Repair of interrupted aortic arch and aortopulmonary window in an infant.

The diagnosis and repair in infancy of interrupted aortic arch and aortopulmonary window is described. Using deep hypothermia and circulatory arrest, aortic continuity was established with a prosthetic graft, which was anastomosed to the aortic orifice of the aortopulmonary window. The pulmonary artery side of the aortopulmonary window was closed directly. Postoperative cardiac catheterization demonstrated a good reconstruction. Previous experience with this rare variety of interrupted aortic arch complex is reviewed.


Tracheal agenesis.

Tracheal agenesis is a rare cause of respiratory distress in the neonatal period. Temporary survival depends on ventilation through the esophagus. Thirty-eight case reports of tracheal agenesis (including one from this institution) have appeared in the literature. In this paper, we present the case reports of our 2 patients and review the literature. Tracheal agenesis is associated with a wide variety of congenital anomalies, the most frequent being ventricular septal defect. A new classification encompassing seven types of tracheal agenesis is described.


Effect of cyproterone acetate on the structure of the adrenal cortex.

Adult male C57 BL/6J mice injected with 0.08 mg/g of cyproterone acetate showed an increase in cellular lipid content in the zona fasciculata and zona reticularis of the adrenal cortex. In the perimedullary region, densely staining cells aggregated to form scattered nodules. At the ultrastructural level, in the zona glomerulosa and zona fasciculata the number and size of lipid droplets increased. An apparent decrease in mitochondrial number and size and a noticeable diminution in the amount of smooth endoplasmic reticulum were also noted in the zona fasciculata. It is suggested that cyproterone acetate may have blocked steroid synthesis and increased adrenal cholesterol deposits.


Uptake of 3H-L-carnitine by isolated rat epididymal tubules.

The uptake of radiolabeled L-carnitine has been studied in isolated epididymal tubules from the rat. The uptake of 3H-L-carnitine increases with a temperature coefficient KT of 0.22 nmol carnitine.mg protein-1 in the intermal 22--31 degrees and with a low uptake at 4 degrees C. The uptake of radiolabeled carnitine (as percent) is reduced at high concentrations of L-carnitine, by deoxycarnitine but not by D-carnitine. This uptake mechanism is especially active in the distal caput and corpus segments of the epididymis. Thus, an uptake mechanism for carnitine is present in the epididymal cells which besides the carnitine uptake in spermatozoa is responsible for the dramatic increase in carnitine concentration in cauda epididymis.


Effects of estradiol-17 beta on reproduction in adult male rats.

Estradiol-17 beta (E2-17 beta) treatment induced dose-related reduction of sperm population and eventual azoospermia, atrophy of accessory organs, and suppressed serum LH and testosterone levels. In spite of all these alterations mating behavior was not affected, although the number of implantation sites paralleled the reduction of sperm population, suggesting that the primary detectable response to E2-17 beta treatment is related to the steroidogenic components of the testis and the hypothalamic pituitary axis. The duration of treatment is more critical for the induction of azoospermia in the rat than the total dose of E2-17 beta.


Effect of aromatizable androgens and estradiol on prolactin secretion in prepuberal male rats.

Intact and castrated male rats were injected daily for 10 days, beginning at 35 days of age, with either oil or one of the following steroids: testosterone propionate, dihydrotestosterone benzoate, androsterone acetate, androstenedione, androstandiol, or estradiol benzoate. Doses were 200 micrograms/rat/day for all androgens and 0.5 microgram or 2 micrograms/rat/day for estradiol. Significant increments in prolactin levels (fourfold over control values) in intact and castrated males were obtained after testosterone propionate and androstenedione treatment. Dihydrotestosterone, androsterone, and androstandiol did not induce any changes in either intact or castrated rats. Estradiol-treated males showed a four- and sevenfold increment in serum prolactin with the 0.5- and 2-microgram doses, respectively. These results suggest that androgens have a role in the control of prolactin secretion, particularly those that can be aromatized to estrogens by different tissues, including the hypothalamus.


Human spermatozoa: unidirectional rotation of the tail as indicated by head-to-head agglutinates.

Rotating head-to-head agglutinates of human spermatozoa were always observed to turn counter-clockwise. The phenomenon seems to suggest a unidirectional rotatory component in the tail movement that may be related to the substructure of the axoneme.


Spermotoxic properties of IgG fractions from normal rabbit sera.

The antisperm activities of IgG fractions prepared from normal rabbit sera by three different techniques (ammonium sulphate precipitation, gel filtration, and DEAE-Sephadex absorption) were tested using a cytotoxic assay, and antisperm activity detected in fractions prepared by each of these techniques. The nature of the interactions between sperm and IgG molecules from normal sera, and possible functions of "natural" antisperm antibodies, are discussed.


Proliferation of epithelial cells of vas deferens and epididymis in young adult rabbits.

Epithelial proliferation of the vas deferens and epididymis was studied in rabbits after flash or continuous labeling with DNA precursor by autoradiography. A high proliferative capacity of the epithelium was found: after 2 days of labeling, 11% of labeled cells were found in the vas deferens and 20% in the ductus epididymidis.


Fine structure of fetal human testis and epididymis.

Observations on the structure of the human fetal testis and epididymis at 16 weeks' gestation have been made with the light and electron microscope. The fetal testis is organized into solid cords surrounded by a well-defined cellular investment. The basement membrane is multilaminated with a highly redundant basal lamina. The germ cells rest on thin processes from adjacent Sertoli cells. Intercellular bridges between centrally located germ cells have been observed. The epididymis is remarkably well developed. The tall pseudostratified epithelium lines a discrete duct with a patent lumen. Stereocilia and cilia are seen on apical surface of the principal cells.


Interrelationships between androgens and prostaglandins in the vas deferens of prepubertal rats.

Prostaglandin (PG) levels in the genital tract of male rats were measured at different ages. The vas deferens contained the highest amounts of both PGE2 and PGF2 alpha in young adult or prepubertal animals. PGE2 content increased considerably with age. PGE2 alpha was high in younger animals but decreased markedly at 35 days of age and remained low thereafter. PGE2 and PGF2 alpha were reduced following bilateral castration or hypophysectomy. Testosterone propionate (TP) prevented the postoperative fall in PG levels in a dose-dependent manner. Differences were noted in the relationship between changes in organ weight or PGE2 and pge2 alpha content, and the dose of TP injected, the operation, the time of treatment, and the PG studied.


Rouleau formation and fertility of spermatozoa in guinea pigs treated with cyproterone acetate.

The effects of cyproterone acetate (CA) on fertility of spermatozoa and rouleau formation were investigated in male guinea pigs. Twelve of 15 matings during CA treatment resulted in pregnancy even when rouleaux were absent in ejaculates, indicating that the rouleau condition is not necessary for the fertilizing ability of guinea pig spermatozoa. Examination of epididymides and vasa deferentia revealed that rouleaux diminished progressively with treatment time and were absent in the excurrent ducts of all males during the eighth and ninth weeks of treatment. Following a latent period after treatment, rouleaux were first noted in a specific epididymal region and were present throughout the distal excurrent ducts and ejaculates by 6 wk posttreatment. This sequence of rouleau loss and reappearance in the excurrent ducts suggests that rouleau formation is dependent on a regional epididymal influence that requires androgens. Spermatogenesis was not arrested; however, seminal vesicle and body weights were reduced in treated males.


Patterns of transport and binding of sex steroids.

The seminal plasma-sex steroid binding kinetic was evaluated by measuring the amount of labeled hormone extractable after 5 sec to 100 min of incubation. For testosterone in normal subjects, a peak of binding was reached after 30 sec of incubation. In subjects with severe oligoasthenospermia the kinetic pattern for testosterone was different but similar to the binding kinetic between seminal plasma of normal men and estradiol. The phenomena did not occur with frozen plasma samples.


Clomiphene test and clomiphene therapy in idiopathic male infertility.

Clomiphene citrate, 50 mg/day, was administered to 105 patients with idiopathic azoospermia or oligoasthenospermia. Plasma FSH, LH, testosterone, and in a few cases estradiol were evaluated on day 0 and day 15 of therapy. Twelve other patients with no treatment were assayed in the same way. Statistical analysis demonstrated that, as a group, the infertile male population responds normally to clomiphene administration. On the other hand, three types of individual responses were recorded: complete positive response, dissociated positive response, and negative response. Sixty-nine patients were randomly selected for clomiphene therapy, 50 mg/day for 100 days; however, of 54 who completed the treatment schedule, only 11 showed elevated sperm counts. A study of correlations between hormonal and semen responses to clomiphene indicates that a complete or dissociated endocrine response is not an accurate predictor of possible semen amelioration on long-term therapy; on the other hand, sperm characteristics did not improve in those patients who did not demonstrate a positive hormonal response, mainly testosterone, on the 15th day of therapy.


Sperm-agglutinating antibodies in infertile couples.

In a selected group of 150 infertile couples, sperm-agglutinating antibodies were examined by a microagglutination technique. Sperm-agglutinating activity was observed in sera from 12 men (8%) and 16 women (11%). Antibodies in seminal plasma were demonstrated in 8 men with correspondingly high serum titers. The type of agglutination in these cases was head to tail. Head-to-head agglutination was found in only 3 men, who all had agglutinating activity in serum only. An abnormal postcoital test was found in 57% of the couples, and 13% of the men and 14% of the women in these couples had agglutinating antibodies. A negative postcoital test was related more often to high than to low titer in female sera.


Serum and seminal gonadotropins in normal and infertile men: correlations with sperm count, prolactinemia, and seminal prolactin.

Serum and seminal gonadotropins were evaluated in 30 normozoospermic and 30 oligozoospermic patients. Mean values of basal serum gonadotropins were higher in the oligozoospermic group than in the normozoospermic group: 3.8 versus 1.8 ng/ml and 3.3 versus 2.2 ng/ml for FSH and LH, respectively. Seminal FSH levels were comparable in the normozoospermic and oligozoospermic groups (0.8 versus 0.8 ng/ml, respectively) and were constantly lower than serum FSH levels in both groups. Seminal LH values were constantly higher than serum LH values in the normozoospermic group, whereas in the oligozoospermic group seminal LH values were higher, similar, or lower than serum LH values. However, no significant difference was noted between the two groups for seminal LH values: 3.6 (normozoospermic group) versus 4.1 ng/ml (oligozoospermic group).


Endocrine studies of azoospermia. I. Serum steroid levels in Sertoli cell only syndrome.

Estrone, estradiol, estriol, progesterone, 17 alpha-hydroxyprogesterone, testosterone, and dihydrotestosterone levels were determined in sera of 20 fertile men and 15 male patients with Sertoli cell only syndrome. In men with Sertoli cel only syndrome there was a significant decrease in serum estrone, estradiol, progesterone, 17 alpha-hydroxyprogesterone, and dihydrotestosterone and a significant increase in serum estriol and testosterone. Changes in endocrine profile discussed in relation to the possible role of inhibin.


