Acute ocular leukemia.

A 71-year-old woman had a history of recent weight loss and bilateral decreased visual acuity, bilateral serous detachment, and mental depression. Fluorescein angiograms showed a myriad of retinal pigment epithelial leakage points. Despite extensive evaluation, the cause of her weight loss and ocular process remained uncertain until her death, when postmortem examination revealed leukemia infiltrates of many organs, including the choroid. After death, we correlated the clinical signs and fluorescein angiograms with the histopathologic findings. This case shows that choroidal disease may be a symptom of undetected leukemia.


Comparison of therapeutic routes in experimental Pseudomonas keratitis.

We determined the efficacy of tobramycin administered by topical, intramuscular, and subconjunctival routes in guinea pigs and rabbits with experimental Pseudomonas keratitis. The topical route of administration was consistently more effective than either subconjunctival or intramuscular routes. Subconjunctival injection of antibiotic did not enhance the effectiveness of topical therapy in either guinea pigs or rabbits. Intramuscular tobramycin was more effective than saline in guinea pigs with keratitis but not in rabbits with keratitis.


Pediatric ocular photography platform.

We designed a rigid support platform to facilitate ocular photography of infants or small animals. The platform is versatile because it is compatible with either the Zeiss fundus camera or Zeiss Photo Slit Lamp.


Bacillus licheniformis corneal ulcer.

A 46-year-old woman developed a corneal ulcer after an injury to the right eye. Cultures were positive for Bacillus licheniformis. Although resistant to some antibiotics, the corneal ulcer resolved after treatment with topical, subconjunctival, and intramuscular gentamicin sulfate.


Biconcave contact lens for vitreous surgery.

I designed a biconcave floating contact lens used for trans pars plana vitreous surgery. The lens uses the prismatic power of strong optical lenses to bring into view portions of the fundus that otherwise would be difficult to see.


Scleral spreading forceps for drainage of subretinal fluid.

To faciliate drainage of subretinal fluid I modified cross-action forceps so that the 10-mm angulated tip had eight semicircular opposed teeth each 1 mm long.


Wear striation direction on primate teeth: a scanning electron microscope examination.

Two experimental methods were used to produce wear striations in one direction on unworn teeth. These include: (1) sliding 22 American Indian (Juntunen site, Michigan; Late Woodland) newly erupted incisors, by hand, across a flat grass surface covered with fine loose sand; and (2) using a unidirectional motor driven mechanical wear machine to draw 56 modern human dental extractions across a flat glass surface covered with silicon carbide powder of different grit sizes. A scanning electron microscope examination of individual wear striation morphology indicates that these wear striations begin with broad pits and have extending grooves that become narrower; characteristics that indicate the motion of wear. Patterns of wear striations on the worn dentitions of American Indians (Juntunen site) and the paleocene primate Phenacolemur pagei show similar characteristics and correspond to the buccal phase of mastication when the mandible is drawn upward, forward and slightly medially into centric occlusion. The data provided by this study can be used to test competing hypotheses concerning the direction of mandibular movement during mastication and food preparation.


Family studies of tooth size factors in the permanent dentition.

Correlations between dimensions of the permanent teeth in Australian Aboriginals were studied by factor analysis to disclose the main sources of shared variability. Findings indicated that in both males and females most of the common variability in the tooth dimensions could be accounted for by factors representing mesiodistal size of anterior teeth, buccolingual size of anterior teeth, generalized size of the premolars and generalized size of the molars. Factor scores derived from the analysis were used to calculate intraclass correlations among brothers and among sisters. These correlations tended to be higher for the factors contributing most to the common variability indicating that the factors might represent fields under direct genetic control. There was no trend for intraclass correlations among siblings derived from multivariate scores to be consistently higher than those based on observed tooth dimensions. The main advantage to the user of factor analysis is the ability to interpret associations between interrelated variables more objectively than is possible by conventional correlation methods.


Relationships between non-metric skeletal traits and cranial size and shape.

A long-standing controversy exists about the comparative utility of metric and non-metric traits as biological indicators in population studies. We hypothesize that the underlying scale which determines the presence or absence of a cranial non-metric trait is an expression of general and/or local size variation in the cranium. Therefore metric and non-metric traits will share a common developmental determination. The hypothesis implies that the underlying scale of a non-metric trait will be correlated with measures of cranial size and shape. Forty-eight cranial metric and twenty-five cranial non-metric traits were scored on the left side of adult male crania from four North American Indian populations. New threshold traits were generated for each non-metric trait by dichotomizing discriminant scores produced by discriminant function analysis. The discriminant analysis was performed using metric traits to discriminate between groups formed by non-metric trait presence or absence. Every non-metric trait tested was significantly correlated with its threshold trait in at least one population. The correlations were of moderate to high levels depending on the trait and population sample studied. This implies that metric and non-metric traits share a moderate to high degree of developmental determination. The cause of these correlations may lie in the common effects that growth and development of the soft tissue and functional spaces of the cranium exert on both metric and non-metric traits.


A multivariate analysis of fatness and relative fat patterning.

Skinfold measurements (triceps, subscapular, suprailiac and medial calf) in four samples (376 boys, 352 girs, 338 men and 380 women from rural Colombia) were subjected to principal components analysis to identify components of obesity and relative fat patterning. Three components emerged which were similar in the four samples: a first component of fatness explaining 70-80% of the variance and two fat pattern components each explaining 10-15% of the variance: trunk-extremity and upper-lower body. Fatness and the trunk-extremity pattern components changed with age in children (7-12 years), but none of the components changed with age in adults (25-60+). The fatter tended to be more patterned in both age groups. Canonical correlation analysis revealed that socioeconomic status was more related to fatness than to patterning. With the exception of brothers, all first degree relatives (sib, parent-off-spring) and spouses were correlated in fatness. Some of the correlations between relatives--usually sibs, but not spouses--were also significant for the pattern components, suggesting a genetic basis for the known stability of this characteristic (Garn, '55a). Principal components analysis is a useful multivariate alternative for quantitative studies of anthropometric patterning.


Comparative and functional morphology of hominoid fingers.

Comparisons of hominoid metacarpals and phalanges reveal differences, many of which are closely linked to locomotor hand postures. The African apes display features of the metacarpals and phalanges which distinguish them from the other Hominoidea. These features are most evident in digits III and IV. The orangutan hand is demonstrably less well adapted to knuckle-walking and is distinctive in its adaptation to power and hook grasping of vertical and horizontal supports, respectively. Orangutan fingers possess a "double-locking" mechanism (Napier, '60), and a slight ulnad shift in the axis of the hand which results in lengthened phalanges of ray IV. Hylobatid apes are more like orangutans in their finger morphology than any of the other Hominoidea, but exhibit unique features of their own. These include elongate phalanges of fingers II-V. Human metacarpals II-V form two sets composed of II-III, and IV-V. The heads of both metacarpals II and III are characterized by axial torsion. This reflects the enhanced manipulatory role of the third finger in humans. Human distal phalanges are unique in the development of pronounced apical tufts. Multivariate analysis of metacarpal III and proximal III yields variables that array the extant apes along an arboreal-terrestrial axis, from hylobatid apes to male gorillas. The positions of taxa on this discriminant concur with observations on the locomotion of free-ranging apes.


Population genetic data on properdin factor B (Bf) in northern Germany.

Properdin factor B phenotypes were determined in 1,112 unrelated individuals and in 151 mother/child combinations from Northern Germany. Gene frequencies were : F = 0.1960, S= 0.7905, F1 = 0.0072, S1 = 0.0063. The data of the mother/child combinations are in full accordance with the postulated gene model.


Digital dermatoglyphics of 107 Bengalis.

I analyzed the finger prints of 59 male and 48 female unrelated Bengalis in a rehabilitation camp of Dacca, Bangladesh. The most common pattern type in the Bengalis was the ulnar loop (53%), then whorls (40%); arches (5%) and radial loops (2%) were the least common. Radial loops occurred most frequently on the index fingers. I have shown the arch/whorl, whorl/loop, and pattern intensity indices, and I have presented ridge counts by individual digits and by total digital ridge count. Digital dermatoglyphics in the male Bangladeshis were similar to previous findings in male Brahmins of Bengal. However, there were more whorls and arches, fewer loops, and a higher mean total digital ridge count in the female Bangladeshis than in female Brahmins.


The interaction of stressors in the induction of increased levels of fluctuating asymmetry in the laboratory rat.

Recent studies on fluctuating dental asymmetry have isolated single stressors as causative agents. Since most stressors are composite in nature, the present study was designed to determine the effects of the interaction of stressors in the induction of fluctuating dental asymmetry. Pregnant rats were assigned to one of six treatment groups and stressed with various combinations of heat, cold, noise and protein deprivation. The levels of fluctuating dental asymmetry were assessed and it was found that all protocols produced higher levels of asymmetry than found for control animals. Noise and reduced protein exhibited an additive effect and the interaction of stressors produced a reduction in litter size. Suggestions were offered for further research in this expanding field.


Isometric endurance in fast and slow muscles in the cat.

By use of a method of sequential stimulation described previously, the ability to sustain tensions of 3--100% of the initial strength (maximum isometric tension that could be developed in the fresh muscle) to fatigue (endurance) was assessed in the soleus (slow-twitch), medial gastrocnemius (mixed, fast-twitch), and plantaris (mainly fast-twitch) muscles. For all fractions of the initial strength the endurance was longest in soleus and shortest in plantaris. However, although plantaris fatigued at any tension examined, soleus could maintain a tension of up to 30% of its initial strength indefinitely with no sign of fatigue. Part of the difference in endurance between these two muscles could be accounted for in terms of blood flow because arterial occlusion sharply reduced the endurance of soleus but had only a small effect on endurance in plantaris. However, even with an occluded circulation, soleus still had substantially longer endurance than either medial gastrocnemius or plantaris. The origin of fatigue in any of the three muscles examined appeared to be in the muscle; there was no evidence of failure of transmission at the neuromuscular junction.


Effect of microvibration on activity of ureteral and portal smooth muscles.

Spontaneous contractions were elicited by microvibrations (1--80 Hz, 50--400 micron) imposed upon quiescent ureter and portal venous smooth muscles of dogs. The microvibrations increased the rate of spontaneous contractions. A microvibration of larger amplitude gave rise to a more profound increase at each frequency. The acceleration was often accompanied by a reduction in contractile force. The positive chronotropic effect was enhanced by increases in frequency from 20 to 40 Hz and not affected by administration of autonomic blocking agents and tetrodotoxin, but disappeared in a Ca-free environment and reappeared on addition of Ba2+. the simulating action of microvibration was almost proportional to external Ca2+ concentrations ranging from 2.2 to 6.2 mM. The microvibrations were able to elicit spontaneous activity in the preparation, which had been made quiescent by administration of Mn2+. These findings suggested that the positive chronotropic effect may be closely related to an increased Ca2+ influx through the membrane of smooth muscle. Active tension in the ureter in a state of contracture was depressed by imposed microvibrations.


