expansion did not change the rate constant of transcapillary albumin loss; 2) nonsteady state PV could be calculated from a single preinfusion RIHSA dose; and 3) sequestration of blood may be a part of the rat's response to volume expansion.


Influence of parathyroid hormone on glomerular ultrafiltration in the rat. Experiments were performed on 22 plasma-expanded Munich-Wistar rats to investigated the effects of parathyroid hormone (PTH) on the determinants of glomerular ultrafiltration. Mean values for single nephron filtration rate (SNGFR), glomerular plasma flow rate (QA), systemic oncotic pressure, and transglomerular hydraulic pressure difference (deltaP) were similar in acutely thyroparathyroidectomized (TPTX) rats and non-TPTX rats. Nevertheless, the glomerular capillary ultrafiltration coefficient (Kf) was uniformly higher in TPTX rats (greater than 0.113 +/- 0.005 (SE) nl/(s.mmHg)] than in non-TPTX controls (0.088 +/- 0.005). In TPTX rats, infusion of a submaximal dose (1 U/kg per min) of PTH resulted in significant decreases in SNGFR at constant QA and deltaP, due primarily to return of Kf to non-TPTX levels. Infusion of 10 U/kg per min of PTH to non-TPTX rats further reduced Kf, on average to 0.042 +/- 0.001 nl/(s.mmHg), leading to further reduction in SNGFR, whereas QA and deltaP again remained constant. These findings suggest that PTH may play an important role in modulating Kf, and consequently, SNGFR.


Comparison using central core model of renal medulla of the rabbit and rat. The studies presented here use a central core model of the renal medulla, the details of which have been given elsewhere (Foster et al., Mathematical Biosci. 32: 307-335, 337-360, 1976). The central core model of the rabbit medulla predicts concentration gradients and volume flow rates in line with what is known for the rabbit. The handling of urea, however, is not consistent with the scheme proposed by Kokko and Rector (Kidney Intern. 2: 214-233, 1972). Moreover, the low concentration of urea predicted for the urine suggests an absence in the model of some form of mediated transport for urea in the inner medulla. The central core model of the rat medulla failed to predict results consistent with what is known about the rat. Substitution of the rabbit thermodynamic parameters into the model for the rat resulted in predictions that more closely resembled what one might expect, but were not entirely satisfactory. The implication is that there may be an interspecies difference in the concentration machinery between the rabbit and rat.


Muscle buffer values.

Muscle buffer values. The in vitro skeletal and cardiac muscle buffer values have been determined for normal and potassium-depleted dogs. Depletion produced a statistically significant decrease in buffer value for both skeletal 66 vs. 61 sl, and cardiac muscle, 64 vs. 55 sl. The decreased cardiac muscle buffer value was obtained despite no statistically significant loss of cardiac muscle potassium.


Quantitation of renal uric acid synthesis in the chicken. The contribution of uric acid synthesized in the kidney (nephrogenic uric acid) to the total uric acid excreted in the urine was studied in the chicken by use of the isotope-dilution technique. In the non-fasted chicken the urine-to-plasma specific activity ratio (SAR) of [14C]uric acid was 0.83, suggesting that a minimum of 17% of the uric acid excreted in the urine is synthesized in the kidney. During allopurinol infusion into the renal portal circulation of one kidney the SAR increased to 0.99, indicating that the renal synthesis of uric acid was almost completely inhibited and that the SAR is a valid indicator of the contribution of nephrogenic uric acid excreted into the urine without first entering the circulation. Chickens fasted for 18 h showed a lower rate of renal synthesis of uric acid. Hypoxanthine infusion into the systemic circulation increased the rate of renal synthesis of uric acid in both fasted and nonfasted chickens, suggesting that circulating precursor levels may in part regulate the renal synthesis of uric acid.


Cardiac output changes during neonatal growth. Changes in resting cardiac output (CO), stroke volume (SV), and systemic vascular resistance (SVR) during neonatal growth were studied in chronically instrumented lambs from the 1st to 5th wk of age; adult nonpregnant sheep values measured simultaneously were used as standard reference. Neonatal responses to autonomic agonists and antagonists were also investigated. Total CO increased linearly with neonatal growth, but decreased strikingly when expressed per weight unit; at 5 wk of age, CO/kg was still significantly higher than the adult value. SV also increased with neonatal growth but did not change when related to body weight; at 5 wk of age, SV/kg values were still higher than those of adult sheep. SVR changed reciprocally to CO. The decrease in CO/kg during neonatal growth paralleled the progressive decline in heart rate (HR). Beta receptor stimulation increased neonatal CO markedly and the increment was the same from the first through the fifth neonatal week. Beta blockade had insignificant effects, but cholinergic blockade produced moderate CO increases.


Cardiac performance: independence of adrenergic inotropic and chronotropic effects. During right atrial pacing in open-chest anesthetized dogs, the relationships between reduction in stroke volume and rise in heart rate were identical in control experiments, during intravenous infusion of isoproterenol, and after blockade of adrenergic beta-receptors by propranolol. To examine the mechanism of this constant relationship, left ventricular volume was estimated by continuous recordings of myocardial chord length (MCL) between ultrasonic elements inserted into the anterior ventricular wall. Diastolic filling curves were curtailed by raising heart rate and end-diastolic MCL was reduced. At constant heart rate, end-diastolic MCL was not altered by isoproterenol infusion, except for a slight rise at heart rates exceeding 220 beats/min. End-systolic MCL, however, was reduced, accounting for larger stroke volume during isoproterenol than during propranolol infusion. The reduction in end-systolic MCL was constant at all heart rates examined. Hence, chronotropic changes influence end-diastolic volume and inotropic changes influence end-systolic volume; their effects on stroke volume regulation are, therefore, virtually independent.