Free amino acids in semen: measurement and significance in normal and oligozoospermic men.

Measurement of free amino acids in seminal plasma from fertile and infertile oligozoospermic subjects revealed a quantitative reduction of these molecules in infertile patients. Study of the effect of acidic media on seminal plasma appears to suggest the primary role of free amino acids in the "protection" of spermatozoa in the vagina, and the failure of sperm progression in the female genital tract may be due to a decrease of these molecules in semen of infertile patients.


Aerobic and anaerobic bacterial flora in semen from fertile and infertile groups of men.

Semen samples were collected by masturbation under asceptic conditions from men who had sired children within the past 6 mo (group A) and asymptomatic men attending an infertility clinic who had not sired children and whose wives were asymptomatic for infertility (group B). These 109 semen samples were analyzed and cultured for isolation of aerobic and anerobic organisms. Overall, 68% of the specimens had positive bacterial cultures: 54% of the samples from group A were positive and 73% from group B were positive. Mixed bacterial flora were isolated from both groups but in group B they were more varied and present in a higher colony count than in group A. Staphylococcus epidermidis, Staph. aureus, Corynebacterium species, Mycoplasma hominis, and Ureaplasma urealyticum were isolated from group A. Group B revealed these organisma plus Streptococcus pneumoniae type III, Strep. pyogenes group A, Strep. feacalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Candida albicans, Bacteroides species, Peptostreptococcus species, and Eubacterium species. Semen samples from group A were of better quality than those from group B. In addition, the antibacterial effect of seminal plasma from group A was greater than that from group B.


Male sterility associated with familial translocation heterozygosity: t(8;15) (q22;p11).

During the investigation of the family of a subject consulting for primary sterility, the same oligoteratospermia was found in two of his brothers. The three karyotypes of these subjects exhibited an equilibrated reciprocal autosomal translocation t(8;15) (q22;p11), which was also detected in their mother. The karyotypes of the remaining siblings, one brother and one sister, were normal. The semen analysis of the sterile subjects suggests that the block of gamete production occurs at the beginning of spermiogenesis. The chromosomal anomaly, which has no effect on the reproduction of the mother, leads to sterility of the male offspring bearing it.


Experimental comparative study of surgical and needle biopsies of the testis.

Testis biopsy was performed on 78 rats in order to compare needle and surgical biopsies. The rats were autopsied 7, 15, 30, 60, and 90 days after biopsy. Both techniques provided tissue of equally good quality for histopathological examination and led to irreversible hypospermatogenesis of the biopsied and the contralateral testes.


Differences in concanavalin A-FITC binding to rat spermatozoa during epididymal maturation and capacitation.

Rat spermatozoa from the caput epididymis and cauda epididymis, but not from the testis, demonstrated a crescent of greenish fluorescence on the convex surface of the sperm head, as observed by fluorescence microscopy after staining with concanavalin A-fluorescein isothiocyanate. The percentage of spermatozoa displaying this fluorescent zone decreased during incubation under capacitating conditions, both in vivo and in vitro, suggesting that a glycoprotein zone that is capable of binding concanavalin A was removed or altered during the capacitation period.


Scanning-electron-microscopy-x-ray microanalysis and distribution of elements within the head of human spermatozoa.

Scanning electron microscopy (SEM) combined with x-ray analysis has been utilized to investigate the distribution of several elements within the head of human spermatozoon. Despite minor individual variations, a preferential localization of elements (Ca, K, S, P) has been found in the head portion of the cell that corresponds to the post-acrosomal cap and is involved in the fusion of gametes during fertilization.


Testosterone concentration in different functional compartments of the male reproductive tract.

The concentration of testosterone in testicular tissue (TT), spermatic vein blood (SVB), cubital blood (CB), and seminal fluid (SF) was estimated using a radioimmunoassay technique in a total of 50 normospermic, oligozoospermic, and azoospermic men. Testosterone was also determined in cauda epididymis-vas deferens ductus wash fluid (WF) in 6 normospermic men. In 2 oligozoospermic men the testosterone concentration in TT was 556 and 725 ng/g tissue, respectively. In 9 normospermic men the mean SVB testosterone concentration was 473 ng/ml. CB and SF concentrations of this steroid were 6.8 and 0.4 ng/ml in normospermic, 6.4 and 0.5 ng/ml in oligozoospermic, and 4.9 and 0.4 ng/ml in azoospermic men, respectively; the difference among the three groups was not significant. The SVB:CB and SVB:SF ratios in normospermic men were 71 and 1549, respectively, while the CB:SF ratio was 18 in normospermic, 18 in oligozoospermic, and 16.6 in azoospermic men. Testosterone could not be detected in individual specimens of WF, but after pooling of samples a concentration of 0.08 ng/ml WF was estimated. These results demonstrate the relative concentrations of testosterone in the different functional compartments of the reproductive tract in man and facilitate a better understanding of its function.


Thyroid gland and epididymal function in rats--histological study.

An experiment was designed to determine the relation between the hypofunction of the thyroid gland and the structure of the epididymis. The hypothyroid condition was associated with decreased mitosis, insufficient vascularization, decreased nuclear size, and chromatin decondensation. In thyroidectomized rats injected with T3, no morphological changes in the epididymis were observed.


Binding of 17-beta-estradiol to the outer surface and nucleus of human spermatozoa.

The binding of 3H-17-beta-estradiol to human ejaculated spermatozoa and to its subcellular structures was studied. The binding kinetics of the labeled steroid to whole spermatozoa followed a parabolic pattern. Scatchard-type plots showed the presence of high-affinity binding sites (1.56 +/- 0.23 X 10(4) per sperm cell) with an apparent Kd of 6.6 X 10(-10) M. In competition experiments testosterone was partially effective in decreasing 17-beta-estradiol binding, whereas progesterone and 17-alpha-estradiol were ineffective. Study of membrane fractions obtained from estradiol-labeled spermatozoa showed that under saturating conditions 75-84% of the bound steroid was bound to sperm membranes. Nuclear fractions obtained from estradiol-labeled spermatozoa showed only 10% of the total bound radioactivity. When isolated sperm nuclei were incubated in the presence of the purified receptor-17-beta-estradiol complex obtained from the high speed supernatant of human uterus almost no transfer of radioactivity to the nuclei was observed.


Serum immunoglobulins IgG and IgM in the seminal plasma of men with normospermia, oligozoospermia, and azoospermia.

The seminal plasma of eight males with normospermia, seven with oligozoospermia, and eight with azoospermia was examined for the presence of IgG and IgM by means of double-gel immunodiffusion. IgG was present in every seminal plasma sample. The highest titers of IgG were found in azoospermic and normospermic samples, but the lowest IgG titers were seen only in normospermic samples. IgM was detected only in some cases, mainly in the azoospermic group. Testicular biopsy was performed in all the azoospermic patients, but IgM was found only in the cases demonstrating spermatogenic arrest and was not found in the cases with complete spermatogenesis. It is concluded that the IgM present in the seminal plasma was of testicular origin and was associated with injury of the male genital system.


Effects of antigenic competition between sperm autoantigens and ovalbumin upon humoral and cell-mediated immunity and the development of autoimmune aspermatogenic orchitis (AIAO) in guinea pigs.

The effects of antigenic competition between ovalbumin and sperm autoantigens have been studied in guinea pigs. There was an inhibition of antiovalbumin antibody production up to 60 days after immunization. The cell-mediated immunity against ovalbumin was also depressed at day 30. The simultaneous immunization with both antigens has no effect upon the humoral and cell-mediated immunity against spermatozoa. During the period of inhibition of the humoral and cell-mediated antiovalbumin response, the number of animals developing autoimmune aspermatogenic orchitis was diminished compared to those immunized with spermatozoa alone. Later on, there was no difference between the two groups. The transient inhibition of the immune response against ovalbumin can be explained by the particulate nature of the autoantigens. The sperm cells may be easily trapped by the dendritic reticular cells of the draining lymph nodes. This in turn could affect T cell recognition at early stages, orienting it predominantly toward the sperm autoantigens. At day 90 the situation returned to that present in animals immunized with ovalbumin alone.


Varicocelectomy in patients with azoospermia.

The results of surgical treatment of 33 men with azoospermia and varicocele are presented. Microscopic examination of a testicular biospy revealed the Sertoli-cells-only syndrome in nine subjects while degenerative changes in the seminiferous tubules of one or both testes were present in another six persons. In 15 cases decreased spermatogenesis was noted in the testis on the side ipsilateral to the varicocele. In the remaining three subjects the biopsy revealed active spermatogenesis but with absent spermiogenesis. In all cases the changes were equal or more advanced on the affected side. Improvement of the spermiogram was noted in 12 men (34%) and spermatozoa appeared in the ejaculate within 2 to 14 months after operation. In three spouses four gestations occurred. Only in one case where the spermiogram showed improvement were the degenerative changes present in both testes. In the remainder of subjects demonstrating improvement in semen quality, irreversible changes were absent in at least one testis.


Impaired spermiogenesis as a common finding among professional drivers.

The effect of long-term driving upon spermiogenesis was investigated in 2984 patients, including 281 professional drivers. The incidence of pathospermia was significantly increased among the 281 occupational drivers as compared to other professionals. The ratio of severe pathospermia was increased in proportion to the number of years of driving. The deterioration of spermiogenesis was mild among car drivers, but was severe in agricultural-industrial hard machinery and farm equipment drivers. There was a higher incidence of impaired fertility in drivers as compared to other professionals. The possible factors influencing these results are discussed.


Effect of alpha-chlorohydrin on epididymal sperm and epididymal plasma in swine.

Investigation of the contraceptive mechanism of alpha-chlorohydrin was done by analyses of epididymal plasma and certain epididymal sperm characteristics after oral administration of 0, 5, 10 or 30 mg/kg, day of the drug to boars for 15 days. Water resorption in caput epididymidis was slightly decreased in all treatment groups. Sodium, potassium, chloride, glycerylphosphorylcholine levels, and seminal antigens in epididymal plasma were not altered significantly by 10 or 30 mg/kg of the drug. The boars on 5 mg/kg exhibited significantly elevated sodium, potassium, or chloride values in various segments. Motility was significantly lower on corpus and proximal cauda epididymal spermatozoa from alpha-chlorohydrin treated boars. Only boars receiving 30 mg/kg exhibited impaired sperm motility in the distal cauda. The movement of the cytoplasmic droplets to the distal position was retarded in boars on the two highest dose levels. The results suggest that the contraceptive effects of alpha-chlorohydrin in the boar is probably not mediated via an impaired epididymal function.