Determination of unidirectional fluxes of phosphate across plasma membrane in isolated perfused rat liver.

In livers labeled with 32P by intraperitoneal injection 18 h before perfusion the unidirectional efflux of inorganic phosphate (Pi) was a linear function of the concentration of Pi in the intracellular exchangeable pool of Pi (range, 0--1 mumol/g liver). Calculations of the efflux were based on determination of the specific radioactivity of Pi in the intracellular exchangeable pool of Pi by a new method. Zero efflux was found at biopsy concentrations of Pi of about 1.8 mumol/g liver. The influx of Pi was calculated from the efflux and the net uptake of Pi; it was found to be related to the extracellular concentration of Pi in a fashion that was approximately linear. An increase in the concentration of Pi in the input medium gave rise to an increased influx and, with a time delay, also to a gradually increasing efflux. The increased efflux could be explained as a consequence of an increased intracellular concentration of exchangeable Pi.


Effect of ammonium chloride on osmotic behavior of red cells in nonelectrolytes.

Ammonium chloride, demonstrated to be a permeating electrolyte for human red cells in water or sodium chloride solutions, has been shown to act as if it contributes osmotic support in the presence of sucrose. The additional protection provided by ammonium chloride against hemolysis in hypotonic sucrose was found to approximate the milliosmolar concentration of the added salt. In view of previous suggestions that potassium loss was responsible for the increased protection observed with hypotonic nonelectrolyte alone, it was considered reasonable that the further protection afforded by ammonium chloride might reflect a comparable mechanism. Such a relationship was not observed. When added to isosmotic sucrose, ammonium chloride was found to be as effective as sodium chloride in preventing rather than augmenting potassium loss, in accord with the observations of others. Under hypotonic conditions, however, the addition of ammonium chloride had no effect on potassium loss beyond that observed in hypotonic sucrose alone. Equivalent additions of sodium chloride eliminated the potassium loss entirely. It was concluded that sucrose, and possibly other nonelectrolytes, acted to modify the red cell's permeability to ammonium chloride. It is this conversion of ammonium chloride to an impermeant molecule that is considered to be responsible for the observed osmotic support as well as for the markedly disparate findings in sodium chloride solutions.


Blood:bone disequilibrium. III. Linkage between cell energetics and Ca fluxes.

Specially designed Ussing chambers were used for the quantitation of fluxes of Ca2+ and lactate ions to and from viable calvaria taken from 2- to 3-day-old rat pups and young adult mice. The latter in vitro support Ca2+ levels comparable to plasma levels in vivo. The effects of various metabolic inhibitors and parathyroid hormone were studied. The results support previous findings that Ca influx into bone is a passive concentration-dependent process not significantly affected by alterations in the energy status of the bone cells. In large measure, the efflux from bone also appears to be passive. However, significant alterations in the calcium levels supported by efflux from bone were observed as acute effects of metabolic inhibitors. Part of the metabolically derived efflux may be attributed to acid production (aerobic glycolysis). However, part must be ascribed to cellular activities not yet defined.


Uptake and metabolism of [3H]norepinephrine in uterine nerves of pregnant guinea pig.

Myometrial tissue slices from virgin, pregnant (uni- or bilateral pregnancy), and puerperal animals were incubated in media containing [3H]norepinephrine ([3H]NE), and the neuronal and extraneuronal uptake was estimated. The metabolic fate of [3H]NE was elucidated by the chromatographic separation of [3H]NE, [3H]normetanephrine and 3H-labeled acid metabolites. An early and extensive reduction in both total and neuronal uptakes occurred in the myometrial regions surrounding the fetuses, and at term pregnancy no neuronal [3H]NE uptake at all was found in tissue slices from the fetus-containing horns. Concomitantly, the fraction of unchanged [3H]NE decreased with a corresponding increment in its metabolites. Similar changes, though less extensive, also occurred in the empty horn in unilateral pregnancy. The total amount of neuronal uptake in the cervix seemed unchanged compared to virgin animals. Earlier and present data support the following suggestion that in uterine horns harboring fetuses, an extensive axonal degeneration occurs; in those devoid of fetuses (unilateral pregnancy), the nerve terminals are to a great extent structurally intact, but functionally damaged. Recovery of the pregnancy-induced impairment of the adrenergic nerve plexus is slow and incomplete.


Nutritional and hormonal regulation of pyruvate metabolism in the liver.

The effect of fasting, glucose, and glucagon injection on pyruvate metabolism of rat liver mitochondria was studied. Fasting for 24 h caused a) a twofold increase in mitochondrial pyruvate uptake, b) fivefold increase in CO2 fixation, and c) no change in pyruvate decarboxylation. Injection of glucose to fasted rats 2 h prior to preparation suppressed by one-half the increase in mitochondrial pyruvate uptake and CO2 fixation and increased hepatic pyruvate content. Injection of glucagon together with glucose abolished the depression of pyruvate uptake by glucose but did not prevent the decrease in mitochondrial CO2 fixation or hepatic ketone content caused by glucose alone. The effects of insulin injection resembled that of glucose in decreasing hepatic ketone content, but differed by increasing pyruvate uptake without much change in CO2 fixation. It is concluded that the increase in gluconeogenesis induced by fasting is due to an increase in pyruvate uptake and carboxylation by hepatic mitochondria. The latter is due to the increased mobilization and oxidation of fatty acids induced by reciprocal changes in insulin and glucagon.


Developmental changes in thymidine kinase, DNA, and fat cellularity in Zucker rats.

Thymidine kinase activity and the pattern of DNA accretion in the genetically obese Zucker rat (fafa) were shown to develop in a manner fundamentally different from that of the lean rat. In normal lean Zucker rats, fat cell size and number, thymidine kinase activity, total DNA, and DNA in lipid-filled and nonlipid-filled tissue changed as previously reported for the normally growing lean Sprague-Dawley rat. In the epididymal depot of the developing obese rat, the progressive obesity is characterized by marked early enlargement of fat cell size, elevated thymidine kinase activity until 273 days of age, increased rate of total tissue DNA accretion until 182 days of age, and fat cell hyperplasia that becomes manifest after an apparent "peak" cell size is reached at 98 days of age.


alpha-Ketoisocaproate stimulates branched-chain amino acid transaminase in kidney and muscle.

We have reported that branched-chain amino acid transaminase (BATase) activity of isolated rat kidney is stimulated by perfusion with alpha-ketoisocaproate (KL). This study examines the mechanism of this effect in kidney and documents that stimulation occurs in intact skeletal muscle. Increased activity was not attributable to synthesis of enzyme because it occurred in the presence of cycloheximide. The in vivo degradation rate of BATase estimated from sequential measurements of activity following intravenous cycloheximide was longer than 90 min, whereas during in vitro perfusion stimulation could be detected within 5 min. Incubation of supernatant from kidney homogenate with KL stimulated BATase; incubation with alpha-keto-beta-methylvalerate (KI), alpha-ketoisovalerate (KV), leucine (leu), or isovaleryl CoA did not. Perfusion of rat hindquarter with KL increased muscle BATase activity; perfusion with acetoacetate, KI, KV, or leu did not. Again, cycloheximide studies indicated a direct effect of KL on muscle BATase. These findings suggest that alpha-ketoisocaproate can increase BATase activity and thus may be involved in regulation of its activity.


Insulin sensitivity of rat skeletal muscle: effects of starvation and aging.

The effects of starvation and of aging on the sensitivity of skeletal muscle to insulin were studied in the isolated perfused rat hindquarter preparation. As we have shown previously, starvation for 48 h had no effect on glucose uptake in hindquarters perfused with high levels of insulin (5 and 20 mU/ml). On the other hand, in the presence of physiological concentrations of insulin (50--200 muU/ml), glucose utilization was substantially greater in starved rats. Low concentrations of insulin had a greater effect on glucose uptake in fed young (100-g) than in fed older (350-g) rats. Starvation for 48 h enhanced glucose uptake in both young and older rats; however, the relative differences persisted. Starvation had similar effects on glucose utilization by the incubated soleus and extensor digitorum longus muscle. In addition, it augmented the stimulation by insulin of alpha-aminoisobutyric acid transport into the incubated extensor digitorum longus muscle. These results suggest that the in vitro sensitivity of skeletal muscle to physiological concentrations of insulin is enhanced during starvation. The basis for these findings and their physiological implications remain to be determined.


Mechanism of inhibition of alanine absorption by Na ricinoleate.

The mechanism of inhibition of alanine absorption by Na ricinoleate has been examined in the rabbit intestine. This fatty acid in a concentration of 2--5 mM inhibits alanine absorption in vivo and in vitro. The inhibition is more evident in the jejunum than in the ileum. Strips of ileal mucosa treated with Na ricinoleate gain Na. Sodium ricinoleate inhibits alanine influx across rabbit ileum, even in the presence of a sodium gradient across these cells. The results suggest that the main action of Na ricinoleate is on the alanine-transport system at the brush-border membrane. The fatty acid may also inhibit amino acid absorption by increasing intestinal cell Na concentration, which results in a decreased Na gradient across the brush-border membrane.


Scanning esophageal impedance probe for measurement of luminal cross section.

A scanning esophageal probe for measuring luminal cross section is described. Current is injected into electrode assemblies so that a variable voltage output directly proportional to interelectrode impedance and inversely proportional to cross-sectional area of the medium around the electrodes may be measured. The device is capable of measuring the cross section of glass cylinders. It was used in one esophagus to measure the cross-sectional area of different sizes of swallowed bolus. The probe offers a safe and repeatable method of studying dynamic changes in luminal dimensions of the esophagus.


Calcium absorption and intestinal calcium-binding protein: quantitative relationship.

The concentration of the vitamin D-induced calcium-binding protein (CaBP) and calcium absorption from the duodenum were investigated in chicks with an in vivo ligated-loop technique. The relation between CaBP and calcium absorption was dependent on a) source of vitamin D activity (either vitamin D3 or 1,25-dihydroxycholecalciferol); b) dosage of vitamin D3; c) time after administration of vitamin D3 to rachitic animals. To aid in the interpretation of these results, a phenomenological model was developed in which CaBP was viewed as being linearly related to a portion of calcium absorption. The model, when applied to the data, suggests that there is a "nonfunctional" pool of CaBP the size of which is determined by the vitamin D status of the animal. After correction for this nonfunctional pool, the proportionality between CaBP and calcium absorption is independent of the vitamin D status of the animal.


Age-dependent inhibition of suckling by cholecystokinin.

