摘要:

On the basis of the results of a variety of teratogenicity studies in Sprague-Dawley-derived albino rats, carried out over several years in our laboratory, an appraisal of the principal experimental procedures is set forth. Various categories of chemicals were used for the evaluation of dosage-related teratogenic potency. Salicylate, prednisolone, cyclophosphamide, 5-hydroxytryptamine (serotonin), glycinonitrile, and dimethylformamide have proven to be teratogenic under certain of the experimental conditions used. Particular differences in the embryotropic effects of acetylsalicylic acid were caused by qualitative and quantitative changes of the vehicle. Fetal morphological abnormalities, classified either as ‘malformations’ or as ‘anomalies’, may occur independently of overt maternal toxicity and/or embryotoxicity. Further, they may be closely correlated with general inhibitory effects on growth. Drugs may affect developing tissues and organs selectively due to their pharmacological activity and/or specific organ toxicity. The limitation of maternal treatment to a very short period of gestation may disclose a specific susceptibility of developmental stages of the embryo or fetus. Finally, the importance of data collected from a historical control population to the interpretation of teratogenicity data is emp

ISSN:0031-7012    

DOI:10.1159/000138688

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

The calcium channel antagonists verapamil, gallopamil and nifedipine were tested for their effects on acid secretion stimulated by histamine and dibutyryl-cyclic AMP in isolated and enriched guinea pig parietal cells, on adenylate cyclase activity mediated by histamine H2 receptors, on histamine-stimulated increase in cytosolic-free Ca2+ concentration [Ca2+], on gastric H+/K+-ATPase activity and on H+/K+-ATPase-mediated proton uptake in intact gastric membrane vesicles. Verapamil and gallopamil impaired all cellular and enzymatic test systems studied. Both drugs affected with highest potency the acid secretion in the parietal cell preparation (IC50: 1–2 µmol/l) and the H+/K+-ATPase-mediated H+ uptake in gastric membrane vesicles, whereas their inhibitory action was less pronounced on adenylate cyclase and on histamine-induced increase in cytosolic-free [Ca2+]. The type of interaction found in the gastric membrane vesicle preparation indicates that both drugs act as protonophores. Nifedipine was less effective as an inhibitor of acid secretion in the parietal cell preparation and in reducing proton concentration in isolated gastric membrane vesicles. The drug failed to block adenylate cyclase and H+/K+-ATPase activity. Since nifedipine is a more effective calcium channel blocking agent but a less lipophilic drug than verapamil and gallopamil, we conclude that the antisecretory activity of calcium channel antagonists in vitro is mediated by a nonspecific, i.e. a protonophoric, action. We suggest that verapamil exhibits its antisecretory activity in vivo partially by its protonophoric action at the secretory membrane of the parietal cell, whereas the decrease in acid secretion by nifedipine is not mediated by this mechani

ISSN:0031-7012    

DOI:10.1159/000138633

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

Pinacidil and diazoxide induced concentration-related relaxations of the longitudinal muscle of the mouse distal colon. The relaxing effects of pinacidil and diazoxide were unaffected by tetraethylammonium, but were antagonized by tolbutamide and glibenclamide. Relaxations provoked by nifedipine were not counteracted by the two hypoglycaemic sulfonylureas. It is tempting to suggest that the relaxation response to pinacidil and diazoxide could reflect the ability of both compounds to interfere with membrane K+ channels sharing common pharmacological properties with the K+ATP channels recently described in other tissues.

ISSN:0031-7012    

DOI:10.1159/000138634

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

Thromboxane A2 (TXA2) is a bioactive metabolite of arachidonic acid which produces vascular smooth muscle contraction and blood platelet aggregation. The goal of this study is to establish whether there are age-dependent differences of vascular contractility to TXA2. Thoracic aorta of F-344 rats of age 4–6 months (young) and 22–23 months (old) were used as a model to examine responses to U46619 [(15S)-hydroxy-11α, 9α-(epoxymetha-no)prosta-5Z,13E-dienoic acid; a TXA2 agonist] alone or in the presence of prostanoid (SQ 29,548) or nonprostanoid (trimetoquinol, TMQ) endoperoxide/TXA2 receptor antagonists. Maximal contractile responses (84 and 89% relative to KC1) and EC50 values (23 and 55 nmol/l, respectively) to U46619 were the same in aortic strips of young and old animals. Experimentally determined pA2 and pKB values for SQ 29,548 and TMQ as antagonists of U46619-mediated contraction were unchanged in aorta of young (9.09 and 5.83, respectively) and old (9.41 and 6.10, respectively) rats. We conclude that the reactivity and population of TXA2 receptors in rat vascular smooth muscle are unaffected by the aging pr