Acid phosphatase activity in human semen.

Acid phosphatase activity was examined in normal and abnormal human semen of individuals not suffering from testosterone deficiency. No differences in enzymatic activity between the examined groups were observed. The presence of tartaric acid caused an inhibition of about 95% of enzymatic activity.


[Quantification of ventricular volume. Comparative study of 2 angiographic methods].

The left ventricular volumes and the ejection fraction were measured in 78 patients who had different cardiopathies, in more than 50% the diagnosis of ischaemic heart disease of coronary origin was made. Every cineangiocardiogram was carefully observed to find those who had normal and abnormal ventricular contraction. The ventricular volumes were calculated by the Green method and afterwards the results were compared with the values obtained by the Sandler and Dodge method. A very good correlation was found between the two methods and we got the conclusion that although it is preferable to calculate ventricular volumes and the ejection fraction with biplane method or with Saudler and Dodge's monoplane, the results of the present work permit the use of Green's method in calculating ventricular volumes and obtaining confident results, independently of the ventricular contraction type with the exception of those who have large ventricular aneurisms.


[Changes induced by hypertonic solutions in the transportation of calcium by the cardiac reticular sarcoplasma].

In the sarcoplasmic reticulum of the myocardium, celular organell which function is to regulate the cytoplasmic concentration of calcium in contraction and relaxation, we have studied the effect of hypertonic solutions of sucrose between 1 and 6.96 times the normal tonicity in order to observe the behavior of the internal linked or free calcium of this structure, as well as to prove the hypothesis that hypertonic solutions encourage the calcium exit of the sarcoplasmatic reticulum with the resulting signs of contractures. The following results were obtained: 1. The ATP hydrolisis and calcium transport rate are 14% and 90% respectively of the maximum speeds of 10(-5) M in calcium, while for concentrations of 10(-7) M or ess of the said cation, the transport rates and the ATPase do not reach 5% of the maximum values. 2. Between 1 and 2.54 times of the normal tonicity the calcium uptake remains between 400 and 500 nmoles of calcium/mg protein/min, the transported amount of calcium varies between 14 and 16 nmoles/mg protein and the rate of the ATP hydrolysis increases a 37% to 0.4 M in sucrose. 3. Between 0.4 and 1.2 M in sucrose of 2.54 to 6.96 times the isotonicity, the calcium transport rate velocity as well as the ATP hydrolisis are strongly inhibited. The vesicles volume minimizes and the amount of linked calcium remains within the control values, proving that the capacity of linking this cathion is independent from sarcoplasmic reticulum volume. These results show that the sarcoplasmic reticulum is involved in the contractures induced by hypertonic solutions in intact cells, since the osmolarity increase produces changes of volume which results in a decrease of the calcium transportation velocity or in an increase of the exit of said cathion.


[Phonomechanocardiographic study of congestive myocardiopathy].

There were studied 14 patients with congestive myocardiopathy demonstrated by cardiac catheterism at nine, echocardiogramme at five and/or necropsy at four. There were registered mytral insufficiency blowings at thirteen and tricusp insufficiency blowings at five. Of them, there were 11 that presented pathologic noises III and IV. Right apexcardiogramme showed growth of such cavity at the twelve patients that were studied. "a" index of the same precordiogramme had qualitative correlation with systolic pulmonary pression. Apexcardiogramme showed ventricular growth at twelve from thirteen patients and "a" index was also qualitatively correlated with direct deermination of the left ventricule's telediastolic pression. Chronocardiometry was anormal at all of them. Short expulsive period, long pre-expulsive period, expulsion's fraction diminution reckoned by this method and systolic quotient, all of them diminished, translated the cardiac expense fall by "pump" fail. Elongation of pre-isosystolic phase, isosystolic phase, true isosystolic phase, and diminution of ventricular pression's elevation middle velocity and contractility index were consequences of myocardic contraction's bad quality. Decrement of ventricular pression's elevation velocity, added to the important elevation of left ventricle's final diastolic pression determined the "pseudonormality" of IIa-0 interval, and of the integrated isovolumetric pression. Shortening of fast filled's phase is explained by a minor ventricular filled in order to the volume's increase and diastolic pression's increase (Board VII). By last, shortening of Q-IIa interval, coinciding with the cardiac frecuence's increase is explained by catecolamins' increased secretion like compensating mechanism of chronic cardiac insufficiency. Phonomechanocardiogramme is useful for entity's diagnostic and it informs about ventricular disfunction which characterise the suffering.


[Evaluation of radioactive phosphate scintillography in relation to time elapsed after acute myocardial infarct].

A consecutive series of 205 myocardial scans, performed with 99mTc-labeled phosphates, in 185 patients with acute chest pain, were independently evaluated by comparing myocardial concentration intensity of the tracer to that in bone, and by rating this intensity by a six-category rating scale, which imply five criterion levels for calling an image "positive". The optimal criterion level was determined for each day of evolution of illness, as the one in which a shift to a more lax criterion level produces a bigger increment in false-positive results than in True-positive results, and in which a shift to a stricter criterion level causes a greater decrease in true positive results than in false-negative results. In all instances, the optimal criterion level was that with a moderate (2+) myocardial tracer concentration, lower than rib uptake, but with a focal pattern of myocardial distribution of the tracer (2F). By using this optimal criterion level, our results agree with the general consensus in that the procedure's usefullness is restricted to the first five days of evolution of illness. However, our daily statistical analysis showed that the best period to obtain the maximal diagnostic efficiency lies between the third and fourth days after the onset of acute chest pain. A negative result during this period, in patients with ECG and CPK serum concentration compatible with acute myocardial infarction, should be considered of prognostic significance, since it may translate a defficient colateral coronary circulation.


[Clinical, echocardiographic and hemodynamic sequence in cerebral arteriovenous fistula].

It is presented a fatal case of cerebral arteriovenous tube in which it was obtained clinical, radiological, electric, echocardiographic and haemodinamic sequencial information since the birth. Data suggested biventricular overcharge's existence initially without cardiac insufficiency. Finally appeared right ventricular expansion's data and biventricular hypertrophy, with left ventricular fluxe's diminution and cardiac insufficiency's data and shock.


[Evaluation of the electrocardiogram in tricuspid atresia].

Due to the broad behaviour variability of the tricuspid atresia by the defects to which it is associated, the authors propose another classification, based on the position of the great vessels and the characteristics of the pulmonary flow, in addition to the extent of the intracardiac septal defects (atrial septal defect and ventricular septal defect) and the presence of patent ductus arterious. Eleven patients with tricuspid atresia with situs solitus and heart normo-placed are studied for diagnosis confirmation by catheterism or autopsy. Electrocardiograms are studied and observed in two patients with transposition of the great vessels and pulmonary oligohemia, a more evident right auricular enlargement (P of greater voltage in DII and AP heading right in the front plane), the AQRS deviated to the right, up and backwards, with less evidence of the left ventricular power than in other varieties of tricuspid atresia. These characteristics gave a diagnosis useful for this variation. On those patients without transposition and pulmonary flow increase, it is observed that growing appearance of the left auricle is more evident and so is the power of the free wall of the right ventricle (high R in right precordial deviations), the AQRS heads left as in most of the cases, but forward and upwards also. This electrocardiographic information is considered to have great importance to establish a diagnosis of the variations of tricuspid atresia due to associated malformations. Common varieties have already been extensively described by other authors and are not subject to special study. Bibliography on this matter is reviewed.


Impairment of cerebral blood flow autoregulation after hypertonic urea administration.

The effect of unilateral intracarotid administration of 3 M urea on resting cerebral blood flow, arterial blood pressure, perfusion pressure-cerebral blood flow relation, ECoG and Evans blue permeability was tested in dogs. The injection of urea was without effect on ECoG and enhanced the arterial blood pressure temporarily. Cerebral blood flow measured 10 min after the urea injection was not affected. Extravasation of Evans blue was observed in the urea-perfused hemisphere for about 40 min following the urea administration. Cerebral perfusion pressure-blood flow relation for the urea affected hemisphere studied at the time when blood-brain barrier to protein was restored revealed loss of the normal autoregulatory response, despite that it was preserved in the control hemisphere.


Graded flow reductions and O2 consumption of small partially ischemic region of dog left ventricle.

The relationship of O2 supply and demand was studied in a small region of a normally functioning left ventricle in 11 pentobarbital anesthetized open chest dogs. A small myocardial vein was catheterized for flow and venous O2 content measurements. An electromagnetic flow probe and screw-type occluder were placed on the supply artery. Arterial flow reductions produced a lesser decrease in venous outflow. This indicated that collateral channels were functional even with relatively small reduction in arterial flow. Even with complete arterial blockage, venous flow never fell below 13.7% of control. Supply had to be reduced to 80.8% of control before we could predict with 95% confidence that O2 demand would fall. Using this technique, it would be possible to test antianginal agents' actions on the O2 supply and demand relation in a region of flow restricted myocardium.


The effects of phenytoin on motor function in awake cats.

Adult cats were monitored for their performance of a variety of motor functions before and after acute administration of phenytoin (5, 10 or 20 mg/kg) in a schedule in which each animal received all drug doses. The only significant loss in motor function was balance and coordination. Half the animals could not balance or walk along a narrow-edged beam after 20 mg/kg of phenytoin although their performance was not impaired at lower drug doses or on wider surfaces. There were no effects of phenytoin on the righting reflex, flexor reflex, muscle strength, the hopping response, the blind placing response or visually aided placing. The data suggest that phenytoin has a selective effect on higher order neuronal systems involved with balance and locomotion rather than simple reflex pathways.


Inhibitory effects of aromatic oligopeptides on the excitability of identifiable giant neurones of an African giant snail (Achatina fulica Férussac).

Effects of an aromatic tripeptide, L-Lys-L-Phe-L-Tyr and its related dipeptides on the excitability of two identifiable giant neurones (the TAN, tonically autoactive neurone and the PON, periodically oscillating neurone) in the suboesophageal ganglia of the African giant snail, Achatina fulica Férussac, were examined. Of 33 substances examined, three aromatic oligopeptides showed a marked inhibitory effect on the TAN excitability. The critical concentrations of these substances in bath application were: L-Lys-LPhe-L-Tyr (6.6 x 10(-6) approximately 2.2 x 10(-5) M), L-Phe-L-Tyr (9.1 x 10(-6) approximately 3.0 x 10(-5) M) and L-Phe-L-Trp (2.4 x 10(-5) approximately 7.3 x 10(-5) M). The microdrop application (100 micron in diameter) of a solution of the three inhibitory oligopeptides on the TAN surface hyperpolarized the TAN membrane potential and eliminated the spike discharges, in both the physiological and the chloride-free (replaced with acetate) conditions. The current-voltage relationships (I-V curve) of the TAN neuromembrane were measured by the injection of a transmembrane triangular current. The TAN I-V curve measured in the presence of L-Lys-L-Phe-L-Tyr or L-Phe-L-Trp was almost concordant to that of the normal state, if the two I-V curves were superimposed using the firing level as the reference point. The same three aromatic oligopeptides also showed an inhibitory effect on the PON excitability. The critical concentrations needed to produce the effects were much higher than those in the case of the TAN.