The effects of exogenous cholecystokinin (10--40 U/kg body wt) on neonatal rat suckling were studied in 5-, 10-, 15-, and 20-day-old rats that were equipped with tongue cannulas. Milk (0.1 ml over 10 s) was delivered through the tongue cannula once every minute, providing a rat was still suckling. Cholecystokinin, a well-established inhibitor of adult rat feeding, did not reduce milk intake volume of 5- and 10-day-old rats. It did, however, depress milk intake of 15- and especially of 20-day-old rats. Despite its effect on milk intake, cholecystokinin never lengthened the latency to attach to the nipple and, paradoxically, reduced it on certain occasions. The implications of these findings for the events controlling various aspects of suckling behavior throughout the course of the nursing-suckling period in rats and for the mechanism of action of cholecystokinin are discussed.


Actions of peptides isolated from amphibian skin on amylase release from dispersed pancreatic acini.

In dispersed acini prepared from guinea pig pancreas, peptides isolated from amphibian skin (caerulein, bombesin, litorin, and physalaemin) as well as eledoisin, a peptide isolated from the posterior salivary gland of a Mediterranean octopod, caused a significant increase in amylase release. Each amphibian peptide potentiated the stimulation of amylase release caused by vasoactive intestinal peptide or secretin in that the increase in amylase release caused by an amphibian peptide plus vasoactive intestinal peptide or secretin was significantly greater than the sum of the increase caused by each secretagogue acting alone. Potentiation of amylase secretion did not occur with an amphibian peptide plus cholecystokinin or carbachol.


Use of microspheres to measure small intestinal villus blood flow in the dog.

The accuracy of using 7- to 10-micron microspheres to measure blood flow to dog small intestinal villi was studied. These spheres appear to pass unimpeded through the afferent arterioles of the villus and lodge at the villus tip because 1) virtually all villus spheres were located at the tip, 2) flow determined by visually counting spheres did not differ significantly from flow determined from radioactivity of the sheared-off villus layer, 3) the size distribution of spheres in the villus and subvillus layers was virtually identical to that administered, indicating no premature impaction of the larger spheres, and 4) spheres lodging in the submucosa during vasoconstriction did not subsequently migrate to the villi during vasodilatation. Studies with 25-micron spheres indicated that 28% of the 7- to 10-micron spheres shunted through vessels greater than 10 micron. Double isotope studies showed that lodges spheres do not migrate and that the injection of 2--4 X 10(6) spheres does not alter villus flow. Thus, 7- to 10-micron microspheres pass to and lodge in villus vessels in proportion to capillary flow and should provide an accurate estimate of villus nutrient blood flow.


Sodium in renal tubular acidification kinetics.

Renal proximal tubules and their peritubular capillaries were perfused with mammalian Ringer solutions containing different sodium concentrations. In stop-flow microperfusion experiments, the pH was measured by means of antimony microelectrodes, permitting calculation of rates of H ion secretion and bicarbonate reabsorption. These rates, as well as transepithelial pH and bicarbonate gradients, were significantly reduced at ambient concentrations of 20 and 4 meq/liter Na+. However, even at the lowest sodium concentrations (4 meq/liter), H ion secretion was still 74%, and bicarbonate reabsorption of 64% of control rates. In similar conditions, sodium reabsorption as measured by the split-droplet technique fell to practically zero. Ouabain, 10(-3) M, in capillaries reduced bicarbonate reabsorption by 31%, and 3 X 10(-4) M furosemide in lumen and capillaries reduced acidification by 29%. At pH 8--9 in capillaries, sodium transport was normal while acidification was markedly reduced. These data show that low sodium levels impair renal tubular acidification, but they do not support a rigid coupling of these transport processes.


Excretion of phenol red by the Necturus kidney.

Phenol red (phenolsulfonphthalein, PSP) is thought to be secreted by proximal kidney tubules in all vertebrates. The present study examined PSP transport by the kidney of the salamander, Necturus maculosus. In Necturus kidneys perfused with oxygenated Ringer solution, the PSP/creatinine clearance ratio was unity. Perfusion with 1 mM octanoate converted net p-aminohippurate (PAH) reabsorption to net secretion, but had no effect on PSP. In seven urethan-anesthetized Necturi, the PSP/inulin clearance ratio averaged 0.85 +/- 0.21 (SD), not significantly different from unity. Thin slices from Necturus kidneys incubated in vitro for 2 h failed to accumulate PSP; slice-to-medium (S/M) concentration ratios averaged 0.8 +/- 0.2 (n = 6). With frog kidney slices, (S/M)PSP was 9.6 +/- 1.4 (n = 6). Necturus kidney slices accumulated PAH ((S/M)PAH = 4.1 +/- 0.7) (n = 6), but uptake was not inhibited by 1 mM PSP. We conclude that Necturus kidney tubules transport PAH, but do not transport PSP. These results are consistent with the hypothesis that the organic acid secretory system in most animals involves several carriers.


Urinary concentrating mechanism in the desert rodent Psammomys obesus.

The mechanism by which osmolality rises in fluid in the juxtamedullary descending limb was examined in Psammomys obesus by micropuncture of the left renal papilla. The concentration of Na, Cl, K, Mg, and phosphorus was determined by electron probe; Cl concentration by both probe and the microcoulometric technique of Ramsay et al. (J. Exp. Biol. 32: 822--829, 1955). The mean urine-to-plasma ultrafiltrate (U/P) osmolality was 5.5 +/- 0.46 (SE). In 43 samples obtained from the end-descending limb in 16 animals, mean values were: tubule fluid-to-plasma ultrafiltrate (TF/P) osmolality, 3.64 +/- 0.30; (TF/P)In, 6.96 +/- 0.52; (TF/P)Na, 3.53 +/- 0.27; (TF/P)Cl-e, 4.11 +/- 0.37 (-e is electron probe determination); and (TF/P)Cl-r, 4.25 +/- 0.37 (-r is determination by method of Ramsay). In terms of percentage of filtered ion remaining at the end-descending limb, Na was 54 +/- 3.7%, Cl-e was 61 +/- 3.6%, and Cl-r was 63 +/- 4.0%. The percentage of filtered chloride remaining averaged 80% or more in three animals, equalled or slightly exceeded 100% in six individual descending limb samples, and in all animals was a function of loop fluid osmolality (y = 8.61x + 31.9, r = 0.66, P less than 0.01). The results are most consistent with the thesis that both water extraction and transepithelial NaCl addition contribute to the rise in osmolality of fluid in the descending limb of the Psammomys.


Response of deep nephrons and the terminal collecting duct to a reduction in renal mass.

Juxtamedullary (JM) nephron and collecting duct function was studied after a two-thirds reduction in renal mass in the young rat. The glomerular filtration rate of JM nephrons was twofold greater in the remnant kidney (RK) group than in controls, but this increase was proportional to the increase measured in surface nephrons. Despite an increase in absolute reabsorption, delivery of sodium and water to the end of the proximal tubule of superficial nephrons and to the bend of Henle's loop of JM nephrons was increased. This was a consequence of an increase in filtered load and a decrease in fractional reabsorption. Potassium handling in surface nephrons was similar to that of sodium and water. In deep nephrons of the RK group, potassium delivery to the bend was increased as a consequence of increased filtered load. The terminal portion of the collecting duct has a role in this adaptive response to a reduction in renal mass. In rats with a RK, reabsorption of water occurred along this segment; however, when the amount reabsorbed was related to delivery, fractional water reabsorption was only 30% of controls. Changes in sodium handling were more profound. In the group with the RK, sodium reabsorption was not detectable along this segment. Thus, while 40% of delivered sodium was reabsorbed in controls, in the remnant kidney group the mean was not different from zero (-1.7%).


Maturational development of glomerular ultrafiltration in the rat.

To ascertain the cause of low glomerular filtration rate in newborn and immature mammals, we measured glomerular pressures and flows directly in immature (30- to 45-day-old) euvolemic Munich-Wistar rats with surface glomeruli. As with total kidney GFR, single nephron (SN)GFR was found to be significantly lower than in adult rats, on average by 40% when corrected for kidney weight. Equality between efferent oncotic pressure and transglomeruler hydraulic pressure difference (deltaP) was usually achieved in immature rats, indicating that the glomerular capillary ultrafiltration coefficient is not a factor limiting SNGFR and GFR in immature rats. Although the average values for deltaP in immature rats were slightly, albeit significantly, lower than in adults, markedly lower values (79 +/- 5 vs. 136 +/- 10 nl/min per g kidney wt) for glomerular plasma flow rate (QA) proved to be the primary factor responsible for the lower SNGFR and GFR values in immature rats. Considerably higher values for afferent and efferent arteriolar resistances contributed to this low QA state in immature rats.


Renin inactivation during in vitro experiments.

Experiments were designed to clarify the factors affecting renin released during in vitro experiments. Kidneys from rat, dog, and pig were used. Experiments were done in which the gas phase was either bubbled through the incubation medium or layered above it. Renin released into the incubation medium disappeared very rapidly when gas was bubbled through the medium. The decline was similar in mediums bubbled with oxygen-CO2 (95%--5%) or nitrogen-CO2 (95%--5%). The half-life of renin activity in the bubbled medium was approximately 15 min in both cases. However, in experiments in which nonbubbled medium was used throughout, renin released into the incubation medium did not disappear after removal of slices. These data are interpreted to mean that the renin released into the incubation medium is inactivated at the air-water interface.


Effects of sodium chloride on early and chronic phases of malignant hypertension in rats.

Malignant hypertension was induced in Sprague-Dawley rats by a complete aortic ligation above the left renal artery. The effects of saline (0.9% NaCl) administration on the development and course of the malignant hypertensive vascular disease were studied and the treated rats were compared to non-saline-treated  animals and to sham-operated controls in the early and chronic phases of the disease. In the early phase, blood pressure, hematocrit, body weight, and hypertensive vascular disease were characteristic of the malignant hypertensive process and were without significant difference in saline- and non-saline-treated animals. In contrast, the sham-operated rats remained normotensive and did not present abnormal histological findings. Plasma renin activity although decreased in the hypertensive saline-treated animals was not suppressed. In the chronic phase, NaCl administration caused an average increase of 40 g body weight during the 1-wk period this solution was given, but did not result in any improvement in blood pressure levels and vascular disease in treated rats compared to non-saline-treated animals.


Instantaneous pressure-volume relationship of right atrium during isovolumic contraction in canine heart.