ISSN:0031-7012    

DOI:10.1159/000138635

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

In the pithed rat we investigated the cardiovascular properties of d,l-nebivolol and its enantiomers. We used the increase in heart rate elicited by (–)-adrenaline and (–)-noradrenaline as a model for studying β1-adrenoceptors. A leftward shift of the logarithmic dose-pressor response curve of (–)-adrenaline reflects β2-adrenoceptor-blocking properties. The blood pressure responses of methoxamine, B-HT 920 and serotonin (5-HT) were studied in order to test whether d,l-nebivolol has α1-, α2- and 5-HT2-receptor-blocking properties. Furthermore, the interaction of d,l-nebivolol with the peripheral sympathetic neurotransmission was investigated in pithed rats by electrical stimulation of the spinal cord. d,l-Nebivolol and d-nebivolol (threshold concentration 10–8 mol/kg) were demonstrated to be selective β1-adrenoceptor antagonists. l-Nebivolol was a factor of 1,000 less potent as β1-adrenoceptor blocker. Up to a dose of 10-5 mol/kg, d,l-nebivolol appeared to have neither α1-, α2 β2-, 5-HT2-, angiotensin II-receptor antagonistic, calcium entry blocking, converting enzyme inhibiting nor direct vasodilating properties and did not interact with the sympathetic neurotransmission in the vascular wall. An explanation for an antihypertensive effect independent of β-adrenoceptor blockade as found in spontaneously hypertensive rats and man could not be found in this model, therefore we suggest that this blood-pressure-lowering effect does not originate from conventional peri

ISSN:0031-7012    

DOI:10.1159/000138636

出版商:S. Karger AG    

年代:1990

数据来源: Karger

ISSN:0031-7012    

DOI:10.1159/000138637

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

The effects of high salt intake (1.0% NaCl in the drinking water) on rats made hypertensive by 2-bromoethylamine hydrobromide (BEA) treatment (200 mg/kg, i.p.) were examined. BEA-induced medullary necrosis resulted in a mild hypertension (146 ± 5 mm Hg) that was exacerbated by 4 weeks of high salt intake (163 ± 6 mmHg). BEA-treated rats had significant salt-induced increases in urinary norepinephrine excretion and hypothalamic and brainstem norepinephrine content, that were not present in BEA-treated rats drinking tap water or control rats drinking saline. BEA treatment in combination with increased salt intake produced a decrease (p < 0.05) in renal dopamine content and adrenal norepinephrine stores relative to BEA treatment alone. BEA treatment also significantly decreased renal norepinephrine stores and dopamine binding sites irrespective of salt intake. Renal α2-adrenergic receptors and central nervous system stores of dopamine and serotonin were unaffected by BEA treatment. Renal function was well preserved as indicated by normal creatinine, glucose and protein excretion; however, significant (p < 0.05) disruption of the urinary concentrating mechanism was present. These studies suggest that BEA-induced hypertension has a neural component that is exacerbated by high salt intake. The primary defect in BEA hypertension appears to be the lack of circulating antihypertensive lipids that attenuate the ability of salt loads to simulate sympathetic nervous system activi

ISSN:0031-7012    

DOI:10.1159/000138638

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

The substituted benzamides or orthopramides are used to treat gastrointestinal and psychotic disorders. The orthopramide clebopride, a potent dopaminergic antagonist, blocks emesis in dogs and stereotyped behavior in rodents. Since the release of prolactin is inhibited by dopamine, antidopaminergic drugs may be useful to increase lactation in nursing mothers. The present work examines the morphological and histological alterations produced by long-term treatment of puerperal and virgin female rats with clebopride. Clebopride induced significant hyperplasia of parenchymal secretory units and stimulated milk secretion in both groups of rats. However, only in virgin rats was mammary weight significantly increased.

ISSN:0031-7012    

DOI:10.1159/000138639

出版商:S. Karger AG    

年代:1990

数据来源: Karger

ISSN:0031-7012    

DOI:10.1159/000138640

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

We studied the effects of arachidonic acid (AA) in the pulmonary and systemic circulations of rabbit under constant blood flow conditions in vivo, using a total heart bypass model. AA (100–150 µg/kg) injected into the pulmonary artery produced a dose-dependent increase in pulmonary arterial pressure (Ppa), without altering systemic arterial pressure (Psa). Conversely, injection of AA into the aorta reduced Psa in a dose-dependent fashion, but did not significantly alter Ppa. FPL55712, a leukotriene receptor antagonist, did not affect any of these responses to AA. Indometacin, a cyclo-oxygenase inhibitor, totally prevented the pulmonary pressor response to intravenously administered AA and reduced the systemic depressor response to intra-arterially administered AA. The thromboxane A2 synthetase inhibitor, 7-(l-imidazolyl)heptanoic acid, totally abolished the increase in Ppa in response to intravenously adminstered AA, but did not alter the dose-dependent decrease in Psa in response to intra-arterially administered AA. These results suggest that in rabbits (1) AA produces pulmonary vasoconstriction and systemic vasodilation, (2) blood metabolites of AA mediate these effects and are then rapidly deactivated, and (3) AA-induced pulmonary vasoconstriction appears to be largely dependent on thromboxane A2

ISSN:0031-7012    

DOI:10.1159/000138641

出版商:S. Karger AG    

年代:1990

数据来源: Karger