Archives internationales de pharmacodynamie et de therapie最新文献

The aim of this study was to assess the pharmacokinetics and subsequent pharmacodynamic interaction of MPC-1304, a dihydropyridine Ca2+ antagonist, with other drugs in animal experiments. We measured the systolic blood pressure and heart rate of conscious spontaneously hypertensive rats implanted with battery-operated biotelemetry devices after combined administration of various drugs. Cimetidine (10 mg/kg) did not affect the reduction in systolic blood pressure and the increase in heart rate induced by MPC-1304, whereas it significantly increased the plasma concentration of a metabolite of MPC-1304 (M-1) compared to that detected when MPC-1304 was administered alone. When MPC-1304 was consecutively administered in combination with rifampicin (400 mg/kg) for 9 days, the plasma concentrations of MPC-1304 and of M-1 significantly decreased compared to those found when MPC-1304 alone was given. In spite of these reductions in plasma concentrations, rifampicin did not attenuate the hypotensive action induced by MPC-1304. When prazosin, reserpine, or methyldopa was administered in combination with MPC-1304, the hypotensive action was enhanced as compared to that by MPC-1304 alone or to that by the co-administered drug used alone (prazosin, reserpine, or methyldopa). Quinidine (10 mg/kg) affected neither the hypotensive action induced by MPC-1304 nor the plasma concentrations of MPC-1304 and M-1. These results indicate that cimetidine and rifampicin interact with MPC-1304 pharmacokinetically, without apparently changing the hypotensive action of MPC-1304, whereas quinidine does not affect the metabolism of MPC-1304, and that other hypotensive drugs, such as prazosin, reserpine, and methyldopa, potentiate the hypotensive action of MPC-1304.

This study describes the receptor-binding characteristics, antimuscarinic and antinicotinic activities of 2 beta-(2'-phenyl-2'-cyclopentyl-2'-hydroxy-ethoxy)tropane (beta-PCT) and its four optical isomers. Both arecoline-induced tremor and nicotine-induced convulsion in mice were antagonized by beta-PCT and its optical isomers. These compounds were less potent than atropine in their antimuscarinic potencies, but more potent than atropine in their antinicotinic activities. The isomer with the 1S-2 beta-2'R configuration was about one order of magnitude more potent than the isomer with the 1R-2 beta-2'S configuration in their antimuscarinic activity, but the antinicotinic potencies of these compounds did not differ significantly. The order of potencies of beta-PCT and its optical isomers to displace the specific binding of [3H]quinuclidinyl benzilate to muscarinic receptors was similar to that of their antimuscarinic potencies. The binding of [3H]nicotine to central nicotinic receptors was not inhibited by these compounds. The findings indicate that beta-PCT and its optical isomers are useful affinity ligands to examine the biochemical and functional characteristics of brain cholinergic receptors.

The effects of R-84760 [(3R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-l-indancarb onyl] tetrahydro-1,4-thiazine hydrochloride] on nociception, locomotion and respiration were examined in rats. R-84760 induced a potent antinociceptive effect in the formalin test. The potency was 930 and 1500 times higher than that of U-50488 and morphine, respectively, when injected subcutaneously. Intracerebroventricular and intrathecal injection, as well as subcutaneous administration of naloxone antagonized the antinociceptive effect of R-84760, suggesting the sites of action of R-84760 were at the spinal and supraspinal levels. R-84760 disturbed the rotarod performance at doses 16 times higher than those needed for antinociception. R-84760 did not affect the arterial blood Pco2, Po2 and pH at a supramaximal dose for antinociception.

We investigated the role of the 5-hydroxytryptamine3 (5-HT3) receptor in the regulation of gastric emptying in rats using various 5-HT3 receptor antagonists, including GK128, a novel and selective 5-HT3 receptor antagonist. GK128 dose-dependently accelerated gastric emptying in rats. The accelerating effect of GK128 on gastric emptying was more potent than that of the other 5-HT3 receptor antagonists used in this study. However, the rank order of potency of the selective 5-HT3 receptor antagonists, except for the benzamide derivatives, on the accelerating effect of gastric emptying, was not consistent with that of their 5-HT3 receptor-binding affinity in the rat cortex. GK128 improved the gastric emptying delayed by m-chlorophenylbiguanide, a 5-HT3 receptor agonist, and by cisplatin, which is known to cause damage to the small intestine and to release 5-HT from enterochromaffin cells. Furthermore, 5,7-dihydroxytryptamine, an indoleamine neurotoxin known to destroy 5-HT-containing neurons, significantly accelerated gastric emptying, and no further acceleration was observed after administration of GK128. These results may suggest that 5-HT3 receptor antagonists induce, at least in part, the acceleration of gastric emptying in rats via a peripheral mechanism, and that endogenous serotonin has an inhibitory regulatory effect on gastric emptying in rats. Furthermore, the difference in rank order between the accelerating effect of gastric emptying and the 5-HT3 receptor antagonistic potencies in the cortex suggests that the 5-HT3-like receptor, modulating gastric emptying, is not identical to the classically defined 5-HT3 receptor.