We studied the contraction of the right atrium in an excised cross-circulated heart preparation. Atrial volume and instantaneous atrial pressure were measured in a water-filled balloon fitted in the spontaneously contracting right atrium. The relation of instantaneous pressure to volume was analyzed by collecting pressure data from multiple isovolumic contractions with different volumes but measured at multiple identical time points in the contraction cycle. The relation was found to be quasi-linear during most of atrial systole and diastole. A linear regression formula P(t) = K(t)[V- VD(t)] was therefore fitted to the data. K(t) and VD(t) of the regression formula are the slope and the volume axis intercept in the pressure-volume plane, respectively. When the atrium beat spontaneously at a regular sinus rhythm with no inotropic intervention. K(t) increased during systole and decreased during diastole, whereas VD(t) decreased during systole and increased during diastole. The average value of K was 13 +/- 1.7 (SE) mmHg . kg . ml-1 at the end of diastole and 33 +/- 0.02 (SE) mmHg . kg . ml-1 at the end of systole. The average value of VD was 0.303 +/- 0.017 (SE) ml . kg-1 at the end of diastole and 0.212 +/- .025 (SE) ml . kg-1 at the end of systole. Enhancement of contractility with epinephrine or Ca2+ significantly increased the value of K at the end of systole, but it did not significantly affect either K at the end of diastole or VD at the end of systole and diastole.


Scattering of cerebral blood flow estimates using 133Xe intracarotid injection.

Computer-generated and real curves were used to study the random error in the blood flow estimates calculated from xenon-133 cerebral clearance curves. The initial count rate affects the scattering under a threshold of 5,000 counts/s, but above this figure its influence is negligible. Flow values, relative weight of gray matter, and processes of analysis have also an effect. For the stochastic analysis, a theoretical standard deviation calculable from each experimental curve was proved. For other methods, empirical formulas were established. Using these formulas, intervals of uncertainty can be calculated allowing a useful comparison of the results obtained on the same patient, from different areas or from subsequent tests. Such intervals also allow the comparison of mean flow values obtained from a particular curve by the three usual processes of analysis. With high initial count rates, more than 75% of the intervals of uncertainty are disjointed. This suggests that the random error plays little part in the differences observed.


Effect of calcium on strophanthidin-induced electrical and mechanical toxicity in cardiac Purkinje fibers.

The role of calcium in the electrical and mechanical toxicity induced by strophanthidin (10(-6) M) was studied in canine Purkinje fibers perfused in vitro. Strophanthidin caused an increase in contractile force ("therapeutic effect") followed by a subsequent decrease and by the onset of arrhythmias ("toxic effects"). The onset of arrhythmias occurred sooner in low- and later in high-calcium solutions with respect to the normal calcium. The positive inotropic (therapeutic) effect of strophanthidin was reduced or prevented by caffeine (1 mM) or by high calcium. The late (toxic) decline in force during exposure to strophanthidin was temporarily reversed by decreasing [Ca]o to a low value. Similarly, the contractile force decreased when [Ca]o was increased from 8.1 to 16.2 mM and this decline was transiently reversed when [Ca]o was reduced to a low value. It is concluded that in Purkinje fibers 1) electrical toxicity may occur independently of an intracellular calcium accumulation, and 2) the mechanical toxicity may be due to an excessive accumulation of calcium in the fiber.


Contributions of nerves and metabolites to exercise vasodilation: a unifying hypothesis.

Neuronal cell bodies exist in arterioles of skeletal muscle and appear to initiate vasodilation during phasic contraction. The following findings indicate that intrinsic nerves rather than metabolites maintain vasodilation during sustained phasic contraction with free flow. 1) Under certain conditions maximal vasodilation can occur without detectable release of metabolites. 2) When metabolites are released during exercise, their concentrations in blood or tissue do not always determine the extent of vasodilation. 3) Vasodilation during sustained contraction can be partly blocked by local anesthetics. The extent of block is inversely proportional to the concentration of metabolites. Dose, time course of block, and other tests of specificity indicate that local anesthetics act on the intrinsic nerves rather than smooth or striated muscle. When contraction stops, neurogenic vasodilation decays rapidly (half time less than 1 min). Sustained vasodilation during recovery is therefore fully accounted for by metabolites. A hypothesis is suggested that integrates the roles of extrinsic nerves, intrinsic nerves, and metabolites in support of muscle contraction.


Low-frequency viscoelastic properties of canine femoral artery in vivo.

Mechanical properties of the canine femoral artery in vivo are measured as a function of frequency (0.0025--0.1 Hz) and as a function of mean pressure (10--16 kPa). Sinusoidal pressure variations are generated with a servo-controlled occluder system. The absolute value of the Young's modulus increases with mean pressure (E = 0.63 X 10(5) exp(0.211P)-N.m-2) at 0.05 Hz; where P is pressure. At heart rate frequencies (average value 2.22 Hz) this relation is: E = 1.25 X 10(5) exp(0.175P) N.m-2. The phase angle of the Young's modulus is independent of pressure at both frequencies. At 0.05 Hz we found: phi = 0.189 - 0.00788 P radians and at 2.22 Hz: phi = 0.0723 + 0.000428 P. The slope of both lines is not significantly different from zero slope (alpha = 0.05). Frequency dependence is studied at a constant pressure level (Pr, average value 14.3 kPa) just below the animals' mean pressure levels (average value 15.9 kPa). The frequency behavior of the elastic modulus is fitted with a function with two poles and two zeros (poles at 0.003 and 0.038 Hz; zeros at 0.0022 and 0.03 Hz).


Variability in erythrocyte deformability among various mammals.

Deformability is an important aspect of erythrocyte physiology and has been extensively studied using human red cells. We have studied erythrocytes from 25 different animals using a viscometric technique. Erythrocyte diameters ranged from 3.3 microns in the goat to 11.4 microns for the elephant seal. Erythrocytes from most species deformed readily when a fluid shear stress was applied. A deformability index of the stressed cell defined as (length - width)/(length + width) correlated with cell size. The erythrocytes of four animals (pygmy goat, goat, Batanga horse, and miniature horse) deformed less than most species. Camel and llama erythrocytes, which were ellipsoidal, did not deform but oriented in the stress field.


Intestinal O2 uptake during sympathetic stimulation and partial arterial occlusion.

In isolated loops of canine small bowel perfused at constant blood flow, stimulating perivascular sympathetic nerves (8--10 Hz) depressed O2 extraction and O2 uptake. Because sympathetic stimulation also decreased 86Rb extraction, the results confirmed earlier studies indicating that sympathetic stimulation closes "precapillary sphincters" and through diffusion limitations reduces the capillary-to-cell flux of oxygen. To determine if sympathetic stimulation could lower O2 uptake under more physiologic circumstances, a second series of experiments was performed during constant arterial pressure perfusion. Sympathetic stimulation reduced blood flow by about 30% in the steady phase. Oxygen extraction did not increase appreciably, so O2 uptake was also reduced. When partial arterial occlusion was used to lower the blood flow to the level that it reached during sympathetic stimulation, large increases (37%) in O2 extraction occurred so that O2 uptake remained near control levels. The results indicate that after arterial occlusion local mechanisms maintain O2 uptake by increasing O2 extraction through capillary density increases, but that this mechanism is impaired by sympathetic stimulation.


Avian cerebral blood flow: influence of the Bohr effect on oxygen supply.

To clarify the problems of altitude tolerance in birds, we studied the combined effect of hypocapnia and hypoxia on cerebral blood flow (CBF) in ducks. CBF was measured by the xenon clearance method. Normocapnic hypoxia causes CBF to increase when the arterial O2 tension (PaO2) falls below 60--70 mmHg. Hypocapnic hypoxia significantly shifts the blood flow curve so that blood flow does not increase until a lower PaO2 (50--60 mmHg) is reached. This gives the appearance that hypocapnia suppresses the hypoxia-induced increase in CBF. However, due to the Bohr effect, the hypocapnic blood contains significantly more O2 than does the normocapnic blood at the same PaO2. Therefore, when CBF is expressed as a function of O2 content, rather than PO2, CBF in the hypocapnic group does not differ significantly from the CBF in the normocapnic group. We interpret this to mean that because of the significantly greater oxygen content of the hypocapnic blood at a given PaO2, the degree of hypoxia experienced by these brains is not as severe as that experienced by the normocapnic brains.


Rabbit cardiovascular responses to aortic nerve stimulation at fixed carotid pressure.

In pentobarbital-anesthetized rabbits with aortic nerves cut, reflex heart rate and mean arterial pressure (MAP) changes were quantified in response to maximal central stimulation of the left aortic nerve (LANS) before and during steady-state changes in isolated carotid intrasinus pressure (ISP). To distinguish possible vagally mediated cardiopulmonary influences, responses were measured before and after vagotomy. Changes in MAP observed by altering ISP within +/- 15 mmHg of the equilibrium pressure (EP) were linear and inversely correlated to changes in ISP, with a slope of approximately 3 both before and after vagotomy (r greater than or equal to 0.929, P less than 0.05). The peak fall in MAP during LANS was dependent upon ISP. The change in the MAP responses to LANS for each mmHg change in ISP ranged from 1.7 with vagi intact to 1.3 after vagotomy. Heart rate was unaltered by isolation of the carotid sinus and was independent of the small changes in ISP between +/- 15 mmHg of EP. These results indicate that blood pressure changes elicited by the aortic baroreflex are extremely sensitive to the degree of carotid sinus compensation. Thus, to assess the sensitivity of any arterial reflex area, the existing level of compensation by other barosensitive areas must be known.


A tethering system for direct measurement of cardiovascular function in the caged baboon.

A device suitable for the continuous measurement of physiological activity in large, conscious monkeys has permitted the direct recording of systemic arterial blood pressure and heart rate in caged baboons. The device comprises a lightweight fiberglass backpack, retained in place on the baboon by a thoracic elastic band and shoulder straps, and a flexible stainless steel tether connecting the pack to an electrocannular slip-ring in the top center of the baboon's cage. A chronically indwelling arterial catheter inserted retrograde into the abdominal aorta via the internal iliac artery and connected to a small pressure transducer on the pack provides direct measurement of blood pressure and heart rate. Body fluids can be sampled or drugs administered via an indwelling catheter in the inferior vena cava. Electrical and fluid connections between the fiberglass pack and recording and infusion equipment located outside the cage pass through the flexible tether and remain protected from the subject. The reliability of the tethering system has been demonstrated in physiological, pharmacological, and behavioral experiments with baboons.


Simple analog circuitry for measuring time to peaks.

Two simple analog circuits are presented for measurement of time to the peak of a wave form. The principle involves measuring the voltage of a triggered and reset analog integrator.


Complementarity vs. reduction as explanation of biological complexity.

The classical structure-function relation is presented as an example of an epistemological complementarity. Complementarity implies that a satisfactory explanation requires two modes of description, neither derivable from nor reducible to the other, as well as mutual incompatibility in a formal logical sense. Complementarity arose from the difficulty in describing conditional measurement processes in the language of causal microscopic laws of physics. Biological structure is associated with description in the language of physical laws, whereas biological function is associated with description of informational processes, i.e., measurement and control, that are complementary in the above sense. An explicit incompatibility between these two modes of description is that laws are expressed as rate-dependent equations, whereas informational processes are expressed as rate-independent nonintegrable constraints. The functional mode allows a simplification of structurally complex organization that is essential, not only for explanation, but for self-description at all levels of biological organization.