[Therapeutic efficiency of penicillamine D in rheumatic arthritis].

1. Penicyllamin is a useful drug in the treatment of some cases of severe rheumatoid arthritis, or in unsuccessful therapeutics. 2. It can lead to remission or to antiinflamatory activity from 20 to 40%. 3. It has a high percentage of iatrogenic effects, but they are generally slight and in a minor percentage the alterations are severe (hematological mainly). 4. Its use requires: a) Correct prescription. b) Careful clinic and paraclinic observation. c) Experience and knowledge in rheumatologic speciality. 5. It may be of use in other connective tissue diseases or in immunological processes with disfavorable consequences to the organism.


[Jugular phlebogram after cardiac surgery].

We studied several parameters of the jugular flebogram in 70 patients who had undergone cardiac surgery. Fifty six of them were on sinusal rithm and 14 in auricular fibrillation. We found among them 39 who had undergone commissurotomy and 16 who had got valvular prothesis. The results of these studies were analyzed and compared with those of 94 normal subjects, taking in consideration the type of surgical intervention and the time elapsed since the operation was performed--the latter in the more numerous group. It is interesting to observe that the sinus grows deeper after the intervention so making the relation xv/yv lower than the unit in 33% of the patients maintaining sinusal rithm. This alteration remained stationary during some years in some of the cases, the results suggesting a greater frequency during the first months of the post-operatory period. We didn't find any relation of this morphologic alteration with the presence of a pericardial construction, pulmonary hypertension, valvular injuries with repercussion on the right heart or modifications on the nenous pressure which we think due to functional changes following the pericardiotomy. It is interesting to observe these mechanographic signs in relation with the post-operatory period of cardiac surgery, but we must avoid hypervaluation of those cases suspicious of pericardial constriction.


Canine gastrointestinal motility effects of prostaglandin F2 alpha in vivo.

Prostaglandin F2 alpha (PGF2 alpha) has recently been implicated in the pathogenesis of some diarrhea in man. PGF2 alpha has been shown to increase the smooth muscle contractile motility of some gastrointestinal muscles in vitro. The in vivo effects of PGF2 alpha on bowel smooth muscles are not clearly delineated. The aim of this study was to investigate the effect of PGF2 alpha on motility of the small and large intestine in the anesthetized dog. Six contractile force transducers were implanted to record contractions from both the circular and longitudinal muscles of the duodenum, ileum and colon. Blood pressure was monitored from the femoral artery and drug injections were made in the femoral vein. The i.v. administration of PGF2 alpha (1 microgram/kg/min) significantly stimulated duodenal circular muscle contractile frequency while depressing the longitudinal muscle contractile tone. In the ileum, PGF2 alpha markedly stimulated circular and longitudinal muscle contractions. In the circular ileum, tone was significantly increased while in the longitudinal ileum it was significantly decreased. In the colon PGF2 alpha did not significantly affect intestinal motility. These results suggest that the diarrheal effects of PGF2 alpha may be related to an effect on small bowel rather than on large bowel motility in the dog.


[Management of persistent ductus arteriosus in the newborn with respiratory insufficiency].

Sixteen newborn babies with severe respiratory distress and patent ductus arteriosus with congestive heart failure are presented. Fifteen of them were premature and one at full term. Management consisted of the accepted medical and ventilatory aids such as digitalis, diuretics, ventilators, etc. Thirteen cases were given indomethacin with clinical closure in five of them (38%). Ten cases underwent surgical closure with 30% mortality. It is recommended that these patients be given indomethacin inicially; if there is no response in 36 hours surgical closure of the duct should be performed prior to progressive deterioration and eventual death.


Studies on the effects of anti-inflammatory action of benzoyl-hydrotropic acid (ketoprofen) and other drugs, with special reference to prostaglandin synthesis.

Effects of ketoprofen, indomethacin, phenylbutazone and acetylsalicylic acid on edema and on in vivo and in vitro synthesis of PGE1, PGE2 and PGF2 alpha in response to carrageenin were studied in rats. Ketoprofen was a potent drug in depressing edema and increased PGE1, PGE2 and PGF2 alpha in response to carrageenin. Ketoprofen also inhibited in vitro synthesis of PGE2 and PGF2 alpha from arachidonic acid. The relative potency of ketoprofen in those parameters was comparable to or greater than that of indomethacin. Phenylbutazone and acetyl-salicylic acid were, however, less potent in this respect. It is suggested that ketoprofen manifests its anti-inflammatory action, at least in part, by inhibiting prostaglandin synthesis.


Developmental change in striatal concentration of homovanillic acid and 3,4-dihydroxyphenylacetic acid in response to apomorphine and haloperidol treatment.

The striatal concentration of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) was estimated following an injection of apomorphine into the developing rat subchronically treated (S.C.) with haloperidol. At the withdrawal stage of haloperidol treatment, striatal HVA and DOPAC levels decreased in the rat aged 14, 24 and 34 days. The haloperidol treatment enhanced the apomorphine-induced reduction of the striatal HVA content at the withdrawal stage in the 24-day-old and 34-day-old rat. These results suggest that a functional link in the feedback control mechanism and dopamine receptors do not fully develop at birth but do so in the early stage of postnatal life.


Effect of morphine on the clearance of endogenous creatinine and blood clinical chemicals in the rat.

The effect of morphine on urine and blood serum concentration of Na+, K+, Cl- and other chemicals was determined using Sprague Dawley rats, previously hydrated with 50 ml/kg of 0.5% NaCl to provoke an increased diuresis. Morphine caused about a 90% decrease in the urine concentration of Na+, K+ and Cl-. This reduction in the urine electrolyte excretion was associated with a small but significant increase in the concentration of the blood Na+ and Cl-. The antidiuresis and the decrease in urine electrolytes caused by morphine was paralleled by a 50% reduction of the endogenous creatinine clearance. An acute dose of 7.5 mg/kg morphine i.p. did not alter the concentration of 13 other clinical blood chemicals with the exception of urea. However, after 18 hr of morphine pellet implantation, a significant increase was found in the blood urea and in the activity of serum transaminases. Lactic dehydrogenases isoenzymes one and two were significantly increased in the blood of rats chronically administered with morphine.


Influence of dimethyl sulfoxide (Me2SO) on vascular smooth muscle.

The present investigation was undertaken to determine the action of dimethyl sulfoxide (Me2SO) on vascular smooth muscle. The rabbit isolated aortic strip preparation was used. In the present study, Me2SO-induced relaxation of isolated rabbit aorta was demonstrated. The degree of relaxation induced by Me2SO was concentration dependent. In the presence of Me2SO the action of norepinephrine, histamine, carbachol and potassium was significantly (P less than .05) antagonized. The control ED50 values were 5.36 + 0.50 + 10(-8) M, 3.38 +/- 0.74 X 10(-6) M, 1.40 +/- 0.82 X 10(-6) M and 2.43 +/- 0.19 x 10(-2) M, respectively. In the presence of Me2SO the ED50 values were 2.23 +/- 0.23 x 10(-6) M, 1.80 +/- 0.40 X 10(-5) M, 1.00 +/- 0.38 X 10(-4) and 4.21 +/- 0.07 x 10(-2) M, respectively. The maximum response of the tissue to the various vasoactive agents was significantly depressed in the presence of Me2SO. When Me2SO was present in the efflux medium, the amount of 45Ca2+ washed out of aortic strips was significantly (P less than .05) reduced when compared to control. The 45Ca2+ efflux studies supported the hypothesis that Me2SO-induced relaxation could possibly result from enhanced binding of activator Ca2+ to high affinity Ca2+ sites.


[Paradox arterial embolism: diagnosis during life].

Paradoxical systemic embolism in the absence of congenital heart disease is often considered a clinical or pathologic rarity. We have recently observed two cases of paradoxical systemic emboli, secondary to massive pulmonary embolization in the presence of a patient foramen ovale in an otherwise normal heart. One case was lethal and the diagnosis was confirmed at autopsy. The other case was diagnosed by cardiac catheterization with dye dilution curves and the patient recovered after recurrences were prevented by the placement of an inferior vena cava umbrella-filter. Paradoxical embolization should be suspected when systemic emboli occur without an apparent cause. The diagnosis can be established by cardiac catheterization, pulmonary angiography and phlebography, and recurrences can be prevented by anticoagulation and partial interruption of the inferior vena cava, when the emboli arise from its territory.


Autoradiographic evidence for passage of vincamine through the blood-brain barrier.

Autoradiographies of the brain and of the cerebellum were performed in 8-month old rats intraperitoneal injection of 3H-labelled vincamine. Only those samples that were processed by freeze-drying or by freeze-substitution gave interpretable results. Some specifically labeled cells were found in the molecular layer of the cerebellar cortex as well as in the internal granular and in the deeper layers of the cerebral cortex. They did not belong to the vascular system. It was concluded that vincamine or its metabolites crosses the blood-brain barrier. Any attempt to explain a possible action of the substance on the brain function should thus also consider the cellular components of the central nervous system and not only the haemodynamics of the cerebral circulation.


The effects of long-term oral treatment with chlorothiazide or furosemide on hereditary diabetes insipidus in rats.

The polyuria of homozygous Brattleboro (BB) female rats is halved when they are given chlorothiazide (about 250 mg/day) or furosemide (about 60 mg/day) orally for one day. The effect of chlorothiazide is still found after 16 days of treatment, whereas the effect of furosemide entirely disappears within 5 days. Both diuretics induce chronically increased plasma renin activity (PRA) and decreased natriuresis as long as they are added to the diet; the effect on Na is more evident during furosemide treatment. Urinary urea content as well as urinary osmolality are increased by chlorothiazide and "free water" output is normalized. Furosemide does not affect urea content and decreases urinary osmolality from the start, as compared to untreated BB homozygotes; it raises "free water" output above BB values.


The influence of 2,2-dimethyl-1-(4-methylphenyl)-1-propanone (SaH 50-283) on food efficiency in rats.