We analyzed the displacement activity of sarpogrelate and its active metabolite (M-1) in the radiolabeled ligand binding to various 5-hydroxytryptamine (5-HT) receptor subtypes using rat brain cortical membranes. Sarpogrelate was shown to have the same affinity as ritanserin for 5-HT2A receptors, with a Ki value of 8.39 nM. The active metabolite of sarpogrelate, M-1, was more active than sarpogrelate itself and of ritanserin, with a Ki value of 1.70 nM. Both sarpogrelate and M-1 had no affinity for 5-HT1A receptors, but these substances, at a concentration of 10 microM, displaced the specific binding to the 5-HT1B receptors of [125I]iodocyanopindolol, resulting in Ki values of 0.881 and 0.859 microM, respectively. The Ki values of sarpogrelate and M-1 are almost the same as that of ritanserin, a specific 5-HT2 receptor antagonist. Sarpogrelate and M-1, as well as ritanserin, are shown to have very low affinity for 5-HT1B receptors. Both sarpogrelate and M-1 had no affinity for 5-HT3 receptor subtypes. In the 5-HT4 receptor binding experiments, sarpogrelate exhibited almost no affinity, while M-1, at the concentration of 10 microM, displaced the binding activity, resulting in a Ki value of 0.838 microM. Both drugs had a weak antagonistic effect on a 5-HT4 receptor-mediated function, i.e., the 5-HT-induced relaxation of rat isolated esophageal tunica muscularis mucosae. In conclusion, sarpogrelate and M-1 have high affinity for 5-HT2A receptors with a relatively high selectivity.

The effect of MET-88 [3-(2, 2, 2-trimethylhydrazinium) propionate], a gamma-butyrobetaine hydroxylase inhibitor, on the ischemic changes of energy metabolism was studied in the anesthetized dog. In the dog pretreated orally with MET-88 (50, 100 or 200 mg/kg/day) or placebo for 10 days, the left anterior descending coronary artery was occluded for 60 min, and the myocardium was taken from the left anterior descending coronary area (ischemic area) and left circumflex area (nonischemic area) for metabolic analysis. In the ischemic area, occlusion of the left anterior descending coronary artery decreased the tissue levels of adenosine triphosphate, adenosine diphosphate and creatine phosphate, increased the tissue levels of adenosine monophosphate and lactate, and decreased the value of the energy charge potential. These metabolic alterations, induced by occlusion of the left anterior descending coronary artery, were dose-dependently attenuated by MET-88. In the nonischemic area, MET-88 did not markedly change either the tissue levels of energy metabolites or the value of the energy charge potential. These results indicate that MET-88 attenuates the derangement of the energy metabolism in the ischemic myocardium, without affecting the energy metabolism in the nonischemic myocardium.

The pharmacological properties of a newly synthesized 3-acetoxy-6 beta-acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine (KT-95) were examined. This compound, as well as (-)-3-acetyl-6 beta-acetylthio-N-cyclopropylmethylnormorphine (KT-90) and morphine, inhibited the twitch response to electrical stimulation of the guinea-pig ileal preparation that contains mu- and kappa-receptors. The inhibitory effect of KT-95 was about 17 times more potent than morphine, and about 4 times more potent than KT-90. In the guinea-pig ileal preparation, KT-95 behaved as a mu-antagonist against morphine in the presence of norbinaltorphimine (3 x 10(-8) M). In the rabbit vas deferens, containing kappa-opioid receptors, KT-95 inhibited the twitch response to electrical stimulation in a concentration-dependent manner. Norbinaltorphimine concentration-dependently caused parallel rightward shifts of the concentration-response curves to KT-95 in the guinea-pig ileum and in the rabbit vas deferens after electrical stimulation, suggesting that KT-95 behaved as an agonist for the kappa-opioid receptor. In the mouse vas deferens, that contains delta-receptors. KT-95 behaved also as a delta-antagonist against Leu-enkephalin in the presence of norbinaltorphimine. KT-95, KT-90 and morphine were examined for their potencies in displacing the specific binding of [3H]naloxone (mu-selective ligand), [3H]U69593 (kappa-selective ligand), and [3H]D-Ala2-D-Leu5-enkephalin (delta-selective ligand) to synaptosomal fractions from rat brain. Although KT-95 had a higher nonselective affinity to mu-receptors than KT-90 and morphine, the affinity of KT-95 to kappa-receptors was about 18 times higher than that of morphine, and about 5 times higher than that of KT-90. In the acetic acid-induced writhing test, subcutaneously injected KT-95 was more potent than morphine. Furthermore, the analgesic effect, induced by KT-95 (0.062 mumol/kg, s.c.), was abolished by simultaneous administration of norbinaltorphimine (0.020 mumol/mouse, s.c.), suggesting that the analgesic action of KT-95 is mediated through the kappa-opioid receptor. In the pressure test, KT-95 was 20.17 times more potent than morphine. The analgesic action, induced by KT-95 (2.05 mumol/kg, s.c.), was also in this test abolished by simultaneous administration of norbinaltorphimine (0.14 mumol/rat, s.c.), suggesting that this action of KT-95 is mediated through the kappa-opioid receptor. These results indicate that KT-95 behaves as a kappa-agonist with mu- and delta-antagonistic activities, and suggest that analgesia, induced by KT-95, is mainly mediated through kappa-receptors.