Fixed interval feeding does not entrain the circadian pacemaker in blind rats.

Male and female rats were blinded by orbital enucleation at 1 or 21 days of age and were housed along with intact controls in a temperature- and light-controlled room (22 +/- 2 degrees C, LD 12:12). At 40 days of age the rats were transferred to running wheel cages connected to an event recorder and their activity patterns were monitored for the next 11--16 wk. After 4--6 wk in the running wheels, the rats were subjected to a fixed interval feeding (FIF) schedule lasting 23 days followed by 4--6 wk of ad libitum feeding and watering. Of 19 blind rats with interpretable activity records, 14 showed no change in their activity patterns associated with the FIF other than the addition of a large component of activity before and after the feeding period every day. It was concluded that, in contrast to the squirrel monkey, FIF is not an important zeitgeber for blind rats.


Response of supraoptic neurosecretory cells to changes in left atrial distension.

Acute studies were conducted in cats to determine the effects of small changes in left atrial pressure (LAP) on the activity of antidromically identified neurons in the supraoptic nucleus (SON). Inflation of left atrial balloons reproducibly altered the frequency of 15% of the SON neurons. More than half of these increased frequency, probably due to a simultaneous increase in arterial pressure. In a second series, the firing rates of 20% of the SON neurons tested were inversely related to changes in LAP produced by pumping blood into or out of the left atrium. A third series of experiments were conducted in which the left atrium was directly stretched by pulling on a suture placed in the atrial wall in addition to one of the above methods of changing LAP. Directly stretching the left atrium inhibited over 70% of the SON neurons; this included all the neurons that responded to changes in LAP. The results suggest that these SON neurons have differential sensitivities to inputs from left atrial receptors.


Analysis of circadian periodicity of plasma cortisol in normal man and in Cushing's syndrome.

In normal subjects, adjusted to a circadian environment, half-hourly plasma cortisol levels over a 24-h span (time series, TS) outline a circadian sinusoidal pattern that may be masked by superimposed short-lived oscillations. The periodogram objectively defines the features (amplitude, phase) of this pattern in individual TS and, more efficiently, in the average and concatenation of homogeneous TS. Concatenation is a procedure by which homogeneous short TS are attached one after the other. Homogeneity is inferred by variance analysis and by a new measure, h, with statistical significance, derived from the spectrum of the concatenated TS. Through concatenation, autocovariance for periodicity identification becomes possible. The TS from three groups of volunteers are highly homogeneous and have a predominant, statistically significant amplitude with peak time near 1100 h. The patterns from patients with Cushing's disease differ markedly in their means and periodic features; by the above criteria, we identify a subgroup with significant h measure and 24-h amplitude. This analysis provides a tool for investigation of the circadian clock in man.


Development of dependence on oxygen in embryo salamanders.

Survival times in anoxia and hypoxia were measured at various stages of development in Ambystoma embryos and larvae of two species. Survival times in anoxia at 20 degrees C shifted from more than 30 h at 2 days after fertilization to 20 h at 10 days of age, to only 4--2 h at 14 days of age. In hypoxia (oxygen pressure equivalent to 3.8% oxygen) similar shifts of survival times appeared about 7 days of age later. During anoxia heart rates decreased, less at younger stages than at older. At older stages the heart stopped beating, sometimes irreversibly. In hypoxia also, hearts at all stages whether in situ or isolated decreased their rates of beat. Oxygen uptakes of larvae diminished in oxygen pressures even as high as 11% oxygen. This critical oxygen pressure did not change between early stages without blood flow and later stages with blood flow. Oxygen uptake was probably not limited by oxygen delivery but presumably by properties of cellular masses. No oxygen debts were paid off. Some parallel changes of tolerances to anoxia in embryo birds and mammals are noted.


Mechanism of morphine-induced mydriasis in the cat.

Neurons that increased their firing rate in response to light stimulation were recorded from the pretectal region and the anterior oculomotor nucleus of sedated immobilized cats while morphine (2 mg/kg iv) was administered. The dose produced mydriasis and an increase in spontaneous firing rate of all light-sensitive neurons recorded from the anterior oculomotor nucleus. This suggested that morphine did not produce mydriasis through inhibition of the third nerve. Phenoxybenzamine, iv or topically, antagonized the mydriasis, indicating a peripheral source of sympathetic input as the basis for morphine-induced mydriasis. Morphine (2 mg/kg iv), administered 1 h after adrenalectomy, produced miosis and increased the spontaneous firing rate of light-sensitive neurons recorded from the oculomotor nucleus. These observations suggest that, in the cat, although morphine activates the oculomotor neurons to produce miosis, the effect is masked by the morphine-induced release of catecholamines, mainly from the adrenal glands, which produced mydriasis.


Renal function in Lophius americanus: effects of angiotensin II.

Arterial blood pressure, urine flow rate, and plasma and urine electrolytes were measured in the aglomerular goosefish (L. americanus) before, during, and after the intravenous infusion of angiotensin II (from 5 to 280 ng/min.kg body wt). Increases in arterial blood pressure were directly related to the logarithm of the angiotensin infusion rate (r = 0.62, P less than 0.005). Angiotensin also increased urine flow from 0.676 +/- 0.065 to 0.755 +/- 0.068 ml/h.kg body wt (P less than 0.005) and Na excretion from 41.0 +/- 5.5 to 54.4 +/- 7.0 mumol/h.kg body wt (P less than 0.001). In 17 of the 19 fish infused with angiotensin the diuretic and natriuretic effects were directly related to the logarithm of the infusion rate (r = 0.44, P less than 0.04 and r = 0.51, P less than 0.02, respectively). There was no relationship between the pressor and the diuretic or natriuretic effects of angiotensin II. These results are consistent with inhibitory effects of angiotensin on solute transport by aglomerular tubules.


Newborn northern fur seals (Callorhinus ursinus)--do they suffer from cold?

Several hundred thousand northern fur seals (C. ursinus) are born each summer during July at St. Paul Island in the Bering Sea. The weather in the area is usually cold, wet, and windy during the breeding season. At birth the pups are small (5--6 kg) and insulated only by a partly wettable pelt and a 2- to 4-mm layer of blubber. In air, the pups' lower critical temperature appears to be below the 6 degrees C 50-yr record low July temperature for the islands. During rainy weather much of the insulative value of the pelt is lost, and the pups, which already have a high resting metabolic rate of 3.5 W.kg-1, must increase heat production by shivering and/or nonshivering thermogenesis to maintain deep body temperature. The high level of metabolism (up to 18 W.kg-1) is supported by a very rich milk. The pups will, nevertheless, become hypothermic if their insulation is not improved through peripheral vasoconstriction and shedding of water from the pelt by periodic shudder. Even with these protections the newborn and very young pups are brought close to their limit of tolerance during rainy and windy days. Unfit pups are likely to succumb under such circumstances.


Preabsorptive intestinal satiety controls of food intake in pigs.

Pigs, 1--3 mo of age, weighing 5--80 kg, were fitted with duodenal, intraportal, or intrajugular catheters. After a 4-h fast, preloads were delivered to the duodenum, and food intake then measured for 10 min (no drinking water). Glucose (5--40%) and NaCl (0.9--6.5%) solutions were used as preloads (5 ml/kg body wt). Food intake expressed as percent control intake (Y) was depressed in proportion to preload concentration (X): for glucose, Y = 109 - 2X; for NaCl, Y = 107 - 13X. When expressed in osmoconcentration, glucose and NaCl preloads had nearly identical satiety effects. Preloads of 40% sorbitol depressed intake to 74% control. Intrathoracic vagotomy reduced the satiety effects of glucose and NaCl solutions by 50%. Tetracaine (0.5%) in the hypertonic preloads blocked 80% of the satiety effects of the glucose and NaCl preloads, but had no effect on sorbitol satiety effect. Injection of glucose or NaCl solutions into the portal or jugular veins had no significant effect. It was concluded that duodenal osmoconcentration to the degree that it exceeds body fluid tonicity contributes to the immediate satiety seen during a meal.


Seasonal changes in membrane lipid transitions and thyroid function in the hedgehog.

Upper (Tf) and lower (Ts) temperature limits of order-disorder transitions in blood cell lipids of hedgehogs, Erinaceus europaeus, were determined over an annual cycle. There was a significant decrease in the temperature of both Tf and Ts from values of 19 and 6 degrees C, respectively, for summer animals to values of 14 and -2.0 degrees C for winter animals. Plasma thyroxine levels decreased from a summer mean of 16.0 nmol/liter to a mean of 2.3 nmol/liter in winter. Basal oxygen consumption also decreased from the summer mean 0.45 ml/g body wt/h to a mean 0.39 ml/g body wt/h in winter. In winter a group of hedgehogs kept indoors at room temperature was compared with a group kept outdoors exposed to natural winter conditions, and there was no significant difference between them in the above parameters. We conclude that the winter membrane lipid and metabolic changes are not a response to low temperature per se but part of a circannual homeostatic adjustment at least partly regulated by thyroid hormone.


Amino acid transport in isolated hepatocytes after partial hepatectomy in the rat.

The effect of partial (70%) hepatectomy on amino acid transport was investigated by measuring the uptake of the nonmetabolizable amino acid analogue alpha-amino-[1(-14C]isobutyric acid in hepatocytes freshly isolated from the liver remnant. In hepatocytes from partially hepatectomized rats, both the influx and the efflux of alpha-aminoisobutyric acid were increased. Quantitative analysis of the relationship between the initial rate of uptake and the substrate concentration indicated that a high-affinity component was responsible for the increased rate of amino acid entry in hepatocytes from partially hepatectomized rats. This component could be detected 90 min after operation, but its Vmax increased with time. The high-affinity component was strictly dependent on sodium and had the properties of a pure A system; its mode of energization partly involved cationic transmembrane gradients. The L system of amino acid transport was not affected after partial hepatectomy. The rapid emergence of a high-affinity amino acid transport system in the liver remnant following partial hepatectomy may play an important role in the regulation of liver regeneration.


Role of hepatic portal osmoreception in the control of ADH release.