The present studies were undertaken to investigate the possible mechanism(s) of action of 2,2-dimethyl-1-(4-methylphenyl)-1-propanone (SaH 50-283) on food efficiency in rats. SaH 50-283, unlike phenformin (DBI), did not inhibit glucose absorption. However, hyperglycemia induced by oral maltose, lactose or starch load was markedly inhibited in animals pretreated with SaH 50-283. The ED25 for lowering blood sugar levels following an oral maltose load was calculated to be 12 mg/kg. SaH 50-283 could be administered as long as 7 hr prior to a maltose load and still maintain its effect. Food efficiency was significantly (P less than .01) lowered in rats pretreated with SaH 50-283 1 hr prior to a 2 hr feeding period of a purified high carbohydrate diet. It was concluded that the lowering of maltase activity in the brush border of animals treated with SaH 50-283 could partially account for its mechanism of action in lowering food efficiency in rats.


Central nervous system responses to cigarette smoke inhalation in the cat.

Intact, pentobarbital anesthetized cats (with and without brainstem stimulating electrode implants) and unanesthetized Sherrington (gamma-driven) decerebrate cats "smoked" cigarettes of varying nicotine content (0.2-2.5 mg). Nicotine free lettuce leaf cigarettes were used as controls. "Smoking doses" of nicotine base (10-25 micrograms/kg) were administered i.v. for comparison. Smoke inhalation produced motor reflex depression which paralleled the nicotine content of the cigarettes "smoked". Patellar reflex facilitation due to mesencephalic reticular stimulation was reduced by doses of nicotine and cigarette smoke. Cigarettes (2.5 mg nicotine) and doses of nicotine (25-50 micrograms/kg, i.v.) significantly reduced rigidity and patellar reflex amplitude in the gamma-decerebrate cat. Dihydro-beta-erythroidine reduced the nicotine and cigarette smoke induced patellar reflex depression but not the diminution in the rigidity. Smoking doses of nicotine suppressed pentobarbital-induced EEG spindles in acutely prepared cats. Nicotine (10-25 micrograms/kg) produced EEG and behavioral arousal in cats with chronic deep electrodes. It was concluded that cigarette smoke produces its pharmacological effects via its nicotine content.


Evidence for a noncholinergic site for nicotine's action in brain: psychopharmacological, electrophysiological and receptor binding studies.

In an effort to investigate the possibility of noncholinergic nicotine sites within the brain, psychopharmacological, biochemical and eletrophysiological studies were undertaken with nicotine and various newly synthesized derivatives of nicotine and piperidine. When 1-10 micrograms of (-)-nicotine was injected into the region of the lateral ventricle of rats through implanted cannulae, there resulted a characteristic prostration immobilization syndrome, which was accompanied by seizures and tremors at the higher dose range. The (+)-isomer possessed 1/100 the activity of the natural (-)-isomer. The syndrome could be prevented by pre-treatment, intraventricularly, with the N-benzyl and N-p-nitrophenylazido derivates of either nicotine or piperide. A variety of neurotransmitters and psychotropic agents, including acetylcholine and anticholinergic drugs, were without antagonistic action. After nicotine, recordings of spontaneous electrical activity from electrodes chronically implanted into the region of the dorsal hippocampus showed a marked decrease in the amplitude and number of 6-8 sec discharges, and the change was correlated with the behavioral syndrome. Receptor binding studies were performed with rat brain slices and various neural preparations using 3H-nicotine, 125I-alpha-bungarotoxin and 14C-d-tubocurarine as ligands; and only with 3H-nicotine was it possible to demostrate any competitive effect with the various nicotine and piperidine antagonists. It was possible to demonstrate stereospecific or specific nicotine binding to only glass fiber filters and, to a lesser extent, brain slices, but not to cell-free preparations. It was concluded that there existed specific noncholinergic sites for nicotine's action which have not been hitherto described.


Morphine and naloxone effects on olfactory evoked electrographic activity in the amygdala.

This research tested morphine and naloxone effects on evoked EEG and unit activity in 3 opiate-relevant brain areas in response to electrical stimulation of the olfactory bulb in acute, unanesthesized rat preparations. Stimulation evoked clear EEG responses in the amygdala (Amyg) and sometimes in the other areas (caudate and central grey); morphine (15 mg/kg) depressed the Amyg response in some rats, but enhanced it in others, and naloxone usually reversed both kinds of effect. Stimulation caused excitatory unit impulse reponses in the Amyg, and morphine unexpectedly increased the magnitude of the stimulus-evoked excitation; naloxone reversed this enhancement. In control rats, naloxone often decreased the Amyg evoked response. Stimulus-evoked increases in unit activity in the caudate and central grey, when they did occur, were depressed by morphine, but naxoxone had no consistent reversing effect. Both the EEG and unit data indicate that morphine excites, or disinhibits, certain neurons associated with the olfactory-Amyg pathway. There was also some evidence that this pathway contains endorphinergic elements.


Anticonvulsant action in a series of benzimidazole anthelmintics.

In mice, the electroconvulsant threshold was elevated after oral administration of 7 benzimidazole anthelmintics at a dose of 100 mg/kg. This effect was most pronounced with cambendazole which also showed an outstanding duration of action. None of the drugs tested elevated the pentetrazole seizure threshold.


The effect of local anaesthetic agents on afferent and motor nerve impulses in the frog.

In the frog nerve-muscle preparation an attempt was made to determine the sites of local anaesthetic activity. The drugs were applied not only to the nerve fiber, but also to other structures of the nerve. Different blocking concentrations proved that the drugs effected different sites. It was shown that small concentrations of the agents effected the sensory endings of afferent nerves and the muscle spindles. The muscle spindle needed the smallest minimal concentration (Cm) to be blocked. The sensory endings of the C fibers needed a higher one and the motor terminal a still higher one. However, all these concentrations belonged to a similar range (3 X, 4 X and 5 X 10(-5) g/ml bupivacaine or etidocaine). To block the nerve trunk a much higher Cm was mandatory (4 X 10(-4) for C fibers and greater than 5 X 10(-4) g/ml for A alpha fibers). This means that the effect of the local anaesthetic drugs on the nervous system is not single but multiple.


Simultaneous assessment of the effects of trimetazidine on the myocardium and coronary vasculature of the dog.

The effects of trimetazidine on the electrical and mechanical activities of the myocardium were investigated in comparison with the effect on the coronary blood flow in blood-perfused preparations excised from dog hearts. In the sinoatrial (SA) node preparation trimetazidine injected into the sinus node artery increased blood flow and depressed SA node automaticity. In the atrioventricular (AV) node preparation trimetazidine injected into the AV node artery or the anterior septal artery increased blood flow and equally prolonged AV conduction time. In the papillary muscle preparation trimetazidine injected into the anterior septal artery increased blood flow and depressed force of contraction. These cardiodepressant actions occurred in the same range of doses of trimetazidine that exerted the vasodilator action. This indicates that trimetazidine has no selective activity on the coronary vasculature alone. Moreover, the vasodilator effect was more short-lived than the cardiodepressant action. Trimetazidine injected into the anterior septal artery affected ventricular bipolar electrograms. This, taken together with the prolongation of AV conduction time obtained with the same route of administration, suggests that the cardiodepressant action of trimetazidine is ascribed to the local anaesthetic or the membrane stabilizing action rather than to the calcium-antagonistic action.


Myocardial biochemical modifications induced by theophylline with reference to its value as antianginal drug.

Theophylline-induced variations of cardiac metabolism have been investigated by determining concentrations of various energetic substrates and of high-energy phosphates in myocardial tissue, the repeated sampling of myocardium being made possible by an extracorporal circulation system. When administered in therapeutic, or even slightly higher doses, theophylline does not modify triglyceride, glycerol and free fatty acid content or phosphocreatine and ATP content in subepicardial and subendocardial layers, but it does lower glycogen and raise lactate concentration. Consequently, the changes in anaerobic glycolysis due to myocardial ischemia may be enhanced if, as is probably the case, theophylline fails to restore the supply of oxygen.


Relative vasodilator potency of ATP, ADP, AMP and adenosine (Ado) in the cat hind limb.

The relative vasodilator potencies of ATP, ADP, AMP and Ado were determined by bioassay using the skinned and unskinned cat hind limb and comparing the increase in blood flow induced by intra-arterial injection of the adenyl compounds. The relative vasodilator potencies of these agents were similar in either hind limb preparation and were as follows: ADP greater than ATP greater than Ado greater than or equal to AMP. ADP was 2-4 times more potent than ATP and about 200 times more potent than Ado or AMP. When the adenyl compounds were incubated in blood for 2 min before injection, their potencies were not changed in the bioassay. Furthermore, in a chemical assay, after Ado and ADP were incubated for 2 min in cat blood (at the concentrations used in the bioassay) only 3% of Ado and 29% of ADP were metabolized. The results indicate that ATP and ADP exert a vasodilator effect that is not dependent upon their conversion to Ado. This deduction cannot be made for AMP because its relative potency was quite similar to Ado. Since a similar relative potency was found in the skinned and the unskinned hind limb, it is concluded that the vasodilator effect due to ATP and ADP is occurring in skeletal muscle but this does not exclude simultaneous cutaneous vasodilation. The vasodilator effect of adenyl compounds may be related to purinergic receptor activation.


Effect of sodium taurocholate on the hepatic transport of bromsulphthalein in rats.

In anaesthetized, bile duct-cannulated rats the hepatic transport of bromsulphthalein (BSP) showed a dose-dependent increase in response to simultaneous administration of taurocholate (TC). The excretion rates of both free (BSP) and conjugated bromsulphthalein (BSP-GSH) were significantly elevated by TC. The simultaneously given TC decreased the hepatic uptake of BSP and BSP-GSH, but did not influence the conjugation of BSP with glutathione (GSH) or the biliary excretion rate of exogenous BSP-GSH. When the liver was depleted of GSH by pretreatment with diethyl-maleate (DEM), TC increased the excretion of free BSP. In DEM-treated rats free BSP markedly depressed the biliary excretion of exogenous BSP-GSH. When TC was given simultaneously with BSP, the inhibitory effect of BSP on the excretion of exogenous BSP-GSH was significantly reduced. TC also diminished the depressing effect of BSP on state III respiration of liver mitochondria in vitro. It is concluded that this effect of TC may play a role also in the increased biliary excretion of intraphepatic conjugated BSP.


Effect of anesthetics on mortality and kidney lesions caused by hypotension.

Unanesthetized rats and rats anesthetized with a number of anesthetics were bled according to different bleeding schedules. In rats bled for 60 min against 30-50 mm Hg marked protection against mortality and the occurrence of kidney lesions was obtained with pentobarbital-Na, enflurane, halothane and methoxyflurane. Less protection was provided by diethylether while little or no protection was obtained with ethylurethane, trichloroethylene and ketamine. Protection was afforded by pentobarbital-Na in the dose range of 50 mg/kg to 6.2 mg/kg. Slight protection was afforded by dehydrobenzperidol. If pentobarbital-Na was administered after the bleeding the protection was slight. At bleeding pressures below 30 mm Hg the protective effect disappeared for all anesthetics used. Protection was not correlated with either depth of anesthesia, hypotensive effect or reduction of the maximum bleeding volume. However, a correlation was found between protective effect and the retardation of bleeding and the prolongation of survival time caused by the different anesthetics.