Regional variation of series elasticity in canine arterial smooth muscles. Segments of carotid, iliac, renal, mesenteric, coronary, and internal thoracic arteries were studied in vitro to correlate the mechanical properties of series (SE) and parallel (PE) elastic elements with connective tissue (CT) composition and with active responses to potassium activation. The PE properties were determined using pressure-diameter data with passive smooth muscle (SM). SE properties were determined from periodic incremental releases imposed during isometric responses to [K+]O at a diameter corresponding to Lmax, the optimum muscle length. Active stress responses and diameter responses were determined using pressure-diameter data for active and passive conditions. Collagen and elastin contents were determined for each sample. No correlation was found between CT content and PE or SE properties for the various sites. A close correlation was found to exist between SE and PE properties at each site, i.e., the sites with the stiffest PE also had the stiffest SE. SM, with stiffer SE, had a larger diameter response with the same active stress response and the same diameter response with a smaller active stress response, compared to SM with more compliant SE. This suggests that passive properties of SM can have a significant influence on the external manifestations of contractile element properties.


Effects of prostaglandins E1, E2, and F2alpha on uterine blood flow in nonpregnant sheep. The effects of prostaglandins E1, E2, and F2alpha (PGE1, PGE2, and PGE2alpha, respectively) on uterine blood flow were investigated in chronically catheterized, nonpregnant sheep equipped with electromagnetic flow probes. PGE1 was found to be a potent dilator of the uterine vascular bed and, at initial arterial concentratios of 1.5 micron (500 ng/ml), produced peak uterine blood flows similar to those achieved by a pulsed dose of 1 microgram 17beta-estradiol; PGE2 had less active vasodilating activity. Conversely, uterine intra-arterial PGF2alpha infusions, which produced initial concentrations of 0.1 micron (50 ng/ml), promptly reduced peak estrogen-stimulated uterine blood flow by 60%. All prostaglandin infusions stimulated increases in uterine contractile frequency and base-line tone. The findings demonstrate the sensitivity of the nonpregnant sheep uterine vasculature to prostaglandins.


Myoglobin function in the isolated fluorocarbon-perfused dog heart. An isolated dog heart preparation perfused with hemoglobin-free fluorocarbon suspension has been developed to study the role of myoglobin in myocardial function. The coronary vasculature was perfused at constant flow, with oxygen consumption determined from arteriovenous PO2 differences. Muscle function was assessed by measurement of pressures generated in a latex balloon placed in the left ventricle. The perfusate consisted of 20% perfluorotributylamine and 80% Ringer's lactate with 16 mM glucose. Steady-state oxygen consumption decreased from 0.30 to 0.11 ml/min per gram dry weight left ventricle, as perfusate PO2 decreased from 690 to 150 mmHg. Left ventricular pressure generation and oxygen consumption were determined before and after addition of 8 mM sodium nitrite, which changed functional ferrous myoglobin to high-spin ferric myoglobin. Over the range of perfusate PO2 studied, nitrite addition did not alter mechanical performance or myocardial oxygen consumption. These data suggest that those conditions necessary for substantial myoglobin-facilitated diffusion of oxygen in the myocardium are not present in the isolated fluorocarbon-perfused dog heart.


Role of tissue hypoxia in local regulation of cerebral microcirculation. The mechanism of action of hypoxia on cerebral blood vessels and its role in the regulation of the cerebral circulation were investigated in anesthetized cats. Arterial hypoxia produced marked cerebral arteriolar vasodilation, which was partially reversed by perfusing the space under the cranial window with artificial cerebrospinal fluid (CSF) containing 6-94% oxygen. More marked increase in the local supply of oxygen, via perfusion of the space under the cranial window with fluorocarbon FC-80 equilibrated with 100% oxygen, completely eliminated the vasodilation induced by arterial hypoxia. Fluorocarbon equilibrated with 100% N2 had no effect on the vasodilation. The vasodilation associated with hypotension was completely reversed by perfusion with fluorocarbon equilibrated with 100% oxygen and was unaffected by perfusion with fluorocarbon or CSF equilibrated with gas not containing oxygen. The vasodilation associated with Metrazole-induced seizures was partially reversed by perfusion with fluorocarbon containing oxygen. The results show that hypoxia dilated cerebral blood vessels entirely via a local mechanism, that hypoxia is the dominant mechanism involved in the vasodilation associated with hypotension, and that it is, at least partially, responsible for the vasodilation associated with seizures.


Segment stroke work and metabolism depend on coronary blood flow in the pig. We determined the mechanical and metabolic effects of graded myocardial ischemia in 23 open-chest, anesthetized pigs. By connecting the midportion of the left anterior descending artery (LAD) to the carotid artery via a constant volume, calibrated pump, we reduced the flow in the LAD to 0, 25, 50, and 75% of control rates for periods of 1 h. Flows of 100% and 150% were also examined. Using pairs of ultrasonic crystals to measure segment dimensions, we calculated segment shortening and thickening, and total and systolic stroke work in the ischemic and normally perfused segments. Blood gases, pH, and lactate and inosine balances were determined from the regional coronary venous blood. At coronary blood flows of 0, 25, 50, and 75% of normal resting flow, total segment work was 8 +/- 8, 25 +/- 4, 51 +/- 5, and 80 +/- 6% of control, respectively, while systolic segment work was -2 +/- 5, -10 +/- 5, 40 +/- 5, and 86 +/- 7% of control, respectively (means +/- SE). Thus, the decrease in total segment stroke work is proportional to the decrease in flow over the range 0-100%. However, no useful work (i.e., systolic work) is done until flow exceeds 25%. Segment shortening and thickening are significantly depressed with flows diminished by only 25%. Segmental inosine production correlates with lactate production and parallels decreased mechanical performance.