Dogs were prepared for experiments by chronic implantation of catheters into the hepatic portal vein. Intraportal infusions of hypertonic saline, 5 ml/min, increased plasma antidiuretic hormones (rat bioassay) in absence of significant changes in systemic plasma osmolality. In the 5th min of 1.8, 2.7, or 3.6% saline infusion, plasma antidiuretic hormone (ADH) increased significantly from 3.2 +/- 0.7 to 14.3 +/- 3.6 (SE) microU/ml, from 2.3 +/- 0.4 to 42.0 +/- 7.6 microU/ml, and from 1.9 +/- 0.6 to 64.4 +/- 16.8 microU/ml, respectively. In control experiments plasma ADH did not change with isotonic saline infused intraportally or with 3.6% saline given into a systemic vein. The transsection of hepatic vagal afferent fibers abolished plasma ADH increase dependent on hypertonic intraportal infusion. The data support the existence of osmoreceptors within the portal vascular bed and indicate ADH involvement in the control of fluid balance by intrahepatic blood osmalality. The information on osmolality changes is neurally transmitted to the hypothalamus via hepatic vagal afferents. A demonstration of an increase in portal but not systemic blood osmolality following food intake suggests that intrahepatic osmoreception may be important in physiological regulation of water metabolism.


Anteroventral third ventricle lesions reduce antidiuretic responses to angiotensin II.

Ablation of anteroventral third ventricle (AV3V) periventricular tissue renders animals temporarily adipsic with no compensatory change in urine volume or concentration. The present experiment was designed to determine whether lesions of the AV3V region attenuate vasopressin (AVP) release in response to intraventricular (ivt) injections of angiotensin II (AII), hypertonic NaCl, and phenylephrine during the adipsic period. Blood pressure, urine conductance, and urine flow rate were monitored in awake, unrestrained animals during a continuous intravenous hydrating infusion. Changes in blood pressure and urine parameters were recorded following ivt injections of 100 ng AII, 500 ng AII, 1 microliter 3% NaCl, and 50 microgram phenylephrine. In addition, a radioimmunoassay (RIA) measured AVP following 500 ng AII ivt in lesioned and nonlesioned animals. Antidiuretic and pressor responses to ivt AII were attenuated after AV3V lesions. In addition, RIA analysis showed a significantly smaller concentration of AVP in lesioned animals following AII injections. These data suggest that the AV3V region is important for AVP release in response to central AII and osmotic stimuli.


Hemodynamics and metabolism of the in vivo vascularly isolated canine pancreas.

Surgical procedures are detailed that have yielded for the first time an in vivo vascularly isolated, autoperfused preparation of the entire pancreas in anesthetized dogs. Previous studies had isolated only part of the pancreas or had resorted to blood-flow techniques not requiring pooled pancreatic venous blood, necessary for metabolic studies of the organ. Pancreatic blood flow (48 ml/min), O2 uptake (180 mumol/min), glucose uptake (51.0 mumol/min), lactate output (6.6 mumol/min), net free fatty acid uptake (2.23 mumol/min), all per 100 g tissue, and various other measured and calculated hemodynamic and metabolic variables were determined on the preparation during control conditions. The stability of the preparation was verified by serial determinations of these parameters and of blood alpha-amylase and beta-glucuronidase levels from 1 to 2.5 h postsurgery. Metabolic rate and glucose uptake were both found to be much higher than in intestinal tissues and approached values characteristic of liver tissue.


Galactose metabolism in isolated perfused suckling-rat liver.

The metabolic conversion of 1, 2, or 4 mM galactose to glucose was studied in isolated livers of suckling rats. Whereas galactose uptake during perfusion with 1 and 2 mM galactose was linear throughout the 90-min experiment, uptake was delayed for 35 min when 4 mM galactose was perfused. Studies with radioactive galactose revealed a parallel disappearance of galactose and the appearance of [14C]glucose; about 80% of the galactose taken up was converted to glucose. Galactose perfusion appeared to reduce the basal amount of glucose derived from substrates other than galactose. The specific activities in the galactose-perfused livers of the three major galactose metabolizing enzymes, galactokinase, galactose-1-phosphate uridylyltransferase, and uridine diphosphogalactose-4-epimerase, revealed that the transferase was significantly lower, whereas that of galactokinase and epimerase were significantly higher than in livers perfused without galactose. No meaningful changes were observed in the levels of either phosphorylated or uridylated hexoses in these studies.


Partial purification of dog angiotensinogen.

Dog angiotensinogen was purified 450-fold from the plasma of nephrectomized dogs by a simple four-step procedure involving precipitation between 1.5 and 2.3 M ammonium sulfate, gel filtration on Sephadex G-150, ion-exchange chromatography on DE-52 cellulose, and affinity chromatography on Concanavalin A-Sepharose. The purity of the final preparation was over 50%. The preparation of dog angiotensinogen had an apparent molecular weight of 80,000 determined by gel filtration on Sephadex G-100. Kinetic studies indicated that the Km of the reaction of dog renin with partially purified dog angiotensinogen (1,840 pmol/ml) was similar to that for the reaction with angiotensinogen in diluted dog plasma (1,820 pmol/ml). Thus the purification procedures employed did not alter the affinity of dog renin for the Leu10-Leu11 bond of dog angiotensinogen. Because the concentration of angiotensinogen in dog plasma is about 700 pmol/ml, a first order reaction with respect to substrate is indicated in vivo.


Quantitative estimation of insulin sensitivity.

We have evaluated the feasibility of using a mathematical model of glucose disappearance to estimate insulin sensitivity. Glucose was injected into conscious dogs at 100, 200, or 300 mg/kg. The measured time course of insulin was regarded as the "input," and the falling glucose concentration as the "output" of the physiological system storing and using glucose. Seven mathematical models of glucose uptake were compared to identify the representation most capable of simulating glucose disappearance. One specific nonlinear model was superior in that it 1) predicted the time course of glucose after glucose injection, 2) had four parameters that could be precisely estimated, and 3) described individual experiments with similar parameter values. Insulin sensitivity index (SI), defined as the dependence of fractional glucose disappearance on plasma insulin, was the ratio of two parameters of the chosen model and could be estimated with good reproducibility from the 300 mg/kg injection experiments (SI = 7.00 X 10(-4) +/- 24% (coefficient of variation) min-1/(microU/ml) (n = 8)). Thus, from a single glucose injection it is possible to obtain a quantitative index of insulin sensitivity that may have clinical applicability.


Unstirred water layer and age-dependent changes in rabbit jejunal D-glucose transport.

The unidirectional flux of solutes into the intestinal mucosal cell is determined by passage through the microvillus membrane and the overlying unstirred water layer, UWL. An in vitro technique was employed to determine the effect of the UWL on glucose transport into the jejunum of suckling, mature, and old rabbits. When the resistance of UWL was high, the uptake from high concentrations of glucose increased as the animals grew older; this change with aging was not seen from low concentrations of glucose. When UWL resistance was minimized by stirring the bulk phase, similar amounts of glucose were absorbed from high doses, but uptake from low doses was greater in young than in old animals. Studies undertaken to determine the kinetic basis of these age-related changes showed that with increasing age i) the apparent passive permeability coefficient P of glucose fell, ii) the maximum transport rate Jdmax rose, and iii) the apparent affinity constant Km increased. These differences were not observed when the resistance of the UWL was high: P and Km were similar in suckling, mature, and old animals, and the increase in glucose uptake with age was due to the greater Jdmax. Thus the potential benefit of the high affinity, high permeability transport system of young animals may be obscured by high resistance of the UWL.


Permeation of long-chain fatty acids and alcohols in rat intestine.

Uptake of long-chain fatty acids and alcohols from micellar bile salt solutions has been studied with everted sacs of rat jejunum. These unidirectional uptake rates are linearly related to lipid concentration if bile salt concentration is constant, but are essentially independent of lipid concentration over a 2.5-fold concentration range if lipid and bile salt concentrations are maintained at a constant ratio. Uptake of lipid from various micellar bile salt solutions was directly related to the experimentally varied monomer activity of solute, thus allowing conversion of uptake rates to permeation coefficients. Natural logarithm of permeation coefficients (ln P) increased linearly for saturated fatty acids of 12--18 carbons, equivalent to an incremental free energy of -695 cal.mol-1 per --CH2--. Alcohols of 10- to 14-carbon chain lengths had a similar relationship on ln P to number of carbons. Previously determined permeation coefficients for fatty acids of 2--10 carbons are now seen to be a nonlinear portion of the curve for ln P versus chain length for all saturated fatty acids.


Stimulation and blockade of cholinergic receptors in terminal liver microcirculation in rats.

This study was designed to establish the existence of cholinergic vascular receptors in the terminal portion of the rat liver microcirculation. The liver microcirculation was observed in vivo by a transillumination technique through a television microscope. The changes in the caliber of the liver sinusoids were measured directly on the television screen. Infusion of the parasympathetic neurotransmitter acetylcholine into the portal venous circulation caused a concentration-dependent dilation of liver sinusoids. Similar dilatation effects were observed for other cholinergic receptor agonists. Atropine, the specific cholinergic receptor blocker, inhibited this dilator effect, displacing the acetylcholine concentration-effect curve to the right. In contrast, physostigmine, the cholinesterase inhibitor, caused displacement of the curve to the left. In conclusion, cholinergic receptors are present in the terminal portion of the liver microcirculation, subserving the functional role of vasodilatation.


A reciprocal adrenergic-cholinergic axoaxonic synapse in the mammalian gut.

Simultaneous stimulation of perivascular nerves inhibited the release of acetylcholine from stimulated cholinergic nerves of the rabbit jejunum. Adrenergic nerves were responsible for this inhibition because it did not occur in animals previously injected with 6-hydroxydopamine. Acetylcholine inhibited the release of transmitter from stimulated adrenergic axons; this effect was blocked by atropine. Since atropine enhanced the release of adrenergic transmitter when both adrenergic and cholinergic nerves were activated simultaneously (at 4.0 Hz), it seems likely that cholinergic nerves also inhibit release of norepinephrine (NE). Radioautographic examination of the myenteric plexus, incubated with tritiated NE, revealed a striking marginal distribution of adrenergic axons around the periphery of the myenteric plexus. Ultrastructural studies, with KMnO4 used to identify adrenergic terminal varicosities, confirmed this distribution and also revealed complexes formed between the terminal varicosities of adrenergic and probable cholinergic axons. The component varicosities forming these complexes contacted one another with no intervening Schwann cell elements. It is concluded that there is a reciprocal axoaxonic synapse between adrenergic and cholinergic neurons in the mammalian myenteric plexus.


Effect of extracellular calcium on amylase release from dispersed pancreatic acini.

In dispersed acini prepared from guinea pig pancreas, removing extracellular calcium did not alter the basal rate of amylase release but reduced the stimulation of enzyme release caused by cholecystokinin, carbachol, secretin, and vasoactive intestinal peptide as well as that caused by derivatives of cyclic nucleotides. In acini incubated in a calcium-free, EGTA-containing medium the increase in amylase release caused by each secretagogue tested did not change during the initial 10 min of incubation, decreased by approximately 65% during the subsequent 40 min, and remained constant thereafter. Removing extracellular calcium did not alter the maximally effective concentrations of cholecystokinin or vasoactive intestinal peptide but abolished the decrease in stimulated enzyme secretion seen with supramaximal concentrations of cholecystokinin. Incubating pancreatic acini with cholecystokinin or carbachol plus secretin or vasoactive intestinal peptide caused potentiation of amylase release, and removing extracellular calcium reduced the stimulation of enzyme release caused by the two secretagogues in combination but did not alter their potentiating interactions.