Contraction of cat nictitating membrane by tetramisole.

Tetramisole produced a dose-dependent persistent contraction of cat nictitating membrane. This was not significantly altered by prior adrenalectomy or reserpinisation and tyraminisation, but was abolished by prior alpha blockade.


Effect of pentobarbital and urethane on the oxygen tension in the kidney of hypotensive rats.

The effect of bleeding against a predetermined pressure on the relative oxygen tension in the kidney was studied in rats anesthetized with either pentobarbital-Na or ethylurethane. In rats bled either for 30 min against 40 mm Hg or for 60 min against 50 mm Hg, the fall in the relative oxygen tension was significantly less during anesthesia with pentobarbital-Na, a highly potent protector against the occurrence of kidney lesions, than during anesthesia with ethylurethane, which possesses only slight protective potency. When rats anesthetized with ethylurethane were allowed to breathe oxygen the relative oxygen tension in the kidney was increased only for 15 to 20 min and accordingly the severity of the kidney lesions was decreased only when the animals were bled for 30 min at 40 mm Hg. When a number of different bleeding schedules were applied, a correlation was found between the average relative oxygen tension during bleeding and the incidence and degree of kidney lesions observed, irrespective of either the bleeding schedule or the anesthetic used. It is concluded that hypoxia may be a major factor in determining the occurrence of kidney lesions after bleeding and that the protective effect of anesthetics depends on their ability to diminish the fall in oxygen tension in the kidney during bleeding.


Action of glomerulopressin on smooth muscle contraction, probably mediated by the release of prostaglandins.

The effect of glomerulopressin on the increase of the contractile tension developed by isolated strips of stomach fundus, duodenum and bladder of rats, was investigated. Glomerulopressin is a glucuronide whose contractile inducing effect was destroyed by beta-glucuronidase. It was observed that glomerulopressin increases the contractile tension of these tissues, and that this action was not blocked by atropine, cyproheptadine, tranylcypromine, but was inhibited by indomethacin, suggesting that the effect of glomerulopressin action was mediated by prostaglandin release.


A cholecystokinin-like peptide in crude substance P from human and bovine brain.

The subfractions of crude substance P (SP), Fa, Fb, and Fc, were assayed for SP-like activity (SP-LA) and cholecystokinin octapeptide-like activity (CCK-8-LA) using radioimmunoassays (RIAs) and bioassays. Crude SP preparations from total human and bovine brains, cortex, and subcortex (amygdala, substantia nigra) contain CCK-8-LA as well as SP-LA. Most of SP-LA was contained in Fb, whereas most of CCK-8-LA was in Fc. Fa gave ambiguous results. Pharmacological results previously obtained with Fc may reflect the activity of CCK-like peptide(s).


Cholinergic potentiation by ouabain in the contraction of guinea-pig vas deferens through pre- and post-synaptic mechanism.

In the guinea-pig vas deferens, the contractions induced by pilocarpine and arecoline, unlike ACh, were markedly reduced by treatment with procaine (10(-6) g/ml) or hemicholinium (5 x 10(-4) g/ml). These reductions by hemicholinium were completely recovered after exposure to choline. The contractile responses to these three agonists were eliminated by atropine (3 x 10(-8) g/ml) but enhanced by neostigmine (3 x 10(-8) g/ml), though these were not affected at all by tetrodotoxin (3 x 10(-8) g/ml) or hexamethonium (10(-5) g/ml). The contractile responses to ACh, pilocarpine and arecoline were potentiated by ouabain (10(-6) g/ml). These potentiations were more marked in pilocarpine and arecoline than those in ACh. The potentiation in response to arecoline was maximal after incubation with ouabain for 5 min but that to ACh for 45 min. The results suggest that pilocarpine and arecoline act as ACh-releaser in this tissue and that the ouabain-induced cholinergic potentiation may be attributable to a dual mechanism, facilitation of ACh release at presynaptic site and alteration of the membrane excitability at postsynaptic site.


Pharmacological evidence of an interaction between serotonergic and dopaminergic neurons in the control of prolactin secretion in male rats.

The purpose of the present study was to investigate the possible interaction between serotonergic and dopaminergic neurons in regulating prolactin (PRL) secretion. We have examined the effect of quipazine, a drug which has been reported to increase plasma PRL levels by acting through a serotonergic mechanism, on PRL release in rats pretreated with penfluridol or alpha-methyl-p-tyrosine (alpha-MPT). The effect of d-fenfluramine, a serotonin releaser, on plasma PRL levels in animals pretreated with penfluridol was also studied. Penfluridol or alpha-MPT treatments significantly stimulated PRL secretion. Quipazine also increased plasma PRL levels in normal male rats. However, this drug was not able to further stimulate PRL release in animals pretreated with penfluridol or alpha-MPT. Like quipazine, d-fenfluramine increased plasma PRL levels in normal rats but it failed to further stimulate PRL secretion in penfluridol-pretreated animals. These findings support the hypothesis that serotonin may stimulate PRL release through an inhibition of dopaminergic neurons.


Effects of intraventricular and intraspinal 6-hydroxydopamine on blood pressure of DOCA-saline hypertensive rats.

The effects of intraventricular and intraspinal administration of 6-hydroxydopamine (6-OH-DA) on the development and maintenance of DOCA-saline hypertension in rats have been investigated. Intraventricular administration of 6-OH-DA prevented the development of DOCA-saline hypertension in rats, but was ineffective in developed DOCA-saline hypertension. Treatment with intraventricular 6-OH-DA on rise in blood pressure was not secondary to a reduction in salt intake, however, since vehicle-treated rats given a similar reduced salt intake became fully hypertensive. The development of DOCA-saline hypertension was unaffected by pretreatment with intraspinal administration of 6-OH-DA, which produced a virtually complete loss of noradrenaline only in the spinal cord. It is suggested that brain adrenergic neurones may participate in the production of DOCA-saline hypertension but the noradrenergic projections in the spinal cords are not essential for this process.


Acute effects of opiate agonists, partial agonists and antagonists on brain monoamines in the rat.

Single doses of 4.5 mg/kg of the opiate agonist, morphine, the partial agonists, cyclazocine, pentazocine, levallorphan and nalorphine, the antagonists, naloxone and naltrexone and dextrorphan were injected i.p. in groups of rats. Behaviour was noted for 30 min following injection and at this time, brains were removed and levels of noradrenaline (NA), dopamine (DA), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined spectrophotofluorimetrically. Only morphine and cyclazocine altered behaviour and 5-HIAA was the only substance which was consistently elevated by all the compounds tested. These results indicate that a causal relationship between the acute effects of opiate agonists, partial agonists and antagonists on brain 5-HT metabolism and their pharmacological actions is unlikely.


Pharmacological and biochemical studies on a new compound, 2-(7-indeyloxymethyl)morpholine hydrochloride (YM-08054-1), and its derivatives with potential antidepressant properties.

Antidepressant properties of a new indene derivative, YM-08054-1, and its related compounds were compared with those of tricyclic antidepressants and viloxazine. The potencies of YM-08054-1 to inhibit uptake of both 14C-norepinephrine (14C-NE) and 14C-5-hydroxytryptamine (14C-5-HT) by the rat brain synaptosomes were similar to those of amitriptyline and imipramine. Other indene derivatives with an N-alkylated morpholine ring were proved to have less effect on the uptake of either 5-HT or NE than was YM-08054-1. YM-08054-1 was the most potent among all of the tested antidepressants in the inhibition of reserpine-induced facilitation of convulsions as well as in the potentiation of reserpine-induced facilitation of convulsions as well as in the potentiation of 5-hydroxytryptophan (5-HTP)-induced syndromes in mice, though the inhibitory effect of this agent on reserpine-induced hypothermia was weaker than that of either amitriptyline or desipramine, suggesting relatively selective effects of YM-08054-1 upon 5-HT rather than NE uptake in vivo. Neither viloxazine nor iprindole potentiated the responses to 5-HTP. YM-08054-1 was devoid of peripheral anticholinergic activity and exhibited weak local anesthetic effect as well as low acute toxicity when compared with amitriptyline. The results indicate that YM-08054-1 has a novel profile as an antidepressant agent which is quite different from that of either viloxazine or tricyclic compounds.


Effects of ethanol and acetaldehyde on the isolated, blood-perfused canine atrium.

In the isolated, blood-perfused canine atrium preparations, ethanol injected into the cannulated sinus node artery consistently produced dose-dependently negative inotropic effects at a dose range of 0.03 to 1 mmol and negative chronotropic effects starting from 0.1 mmol. Ethanol-induced negative inotropic and chronotropic responses were not blocked by an adequate dose of atropine. When acetaldehyde was given into the sinus node artery, positive inotropic and chronotropic effects were dose-relatedly produced from 0.1 to 30 mumol. Acetaldehyde-induced positive inotropic and chronotropic effects were inhibited by treatment with propranolol. However, these positive effects were not suppressed by either imipramine or tetrodotoxin, although imipramine inhibited tyramine-induced actions and tetrodotoxin suppressed acetylcholine-induced positive chronotropic and inotropic effects in atropine-treated preparations. From these results, it is suggested that ethanol has direct depressant properties on pacemaker and contractile activities, and that acetaldehyde has stimulating properties through adrenergic beta-receptors but neither through tyramine-like action nor nerve excitation.


Possible involvement of indirect mechanism in cardiovascular action of dobutamine in dogs.

Possible mechanisms of dobutamine effects on adrenoceptors were investigated in comparison with tyramine, dopamine and noradrenaline after depletion of noradrenaline stores by ephedrine in dogs. Dobutamine, like other amines, induced pressor and positive chronotropic effects. After repeated treatment with ephedrine (total 40 mg/kg), both effects of dobutamine were markedly depressed. However, after ephedrine, the effects of tyramine were eliminated while those of noradrenaline were slightly decreased. Pressor responses to dopamine were reversed to depressor and positive chronotropic responses were abolished. The results suggest that dobutamine differs from other catecholamines in its mode of action and that its cardiovascular actions may be mediated in part through an indirect action on adrenoceptors.


Pentagastrin stimulates tonic and phasic contractile activity of the canine stomach.