The effects of histamine H1 receptor antagonists (H1 antagonists) on action potentials in guinea-pig isolated papillary muscles were examined using a microelectrode technique. Terfenadine (0.03 microM) prolonged the action potential duration at 90% repolarization, without affecting the resting membrane potentials, the action potential amplitude or the maximal upstroke velocity, although its metabolite, terfenadine carboxylate, did not affect any action potential parameters. Astemizole, (+)-chlorpheniramine, and clemastine prolonged the action potential duration at 90% repolarization at 0.03, I and 10 microM, respectively. The action potential duration-prolonging effects of terfenadine and astemizole correspond to the reverse use-dependence phenomenon. However, ebastine and its metabolite, carebastine, did not affect the action potential parameters at 3 microM. Mequitazine, diphenhydramine, epinastine, ketotifen and oxatomide were also without effect at 10 microM. These H1 antagonists suppressed the histamine-induced contractions in guinea-pig isolated ileum longitudinal muscles. However, the potency order was inconsistent with that for prolonging the action potential duration. Terfenadine or astemizole prolonged the action potential duration at concentrations lower than each IC50 value for H1 receptor antagonism. Cimetidine, a H2 receptor antagonist, and thioperamide, a H3 receptor antagonist, had little effect on the action potentials. These results suggest that, in guinea-pig isolated papillary muscles, blockade of histamine receptors does not cause prolongation of the action potential duration, leading to prolongation of electrocardiographic QT intervals, and that H1 antagonists may be classified into three groups: (1) drugs causing prolongation of the action potential duration at concentrations producing H1 antagonism and (2) at concentrations higher than those producing H1 antagonism, and.

The main aim of this study was to investigate the interaction between the effects of caffeine and cocaine on memory consolidation in mice. For this purpose, CD1 mice were used; they were injected intraperitoneally and tested in a one-trial inhibitory avoidance task. The apparatus consisted of two compartments, one lighted and the other in darkness. On the training day, the animal had to go from the lighted to the dark compartment, where it received an electric shock. On the test day, carried out in our experiments 24 hours later, the time the animal waited to enter the dark compartment is the measure of its retention (for further details, see Methods). Three sets of experiments were carried out. In a first set, immediately posttraining, caffeine (0.25, 0.5 and 1 mg/kg) or cocaine (1, 2.5 and 5 mg/kg) administrations enhanced the memory consolidation of mice. In a second set, the D2 dopamine receptor antagonist, (-)-sulpiride, antagonized the enhancing effect of caffeine on memory. In a third set, a clear interaction between caffeine and cocaine was evident. The results are interpreted in terms of interaction of the drugs used with the dopaminergic system.

This review provides a brief overview of some of the structural and functional properties of small arteries, and of the factors which determine these. First, the evidence is reviewed concerning the importance of small arteries in the control of peripheral resistance. Then, receptor-mediated and myogenic excitation-contraction coupling mechanisms are discussed, in particular as regards the crucial role of membrane potential in these vessels. Finally, the characteristics of small arteries in hypertension are reviewed, with special attention to the structural abnormalities and their possible participation in the pathogenesis of the disease. The structural abnormalities of small arteries in hypertension are likely responsible for the reduced vascular reserve in this disease and consequent morbidity. It is suggested, however, that the small arteries are not in themselves determinants of blood pressure, rather they act as effector organs of the cardiovascular system. The further understanding of the physiology and pathophysiology of small arteries thus remains an important goal as regards the elucidation of the function of the cardiovascular system in health and disease.