Stimulation of iron absorption by polychlorinated aromatic hydrocarbons.

Oral and intraperitoneal treatment of rats with a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 33 microgram/kg, causes a 41--67% increase in iron adsorption in vivo. The major effect is on the transfer of iron from the mucosa into the bloodstream rather than on the uptake of iron from the lumen of the gut. These results are confirmed in studies with everted gut sacs. The effect is maximal at 1--2 days with a dose of 22-42 microgram/kg. Calcium transport is inhibited by TCDD treatment, whereas galactose and proline transport are unaffected. Treatment of rats with 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane also stimulates iron transport. Concomitant with iron transport stimulation, aryl hydrocarbon hydroxylase activity in the intestine and liver is increased by TCDD treatment. These studies suggest that polychlorinated aromatic hydrocarbons, which are environmental health hazards, may effect the intestinal absorption of essential mineral nutrients.


Effect of age on intestinal calcium absorption and adaptation to dietary calcium.

To study the reported decline in intestinal calcium absorption with age, calcium active transport, immunoreactive calcium protein (CaBP) content, and alkaline phosphatase activity were measured in the intestine of two strains of rats aged 3-wk--20 mo. Calcium active transport, as measured by everted gut sacs from Sprague-Dawley rats, was greatest at 3 wk, but it declined rapidly with no active transport demonstrable at 3 mo or thereafter. CaBP content closely paralleled the decline in active transport, but alkaline phosphatase activity increased as active transport decreased. Intestinal adaptation to dietary calcium was studied by feeding high- and low-calcium diets to Fischer 344 rats aged 1.5--12 mo. In 1.5-mo-old rats fed a low-calcium diet, there was an increase in calcium active transport, CaBP content, and alkaline phosphatase activity relative to animals fed a high-calcium diet. However, the magnitude of this intestinal adaptation decreased with age until there was only marginal adaptation by 12 mo. The observed changes in calcium active transport with age and diet may be explained by the parallel changes in the vitamin D-dependent CaBP content of the intestine.


Response of Amphiuma small intestine to theophylline: effect on bicarbonate transport.

The electrolyte transport properties of isolated proximal segments of Amphiuma small intestine and their response to theophylline were observed under various conditions. In the absence of theophylline the intestine generates a transepithelial potential (psi ms) serosa negative to mucosa when Cl- and HCO3- are present in the bath. Replacement of Cl- or HCO3- reduced the magnitude and usually reversed the sign of psi ms. Acetazolamide (10(-4) M) nearly abolished the serosa negative psi ms. Theophylline (10 mM) drove psi ms serosa positive, the magnitude depending on the bath Na+ and HCO3- concentrations. Simultaneously it increased the short-circuit current (Isc) and tissue resistance (Rt). The increase in Isc was not due to increase net Na+ transport in Cl-free buffer and was attributed to a residual ion flux. Acetazolamide reduced the Isc, Rt, and the net residual flux observed in theophylline-treated intestine. The magnitude of the acetazolamine effect on Isc was proportional to the Na+ and HCO3- concentrations of the bath. The results suggest that in the absence of theophylline, HCO3-, and Cl- transport are related. Furthermore, acetazolamide inhibits the movement of an ion, possibly HCO3-, secreted in response to theophylline.


PGE1-induced intestinal secretion: mechanism of enhanced transmucosal protein efflux.

The effects of local intra-arterial prostaglandin E1 (PGE1) infusion on net transmucosal volume and protein fluxes, lymphatic volume and protein fluxes, and regional hemodynamics were ascertained in autoperfused segments of cat ileum. After acquiring control values (and tissue samples) for the various parameters, PGE1 (5.0 microgram/min) was infused directly into the superior mesenteric artery. The PGE1 infusions resulted in dramatic increases in ileal lymphatic volume and protein fluxes and blood flow. Infusion of PGE1 caused a reversion of net mucosal volume absorption to net secretion and an increased loss of plasma proteins into the lumen. Ultrastructural analysis of tissue samples taken during the PGE1 infusion indicate major structural damage to the mucosal membrane. The physiological and ultrastructural data acquired in this study suggest that 1) the increased transmucosal protein efflux during intra-arterial PGE1 infusions results from an alteration in mucosal transcapillary fluid exchange and 2) a significant portion of PGE1-induced ileal secretion is passively mediated.


Effects of intraluminal D-glucose and probenecid on urate absorption in the rat proximal tubule.

The in vivo microperfusion technique was employed to examine urate absorption in the proximal convoluted tubule of the rat kidney using [2-14C]urate as the marker for fractional urate absorption. With NaCl as the perfusion solution, water absorption averaged 2.53 +/- 0.16 nl.min-1.mm tubule-1, and the fractional absorption of [2-14C]urate averages 11.6 +/- 1.0%/mm tubule. The addition of D-glucose (50 mg/100 ml) enhanced water absorption to 3.62 +/- 0.19 nl.min-1.mm tubule-1, but inhibited fractional urate absorption to 6.6 +/- 1.2%/mm tubule. Phloridzin (4.4 mg/100 ml), 2-deoxy-D-glucose (45.6 mg/100 ml), and 3-O-methyl-D-glucose (53.9 mg/100 ml) also inhibited the absorption of [2-14C]urate to the same degree as did D-glucose despite differing effects on water absorption. The addition of probenecid (2.8 mg/100 ml) to the NaCl perfusion solution had no effect on water absorption but inhibited [2-14C]urate absorption to 6.4 +/- 0.6%/mm tubule. The addition of both probenecid and phloridzin further reduced [2-14C-A1urate absorption to 3.8 +/- 0.7%/mm tubule. Probenecid alone had no effect on glucose transport. These studies suggest that the presence of either certain hexose sugars, phloridzin, or probenecid in the lumen of the proximal convoluted tubule inhibits the tubular absorption of urate.


Impaired renal bicarbonate reabsorption in the hypothyroid rat.

We previously demonstrated a decrease of sodium reabsorption in the proximal superficial nephron of the hypothyroid rat. The present clearance studies were designed to examine the renal handling of bicarbonate in hypothyroid rats. Hypothyroidism was induced by the intraperitoneal injection of Na131I and the animals were studied 10 or more wk thereafter under anesthesia and compared to their age-matched litter-mates. As is characteristic of hypothyroid animals, insulin clearance was lower and fractional urine flow and sodium excretion rates were higher than in the control rats. At the peak of the bicarbonate diuresis and at similar blood pH, PCO2, and bicarbonate levels, fractional renal bicarbonate excretion was significantly higher in the hypothyroid animals: 22 +/- 2 vs. 15 +/- 1%, P less than 0.02. This perturbation of bicarbonate reabsorption of the hypothyroid rats was independent of the influence of extracellular fluid volume expansion and appears closely related to the impaired sodium reabsorptive capacity characteristic of experimental hypothyroidism.


Renin secretion during dynamic changes in renal perfusion pressure.

Uninephrectomized ewes were prepared with a renal artery flow probe and catheters were implanted into the renal artery, vein, and ureter. The renal perfusion pressure (RPP) of conscious animals was decreased externally by 13 +/- 3, 21 +/- 3, 31 +/- 3 mmHg over 5 min and returned to control levels over 5 min. Reduction of RPP by 13 and 21 mmHg resulted in prompt increases in renin secretion (RS) which were maximal coincident with the nadir of the downward ramp (delta RS 195 +/- 43 P less than 0.05, and 1,077 +/- 208 ng AI/min, P less than 0.01, respectively). Directly measured renal blood flow (RBF) was not decreased and no measurable change occured in GFR. When RPP was reduced by 31 mmHg, RBF and GFR were decreased and renin secretion rose further (delta RS 1,480 +/- 384 AI/min, P less than 0.05). On the upward pressure ramp, RS fell promptly and was nearly at control levels upon restoration of RPP. It was concluded that renin secretion responds rapidly to alterations in RPP in the autoregulatory range and these changes in renin secretion are unlikely to be mediated by a tubular receptor.


Renal prostaglandin E2 secretion and excretion in conscious dogs.

Renal prostaglandin E2 (PGE2) secretion and excretion rates were determined in nine conscious dogs. Renal venous (RV) and urine PGE2 concentrations were measured by radioimmunoassay. In 21 controls tests RV PGE2 ranged from 37 to 215 pg/ml, with a mean concentration of 97 +/- 11 pg/ml. Basal left kidney PGE2 secretion was 317 +/- 42 pg.g-1.mm-1. Urine PGE2 concentration averaged 8,320 +/- 1,510 pg/ml with a PGE2 excretion rate of 3,260 +/- 480 pg/min from both kidneys. Indomethacin (2 mg/kg) reduced RV and urine PGE2 concentrations by 60 and 77%, respectively. Meclofenamate (2 mg/kg) decreased RV and urine PGE2 concentrations by 36 and 48%, respectively. PG inhibition had no significant influence on blood pressure or renal blood flow (RBF). PG inhibition reduced urine flow rate and increased urine osmolality. Indomethacin had no effect on urine sodium concentration or sodium excretion; meclofenamate increased urine sodium concentration and slightly diminished sodium excretion. These data demonstrate that PGE2 is released from the kidney in a conscious animal and that both indomethacin and meclofenamate significantly reduce the renal secretion and excretion of PGE2. In a normal, conscious animal prostaglandins do not control blood pressure or RBF but are involved in the excretion of water.


Intrarenal renin and autoregulation of renal plasma flow and glomerular filtration rate.

Autoregulatory responses of renal plasma flow (RPF) and glomerular filtration rate (GFR) to reductions in renal artery pressure (RAP) were studied in both kidneys of two-kidney, one-clamp dogs and in dogs treated with deoxycorticosterone acetate (DOCA; 25 mg/kg) plus high sodium diets with and without renal arterial clamping. In non-DOCA-treated animals, unilateral renal artery constriction resulted in a significant difference (P = 0.004) in renal renin activity (RRA) between the clamped (171 +/- 37 ng AI.mg-1.h-1) and the contralateral (57 +/- 23 mg AI.mg-1.h-1) kidneys with no change in their relative autoregulatory ability. In dogs treated with DOCA/high sodium there were no differences in RRA between the clamped and contralateral kidneys. The dogs treated with DOCA/high sodium were able to autoregulate both RPF and GFR even though their RRA was only 5.4 ng AI.mg-1.h-1. DOCA/high sodium treatment, however, reduced basal RPF (22%) and GFR (23%) below those in non-DOCA-treated animals. Analysis of the autoregulatory ability of individual kidneys showed no relationship to either RRA or renin secretory rates. These results support the conclusion that the renin-angiotensin system is not necessary component in the autoregulation of RPF or GFR.