Seven strain gage force transducers were sutured in line to the stomach of an anesthetized dog. Quantification of tonic acitivity and of phasic activity (amplitude, frequency and propagation velocity) on 7 locations from fundus to pylorus resulted in an overall picture of gastric motor activity. Pentagastrin (dose-response curve, 1--8192 ng/kg, i.v.) did not change propagation velocity of the contractile waves, but increased the amplitude and frequency of phasic activity on corpus and antrum. Amplitude increased on the antrum more than on the corpus. Frequency increase was uniform over corpus and antrum. Moreover pentagastrin increased muscle tone (tonic activity) in a specific area on the corpus from 12--18 cm to pylorus. The distinct responses to pentagastrin of tonic activity and of amplitude and frequency of phasic activity indicate that pentagastrin acts on 3 different receptor-effector systems.


The effects of ritodrine on experimentally induced intra-uterine growth retardation in the rat.

The effects of oral ritodrine on artificially induced intra-uterine growth retardation in rats were tested in two animal models. In one model, foetal hypotrophy was induced by reduction of the uterine blood supply on ligating of the left uterine artery. In that experiment no significant inhibition of the foetal hypotrophy could be detected in the ritodrine treated animals, but the corresponding reduction of placental weight was inhibited. In the other model, hypotrophy was induced by hypothermia. Oral ritodrine, given twice daily in a dose of 50 mg/kg from day 7 to day 21 of the pregnancy, antagonized the decrease of the foetal weight produced by hypothermia.


Effect of monofluoroacetate on renal H+ excretion in the rat.

In order to investigate the effect of monofluoroacetate (MFA) on renal H+ excretion, anesthetized rats under mannitol diuresis were given intraperitoneally MFA and some of the acido-basic status parameters were determined. Urinary pH and pCO2 did not change after MFA administration, while urinary flow rate increased. MFA induced a decrease in H+ net excretion and in ammonia excretion. Titratable acidity did not change significantly within the experiment.


Decrease in hepatic blood flow during furosemide-induced diuresis.

The effect of furosemide on hepatic hemodynamics was investigated using electromagnetic flow probes positioned around the hepatic-portal vein and common hepatic artery of anesthetized dogs. Furosemide administration induced a vigorous diuresis and concomitantly decreased total hepatic blood flow. Hepatic arterial blood remained relatively stable. Thus, the decrease in total hepatic blood flow was due primarily to a decrease in portal blood flow. When furosemide was given to animals with ureters ligated to prevent extracellular volume contraction, the drug did not reduce total hepatic blood flow, portal blood flow or hepatic arterial blood flow. Thus, furosemide induces a decrease in total hepatic blood flow that appears to involve a mechanism dependent upon the volume contraction produced by the diuretic. The contraction causes a reduction in venous blood flow but not arterial blood flow to the liver.


Induction of disopyramide N-dealkylation by phenobarbital and disopyramide in rat liver.

An in vitro assay for the determination of the activity of disopyramide-N-dealkylation was developed. This reaction was concluded to be catalyzed by the liver microsomal, cytochrome P-450 centered monooxygenase system. Phenobarbital enhanced the N-dealkylation of disopyramide four fold, and disopyramide itself 1.6 fold, whereas methylcholanthrene was without effect. Disopyramide also increased ethoxycoumarin deethylation 1.6 fold, and had a slight increasing effect on the activity of epoxide hydratase, but did not affect the activities of glutathione S-transferase or UDPglucuronosyltransferase.


Bilirubin excretion pattern in manganese-bilirubin cholestasis.

Impaired bilirubin excretion has been investigated as the possible mechanism for the cholestasis observed following the injection of manganese and bilirubin in rats. We studied the biliary excretion pattern of bilirubin in bile under both cholestatic (manganese plus bilirubin) and noncholestatic (manganese or bilirubin alone; manganese plus bilirubin plus sulfobromophthalein) conditions using a diazotization reaction and this layer chromatography. The accumulation of non-C-1-glucuronides or of nonglucuronoconjugates of bilirubin in bile does not seem to be responsible for the cholestasis. The altered biliary bilirubin metabolic pattern of the azodipyrollic fractions observed during manganese-bilirubin cholestasis appeared to be the result of the cholestasis, rather than its cause.


Metronidazole: a comparative study on the intravaginal absorption, metabolism and disposition of a single product and commercial formulation.

The absorption, tissue distribution, metabolism and excretion of 14C-metronidazole (14C-MTZ) were compared during the first 24 hr upon the intravaginal (ivg) administration of 14C-MTZ, either as a single product (ivg-sp) or as a formulation in the form of a commercial cream (ivg-cp). Peak 14C levels in tail blood samples were reached at 1 and 2 hr in ivg-sp and ivg-cp treated rats, respectively. The rate of decline of blood 14C was faster in the ivg-sp treated rats as opposed to their ivg-cp treated counterparts. At the end of 24 hr, the highest 14C concentrations were observed in the kidneys and livers in both treatment groups. While the liver, kidney and lung concentrations of 14C were similar in both groups, the blood, plasma, brain, fat and skeletal muscle levels of 14C were significantly greater in the ivg-cp treated rats as compared with the ivg-sp treated animals. The combined excretion of radio-activity in the urine and feces of ivg-sp treated rats was significantly greater (77.7 +/- 3.0 vs. 58.0 +/- 2.0) than that of the ivg-cp treated animals. Irrespective of the product applied, about 1% of the applied dose remained in the vagina at the end of 24 hr. Unchanged 14C-MTZ and its five metabolites were detected from 0-12 and 12.24 hr urines of both groups. In comparison with the ivg-cp treated rats, the amount of unchanged 14C-MTZ was significantly greater in 0-12 hr urines of ivg-sp treated rats, whereas a reverse situation was observed during 12-24 hr period. The results of this study show that both products are almost completely absorbed through the vaginal mucosa of the rat; however, the kinetics of MTZ-derived radioactivity are different following the administration of equal amounts of each product.


Effects of cytidine-5' diphosphocholine on norepinephrine, dopamine and serotonin synthesis in various regions of the rat brain.

Administered intravenously to rats, CDPcholine, significantly increases the level and the synthesis rate of dopamine, and the level of tyrosine in the corpus striatum (maximum effect for 50 mg/kg, one hour after administration). CDPcholine decreases the level of serotonin and tryptophan and the synthesis rate of serotonin in the midbrain + hypothalamus and in the brain stem. The increase of the striatum dopamine level and the decrease of the brain stem and midbrain serotonin level are correlated with the recognized antiparkinson and neurostimulant action of this nucleotide.


Activity of some drugs on the electroencephalogram of curarized rats during acute and iterative hypercapnic anoxia Hypotheses on mechanisms of action.

The present study is related to the activity of some drugs in a test of acute and iterative hypercapnic anoxia in curarized rats. The interpretation of the results is based on the values of cerebral resistance to anoxia and on the duration of post-anoxic recovery and cerebral electric silence, i.e. the duration of "nul" electroencephalogram. Results obtained allow us to put forward some hypotheses about mechanisms of action. Cerebral or systemic vasodilation or vasoconstriction both seem to be excluded. Membrane activity as well as an increase in cerebral blood perfusion pressure or an impact at the level of the brain neurotransmitters may be taken into consideration. Furthermore, it is possible that extracerebral phenomena (cardiovascular, respiratory, within the blood cells for example) could interact with cerebral phenomena. It would be necessary to undertake further, more extensive studies if we wish to evaluate the potential interest of the experimental model used and the way in which the drugs proposed as treatment for cerebrovascular diseases or ageing processes work.


Excitation of afferent fibres in the cardiac sympathetic nerves induced by coronary occlusion and injection of bradykinin. The influence of acetylsalicylic acid and dipyron.

Afferent impulse activity was recorded in single fibres of the inferior cardiac sympathetic nerve of the cat. When the descending branch of the left coronary artery was ligated for 60 sec an enhancement of afferent impulses was recorded. Elevations in discharge frequency were also induced by injecting bradykinin, epinephrine, and isoprenaline or by general hypoxia due to interruption of the artificial ventilation. When these procedures were after pretreatment with the analgesic agents, acetylsalicylic acid or dipyron a reduction in spike discharge was observed only with bradykinin after application of acetylsalicylic acid. No influence of these pretreatments on the effects of coronary occlusion, general hypoxia and injection of epinephrine and isoprenaline could be observed. These results suggest that bradykinin does not predominate as mediator substance in eliciting ischemic heart pain.


Interaction of cardiopulmonary chemoreceptor (Bezold-Jarisch) and somatosympathetic reflexes.

Cardiopulmonary chemoreceptor (Bezold-Jarisch) and baroreceptor reflexes produce similar overall cardiovascular effects although central integrating mechanisms are not identical. In view of recent reports emphasizing the complexity of baroreceptor mechanisms, the influence of both reflexes on spontaneous sympathetic outflow as well as their interaction with the somatosympathetic reflex were compared in anesthetized cats. The chemoreflex and the baroreceptor reflex were activated by i.v. injection of veratrine and norepinephrine, respectively, and both inhibited spontaneous efferent sympathetic nerve traffic. Stimulation of somatic nerves produces a two-component reflex potential in sympathetic nerves. Activation of cardiopulmonary chemoreceptor and baroreceptor reflexes inhibited the amplitude of the initial (spinal) phase of this somasympathetic reflex slightly and greatly attenuated the secondary (supraspinal) component. These experiments demonstrate that the cardiopulmonary chemoreceptor and baroreceptor reflexes exert similar effects on the somatosympathetic reflex and that the former two reflexes may influence sympathetic mechanisms at spinal as well as supraspinal levels.


Distribution and characterization of the adrenoceptors in dog coronary arteries.

Effects of catecholamines were studied in vitro on different portions of the left coronary artery of the dog. Adrenaline, noradrenaline and isoprenaline produced dose-related contractions in the common portion of the coronary artery which were blocked by phenoxybenzamine. The proximal portions were relaxed by noradrenaline and isoprenaline, but contracted or relaxed by adrenaline following an initial transient contraction. The contraction was blocked by phenoxybenzamine and the relaxation was blocked by propranolol. Adrenaline, noradrenaline and isoprenaline caused only relaxations which were blocked by propranolol in the distal portion and in the small branches. In coronary, femoral and tracheal strips contracted previously by KCl with or without a phenoxybenzamine pretreatment, isoprenaline produced dose-dependent relaxations. The dose-response curves for isoprenaline were shifted to the right on treatment with practolol. The blocking effects of practolol were nearly ten times potent in the coronary artery in comparison with the femoral artery and the trachea. The results indicate that the common portion mainly possesses alpha-adrenoceptors, the proximal portion contains both alpha- and beta-adrenoceptors, and that beta-adrenoceptors dominate in the distal portion and small artery branches. It is also shown that the beta-adrenoceptors in the coronary vessels differ from the femoral and tracheal beta-adrenoceptors in pharmacological feature.


Role of extracellular calcium in isometric contractions of the SHR aorta. Influence of age and antihypertensive treatment.