Effect of volume expansion on renal glucose transport in normal and uremic dogs.

Proximal and distal tubule micropuncture studies were performed in normal and uremic remnant-kidney dogs to examine the tubule mechanism of glucose reabsorption before and after 10% extracellular volume expansion. In normal dogs volume expansion markedly inhibited glucose reabsorption in the proximal convoluted tubule, but the ensuing increase in further distal glucose delivery was nearly completely reabsorbed in the intermediate segment (between late proximal tubule and distal tubule). In the uremic, remnant-kidney dogs, glomerulotubular balance for glucose was well maintained in the proximal convoluted tubule despite an adaptive increase in nephron filtration rate. Volume expansion markedly increased glucose delivery out of the proximal convoluted tubule and an incomplete glucose reabsorption in the intermediate segment led to glycosuria. When glucose delivery to the intermediate segment was increased to a comparable degree by subthreshold glucose loading in hydropenic normal dogs, glucose reabsorption in this segment was virtually complete, suggesting that in the volume-expanded uremic dogs glucose reabsorptive capacity in the intermediate segment was reduced. Thus, the intermediate segment appears to play a significant role in the fine regulation of urinary glucose excretion.


Graphical estimation of ventricular wall force and stress from pressure-volume diagram.

A graphical method is proposed for assessment of ventricular wall circumferential total force and mean stress from the ventricular pressure-volume diagram. A family of force or stress isopleths are first drawn in the pressure-volume plane using a geometric model of the left ventricle and an appropriate version of the Laplace equation. A pressure-volume loop of the ventricle to be analyzed is then drawn in this pressure-volume plane. Total circumferential force in the ventricular wall or its mean circumferential stress can now be read directly from the intersections of the pressure-volume loop with the force or stress isopleths.


Arterial wall properties and dietary atherosclerosis in the racing greyhound.

The effects of experimental (dietary) atherosclerosis on arteries from racing greyhounds were studied. Measurements of pressure and external diameter were made on islated carotid and iliac arteries under active (norepinephrine, 5 microgram/ml) and passive (zero Ca2+ and 2 mM EGTA) smooth muscle conditions. Iliac arteries from diet-fed animals demonstrated substantial intimal lesions, but the carotid arteries were usually grossly involved. Arteries from atherosclerotic animals were stiffer during passive conditions, with the iliac arteries having the greater changes. In iliac arteries from treated animals, collagen and elastin contents were decreased, and the collagen-to-elastin ratio was increased; in carotid arteries from treated animals, elastin content was increased and the collagen-to-elastin ratio was decreased. The maximum range of control of arterial wall mechanics by smooth muscle was diminished in treated iliacs but unchanged in carotids. Both force development and constriction responses associated with smooth muscle activation were diminished in treated iliacs but unchanged in treated carotids. Mechanical properties of series elastic elements in treated iliacs were stiffer, but treated carotids were unchanged.


Increased free fatty acid turnover in CSF during hypotension in dogs.

Cerebrospinal fluid turnover rates of FFA were investigated using ventriculocisternal perfusion techniques. Seven conscious dogs were perfused over a 6-h period from the lateral ventricle to the cisterna magna with mock cerebrospinal fluid (CSF) containing [14C]palmitate and 100 mumol/l of FFA. One hundred and twenty minutes of perfusion were allowed to establish equilibrium of the FFA concentration in the ventricular space. Moderate hemorrhage hypotension was then induced (MABP greater than 60  mmHg) for 3 h, followed by rapid retransfusion and a final hour of perfusion. Cerebral blood flow did not change significantly (45 +/- 6 before, 53 +/- 6 after hemorrhage, and 47 +/- 5 ml.min-1. 100 g-1 after retransfusion). Cerebral arteriovenous difference of O2, glucose, and pH increased significantly during hemorrhage. Hypotension was accompanied by an increased turnover of FFA from 60 to 120 nmol/min (P less than 0.01) in the CSF. FFA turnover was directly correlated with the fatty acid concentration of the CSF (r = 0.77). It is speculated that the increased fatty acid turnover during hypotension may indicate increased phospholipid turnover and/or increased oxidation by tissues lining the ventricular space.


Cardiac performance of isolated perfused hearts from alloxan diabetic rats.

Acute alloxan diabetes (3 days) in the rat resulted in a decreased ability of the isolated perfused working heart to respond to increased atrial filling pressure with normal systolic (aortic) pressure development, using a physiologic concentration of glucose (5 mM) as substrate. The diabetic heart also exhibited impaired cardiac output, which could be attributed entirely to decreased aortic output without any apparent effect on coronary flow. This decrease in ventricular performance was accompanied by a 40% reduction in glucose uptake and a 20% reduction in tissue ATP concentrations even though perfusate glucose levels remained at or near physiologic levels. Perfusion of hearts with 5 mM glucose plus 10(-8) M insulin, with 10 or 30 mM glucose, or 1 mM octanoate reversed the diabetes-related decrease in systolic pressure development, cardiac output, and tissue ATP content. These data demonstrate that the defect in cardiac performance with increased work loads associated with acute insulin deficiency is due to the relative inability of the heart to utilize physiologic concentrations of glucose as substrate for energy production.


Rat pulmonary circulation after chronic hypoxia: hemodynamic and structural features.

In 55 Sprague-Dawley rats (mean wt, 277 +/- 6.2 g) exposed to hypobaric hypoxia (air at 380 mmHg), and 23 weight-matched controls kept in room air, pulmonary and systemic artery pressures were measured daily for 2 wk via indwelling catheters. After each day of exposure, 1 or 2 hypoxic rats, to a total of 20, and 5 control rats were killed during the experiment. In these rats, the pulmonary arterial tree was injected post mortem with barium-gelatin and inflated with formaldehyde solution, and three structural features were quantified microscopically: 1) abnormal extension of muscle into peripheral arteries where it is not normally present (EMPA); 2) increased wall thickness of the normally muscular arteries, expressed as a percentage of external diameter (%WT); and 3) reduction in artery number expressed as an increase in the ratio of alveoli to arteries (A/a). Mean pulmonary artery pressure (Ppa) rose significantly after day 3 of hypoxic exposure (P less than 0.05) and had doubled by day 14; the mean systemic artery pressure (Psa) of hypoxic rats and Ppa and Psa of control rats were unchanged. The level of Ppa correlated with the degree of structural changes; for EMPA, r = 0.84; for %WT, r = 0.64; and for A/a, r = 0.73 (P less than 0.001 in all.


Pulmonary and systemic vascular responses of perinatal goats to prostaglandins E1 and E2.

Effects of prostaglandins of the E series and their metabolites on pulmonary and systemic circulations of newborn and exteriorized fetal goats (anesthetized with chloralose) were evaluated in situ using an isolated perfused left lung lobe preparation. Prostaglandin E1 (PGE1) and, to a lesser extent, prostaglandin E2 (PGE2) infusions resulted in decreases of pulmonary vascular resistance (PVR) of fetal and neonatal goats. Infusions of PGE1 or PGE2 (less than 2 microgram.kg-1.min-1 for 1 min) directly into left pulmonary arterial blood did not affect systemic arterial pressure (SAP). Infusions of PGEs (greater than 2 microgram.kg-1.min-1 for 1 min) resulted in decreases in SAP and heart rate. The dose-response characteristics of the pulmonary circulation in response to PGE1 and PGE2 were not different in fetal and newborn goats. Fetal asphyxia did not alter the dose-response characteristics of pulmonary circulation in response to PGE1. Metabolites (15-keto) of PGE1 and PGE2 had no effect upon PVR or SAP of perinatal goats. These results demonstrate in perinatal mammals 1) vasodilator action of PGE1 and PGE2 on the pulmonary and systemic circulations, and 2) catabolism by the lungs of these prostaglandins.


Transmural distribution of myocardial adenosine content during coronary constriction.

The transmural distribution of tissue adenosine content was determined in samples of the left ventricle of anesthetized open-chest dogs. Transmural tissue samples were obtained and quickly freeze-clamped during either normal coronary perfusion or partial constriction of the inflow tubing to the left common coronary artery. Inner, middle, and outer segments of the samples were assayed for adenosine, inosine, ATP, creatine phosphate, and lactate. In control experiments, there were no significant differences among the tissue contents of the substances in the three segments. However, during a 50.2 +/- 4.7% reduction of coronary inflow, adenosine content of inner, middle, and outer segments was 0.41 +/- 0.007, 0.030 +/- 0.006, and 0.016 +/- 0.003 nmol/mg protein, respectively. Outer segment content was significantly less than either middle or inner content. Lactate distribution was similar to that of adenosine, whereas ATP and creatine phosphate were lowest in the inner segment. Increases of the inner/outer adenosine ratio occurred when the coronary-ventricular pressure index was lower than 1.2. Thus, selective underperfusion of the subendocardium during reduced coronary inflow can result in greater accumulation of adenosine in that region.


Oxygen exchange in the mesenteric microcirculation of the dog.

The relationships of O2 tension in mesenteric lymph (PmlO2) and mesenteric venous blood (PmvO2) to intestinal O2 delivery/O2 consumption (DO2/VO2) were examined after graded hemorrhage (10 dogs), stepwise increments in FIO2 (4 dogs), and regional infusion of papaverine (2 mg/min or IV glucagon (25 microgram/kg) (4 dogs). Measurements included superior mesenteric arterial flow (SMA-Q), PaO2, PmlO2, and arterial and mesenteric venous blood O2 content (CaO2, CmvO2). Intestinal DO2 was calculated as the product of SMA-Q and CaO2, and VO2 was calculated from the Fick equation [SMA-Q X (CaO2 - CmvO2)]. Graded hemorrhage lowered SMA-Q, DO2 and DO2/VO2 and increased splanchnic O2 extraction (CaO2 - CmvO2). Elevation of FIO2 increased PaO2, PmvO2, and PmlO2. Both PmlO2 and PmvO2 varied directly with DO2/VO2 and PaO2, but PmlO2 showed greater sensitivity to PaO2. Papaverine and glucagon both increased SMA-Q, DO2, CmvO2, and PmvO2, BUT PmlO2 rose after papaverine, indicating greater capillary perfusion, and fell after glucagon, suggesting diversion of mesenteric blood flow through arteriovenous shunts. Thus, either PmvO2 or PmlO2 is ordinarily an accurate measure of intestinal tissue oxygenation, but the disparate response after glucagon suggests that PmlO2 is a more reliable indicator.