Isometric contractions induced by noradrenaline (NA), 1.8 X 10(-5) M or by potassium (K+), 127 mM were studied in paired ring-preparations of the thoracic aortae from spontaneously hypertensive rats (SHR) and age-matched normotensive Kyoto-Wistar rats. In rats aged 8--16 weeks, NA-induced contractions were significantly more dependent on extracellular calcium in preparations from the SHR than from the NWR, whereas K+induced contractions showed no difference. Relaxation studies revealed differences between SHR and NWR also in K+-induced contractions. Comparison of responses in NWRs aged 3--4 months and 10--12 months showed a significant increment in Ca++-dependency with age. This age-related difference was less pronounced in SHRs, but the effect of blockade of Ca++-influx by nifedipine was significantly stronger in the old than in the young SHR-aorta. Treatment with propranolol or hydrochlorothiazide + timolol + minoxidil for 4--5 months caused no significant reduction of blood pressure and no change in Ca++-dependency. In contrast, treatment with verapamil (60 mg/kg/day) for 12 months resulted in a significantly lower blood pressure in the treated SHRs than in their controls. A trend towards "nomrlization" of the Ca++-dependency in verapamil treated rats was also observed. The results suggest that an increased Ca++-dependency in the SHR aortae is present already at the age of 8--16 weeks, but becomes more pronounced with age. As an age-related increment in Ca++-dependency is also found in NWRs, the results suggest that the SHR aortae are "functionally" older than the NWR vessels already in young animals. Calcium antagonists seem to be effective in lowering blood pressure in SHRs and represent a promising approach to the treatment of hypertensive vascular disease.


Effects of intracerebroventricularly injected "nerveside" on free behaviour and EEG activity of rats. A pilot study.

"Nerveside", a phosphopeptide extracted from ox and dog brains by Toh, was injected into one lateral ventricle of four rats previously prepared for the injection as well as for recordings of the EEG of the dorsal hippocampus (field CA1) and sensorimotor cortex. "Nerveside" in doses of 150 and 300 micrograms/animal induced a transient stereotyped behaviour and longer lasting alterations of the EEG activity and vigilance pattern. Wakefulness was increased, slow wave sleep and REM-sleep were diminished. The vigilance pattern was characterized by rapid shifts between all three vigilance states. The effects of "nerveside" were visible for about three hours.


On the cardiac efficacy of helveticosol-3',4'-di-nitrate, a new glycoside.

The cardiac and extracardiac effects of a new glycoside, helveticosol-3',4'-di-nitrate (HdN), were compared with those of helveticosol (H) and helveticosol-3',4'-di-propionate (HdP) in isolated guinea-pig heart preparations, in volunteers and dogs. In the atrium and heart, HdN produces positive inotropic effects at the same concentrations as H and at 10 times lower concentrations than HdP. In the heart, the difference between equieffective concentrations of HdN and HdP is smaller, but this is true only for the concentration required to produce the maximum inotropic effect. In the anaesthetized dog equieffective cardiac effects are obtained after oral admiinistration of the glycosides in the ratio 1 : 2 : 0.5 (HdN : HdP : H). After administration of HdN and HdP at equal ratios, no significant differences were observed between the toxic effects in conscious dogs or in the extent of shortening of STI in volunteers. Replacement of the hydrophobic subsituent propionate for the more hydrophilic nitrate residue causes slight changes in cardiac efficiency.


Studies on the inactivation of vasoactive polypeptides by pyridoxal-5'-phosphate.

The pharmacologically active peptides bradykinin (BK) lysylbradykinin or kallidin (LBK) and methionyl-lysylbradykinin (MLBK) were shown to react with pyridoxal-5'-phosphate (PLP) forming Schiff bases; upon reduction with sodium borohydride they were transformed into stable phosphopyridoxyl-kinins (PP-BK, PP-LBK and PP-MLBK). Amino acid analysis showed that the N-terminal alpha-aminogroup of the three kinins were efficiently blocked by phosphopyridoxyl groups: 98.8% for BK; 95.2% for LBK and 98.9% for MLBK. Guanidinium groups did not react with PLP. Estimated by guinea-pig ileum and the vascular permeability of rat skin assays respectively- the PP-kinins had the following average activities compared to the respective kinins: PP-BK, 0.20 and 0.16; PP-LBK, 0.05 and 0.17; PP-MLBK, 0.10 and 0.12. Isoleucyl5-angiotensin II and valyl5-angiotensin I were shown to be 50% inactivated (guinea-pig ileum assay) by reaction with PLP and reduction with borohydride.


The role of endogenous prostaglandins in the renal vascular response to clonidine.

The effect of clonidine has been studied in the isolated perfused rabbit kidney. The drug produced a dose-dependent increase in perfusion pressure and in urine flow both of which could be blocked by phentolamine. Addition of acetylsalicylic acid to the medium caused an increase in perfusion pressure and a decrease in urine volume induced by clonidine. Further addition of prostaglandin E2 to the medium prevented the changes induced by acetylsalicylic acid. These results were taken as evidence that clonidine can increase the biosynthesis of prostaglandins which could act as a modulator system for the effects of the drug in the kidney.


Failure of phenoxybenzamine and pimozide to diminish changes in oxygen consumption and body temperature produced by caffeine.

The effects of a dopamine antagonist (pimozide) and an alpha-adrenergic receptor blocking agent (phenoxybenzamine) on caffeine-induced changes in oxygen consumption. body temperature, blood glucose and non-esterified fatty acids (NEFA) were studied in mice. Both drugs had no effect on the increase of the oxygen consumption produced by caffeine. The decline of the body temperature induced by caffeine was not significantly influenced by pimozide, while phenoxybenzamine accentuated the hypothermic effect of caffeine. The results indicate that alpha-adrenergic and dopamine receptors do not play an essential role in the caffeine-induced stimulation of overall metabolism and hypothermia.


A study of the effect of vinca alkaloid 'vinblastine' on gastrointestinal motility in rats.

Vinblastine an alkaloid of the periwinkleplant (Vinca), produced marked alterations in the motility of gastrointestinal tract in rats. The alkaloid reduced the rate of gastric emptying and slowed the transit of test substance through the small intestine. The effect of the drug on gastric emptying appeared to be dose-dependent. The latency of drug action on gut motility was found to be 5--10 min, when injected through the jugular vein.


Chromatographic fractionation and characterization of the active platelet aggregation inhibitory factor from bromelain.

Isolation and characterization of the platelet aggregation inhibitory factor of bromelain have been presented in this study. Commercial bromelain consists of 3 major components as demonstrated by discontinuous sodium chloride gradient chromatography through carbixymethyl-sephadex column. Fraction I constituted approximately 19% of the total fraction. This fraction had no proteolytic activity or platelet aggregation inhibiting activity, but showed peroxidatic activity. Fraction II and III, which constituted the remainder of the fraction eluted with 135 mM and 800 mM NaCl concentrations, respectively, showed both proteolytic and inhibition of platelet aggregation, but no peroxidatic activity. Immunoelectrophoresis and polyacrylamide electrophoresis showed fraction I with beta-mobility while fraction II and III demonstrated gamma-mobility. It is suggested that the proteolytic activity is associated with the inhibition of platelet aggregation, since oxidation of fractions II and III with sodium tetrathionate abolished both activities. The mechanism of inhibition of platelet aggregation by bromelain is presently unknown but may involve its influence on the prostaglandin synthetic pathway of platelets.


Serum electrolyte and acid base composition. The influence of graded degrees of chronic renal failure.

Data from 41 ambulatory patients with graded degrees of uncomplicated, chronic renal failure were used to define the quantitative relationship between serum acid-base and electrolyte composition and the serum creatinine level. Even in patients with only moderate renal insufficiency, serum total carbon dioxide (tCO2) content was reduced significantly. This early fall in tCO2 was offset by an increase in serum chloride (Cl-), serum undetermined anton concentration (A-) remaining normal. In patients with more severe degrees of renal insufficiency, further decrements in tCO2 occurred that were proportional to the increment in serum creatinine. These latter decrements in tCO2 were associated with equivalent increments in A-, serum Cl- remaining unchanged at the elevated level observed during moderate renal insufficiency. Confidence limits of 95% for tCO2 and A- were calculated from the data.


Leukopenia and hypoxemia. Unrelated effects of hemodialysis.

Hemodialysis-induced hypoxemia has been attributed to membrane-related complement activation leading to pulmonary leukostasis and to hypoventilation secondary to carbon dioxide losses via the dialyzer. We have separately assessed the role of membrane- and dialysis-related factors by using different dialyzers and sequential ultrafiltration and hemodialysis with first-use cellulose dialyzers produced both leukopenia and hypoxemia. With reused cellulose and polyacrylonitrile dialyzers, hypoxemia still occurred, but without leukopenia. Ultrafiltration produced leukopenia and no changes in Pao2; during the subsequent hemodialysis, hypoxemia developed as the leukocyte count increased by 50%. Our data indicate that leukopenia and hypoxemia are unrelated effects of hemodialysis, and favor hypoventilation as the major determinant of hypoxemia during hemodialysis.


Analysis of clinical susceptibility bias in case-control studies. Analysis as illustrated by the menopausal syndrome and the risk of endometrial cancer.

Epidemiologic studies of causes of disease rarely contain adjustments for inequalities in diseases susceptibility caused by baseline differences in clinical phenomena. In the controversial association between estrogens and endometrial cancer, the menopausal syndrome was suspected as an independent risk factor for the development of endometrial cancer, irrespective of estrogen use. To investigate this suspicion, personal interview data from a case-control investigation were collected and analyzed. The odds ratio for the association between menopausal symptoms and endometrial cancer was 1.12 and 0.85 for two different sets of cases and controls assembled at the same institution. When the data were partitioned according to estrogen usage, the odds ratios became consistently less than one. The results suggest that the menopausal syndrome is not a risk factor for endometrial cancer.


Serum thyroid hormone levels in patients with liver disease.

Levels of serum triiodothyronine (T3), reverse triiodothyronine (rT3), and thyroxine (T4) were determined in 29 patients with alcoholic cirrhosis, seven patients with acute hepatitis, and 14 control patients hospitalized for chronic disease. Serum T3 levels were decreased significantly and serum rT3 levels increased significantly in the patients with alcoholic cirrhosis. Serum T3 and T4 levels were lower and rT3 levels higher in the cirrhotic patients who died within three months of the study compared with those who survived. A combination of prothrombin time, aminopyrine breath test results, and rT3 and T3 determinations gave significant predictive information about survival in patients with cirrhosis. The data suggest that assay of serum thyroid hormone levels together with prothrombin time and the aminopyrine breath test may be helpful in assessing the course and prognosis of patients with liver disease.