Archives internationales de pharmacodynamie et de therapie最新文献

The autoregulation of the histamine release via the histamine H3 receptor in the periphery was studied in vivo and in vitro. Antidromic electrical stimulation of the sciatic nerve caused a significant increase in histamine release in the subcutaneous perfusate in the rat hindpaw. (R)alpha-methylhistamine, a specific H3 receptor agonist, significantly and dose-dependently inhibited the increase in release of histamine by antidromic stimulation at intravenous doses of 0.25-2 mg/kg. Thioperamide (2 mg/kg, intraperitoneally), a specific H3 antagonist, prevented the inhibitory effect of (R)alpha-methylhistamine. Substance P perfusion (5-50 microM) also elicited a significant increase in histamine, and a significant inhibition by (R)alpha-methylhistamine and the antagonism of thioperamide were observed. (R)alpha-methylhistamine inhibited the histamine release by substance P from rat peritoneal mast cells in vitro, and thioperamide reduced the response to (R)alpha-methylhistamine. These data suggest that mast cells may have histamine H3 receptors, and that histamine probably modulates its own release through the H3 receptor in neurogenic inflammation.

The therapeutic effect of nizofenone, a cerebroprotective drug, on experimental traumatic head injury was investigated in mice. The animals under halothane anaesthesia were subjected to a severe concussive head trauma and their neurological status was assessed by a string grip-test for 6 consecutive days. The neurological function of the control groups fell markedly 1 hr after trauma and slowly recovered day by day, but some animals failed to restore to the normal level, even on the 6th day. The post-treatment of the head-injured mice with nizofenone (3 mg/kg/day, i.p.) significantly improved the neurological function. The neurological improvement by nizofenone was dose-dependent and a significant amelioration was observed at 0.3 mg/kg/day. Methylprednisolone (30 mg/kg/day, i.v.) did not exert any significant neurological improvement in this therapeutic, experimental condition. In this study, nizofenone treatment was found to beneficially influence the recovery of the neurological function, maybe by reducing the progress of brain injury following head trauma.

The effects of a Ca2+ entry blocker, nifedipine, and a putative intracellular Ca2+ release inhibitor, 8-(N, N-diethylamino) octyl-3,4,5-trimethoxybenzoate (TMB-8), on mesenteric vasoconstriction, induced by angiotensin II, were examined in anesthetized dogs. Injection of angiotensin II (5 and 10 ng/kg) into the mesenteric artery decreased the mesenteric blood flow, which was suppressed during intramesenteric arterial infusion of TMB-8 (30 and 100 micrograms/kg/min) but not of nifedipine (0.03 and 0.1 microgram/kg/min). A higher dose of nifedipine (0.3 microgram/kg/min) only slightly attenuated the mesenteric blood flow response. Intravenous injection of angiotensin II (100 ng/kg) decreased the mesenteric and renal blood flow. Both blood flow responses were suppressed during intravenous infusion of TMB-8 (1 and 2 mg/kg/min). Intravenous infusion of nifedipine (0.1-1.0 microgram/kg/min) suppressed the renal blood flow response, whereas the mesenteric blood flow response was relatively resistant to nifedipine. The present results suggest that a TMB-8-sensitive Ca2+ movement pathway participates in the angiotensin II-induced contraction of the dog mesenteric vasculature in vivo. The Ca2+ influx through dihydropyridine-sensitive Ca2+ channels may not play a significant role in the angiotensin II-induced mesenteric vasoconstriction.

The inhibitory effect of beraprost on the transmembrane action potentials was compared with other cardioprotective drugs during hypoxia in guinea-pig isolated right ventricular muscle. Glibenclamide, like beraprost, inhibited the decrease of the action potential duration, but propanolol and diltiazem did not affect this decrease during hypoxia. In beraprost-treated preparations, the decrease of the myocardial K+ content during hypoxia was inhibited. Furthermore, beraprost prevented the action potential shortening during metabolic inhibition by 2,4-dinitrophenol. It is suggested that beraprost may inhibit the hypoxia- and 2,4-dinitrophenol-induced shortening of the action potential duration by preserving the muscular ATP level. Accordingly, beraprost may have beneficial effects both during hypoxia and metabolic inhibition.

Both the monomethyl and dimethyl esters of succinic acid, administered enterally to fasted rats, caused a rapid increase in plasma insulin. Such was not the case, however, after enteral administration of either succinic acid or the dimethyl ester of glutamic acid. The time course for the appearance of radioactive material in plasma was also vastly different after enteral administration of either [1,4-14C]succinic acid or its dimethyl ester. In the latter case, the separation of acidic and nonacidic radioactive metabolites and the measurement of 14C-labelled D-glucose indicated that, after enteral administration of succinic acid dimethyl ester (2 mmol), its initial appearance rate in plasma averaged 45 +/- 9 microM/min resulting, after 120 min, in a plasma concentration of 1.34 +/- 0.14 mM.

In the present study, the effects of three classes of L-type calcium channel-blocking agents, nifedipine, verapamil and diltiazem, on the lobar arterial pressure and the vasoconstrictor responses in the pulmonary vascular bed were compared to those of cromakalim, a KATP channel activator, in the anaesthetized cat under controlled pulmonary blood flow and constant left atrial pressure. These drugs were infused intralobarly in doses selected which did not raise left atrial pressure, change cardiac output or alter systemic arterial pressure. Intralobar bolus injections of calcium channel-blocking agents and of the K+ channel activator decreased the lobar arterial pressure in a dose-related manner when pulmonary vasomotor tone was actively elevated by intralobar arterial infusion of U46619. The pulmonary vasodilator response to these agents was accompanied by a dose-related decrease of systemic arterial pressure. In decreasing lobar arterial pressure at elevated pulmonary vasomotor tone, the order of potency was nifedipine > verapamil > diltiazem, whereas in reducing systemic arterial pressure, the order of potency was nifedipine > diltiazem > verapamil. The calcium channel-blocking agents were less active than the reference drug, cromakalim, in both vascular beds. Intralobar arterial infusions of nifedipine, verapamil and diltiazem, at the rates of 0.03 mumol/min, 0.2 mumol/min and 0.1 mumol/min, respectively, caused no changes in cardiac output and in systemic and pulmonary arterial pressure. Infusion of all three calcium-channel-blocking agents blocked the pulmonary vasoconstrictor responses to BAY K 8644 (calcium entry promoter) and U46619 (thromboxane A2 mimic). Nifedipine infusion also reduced the pulmonary vasoconstrictor responses to methoxamine and BHT933 (alpha 1- and alpha 2-adrenoceptor agonists, respectively), whereas verapamil infusion reduced the responses only to methoxamine. Infusion of diltiazem caused no significant decrease of responses to either alpha-adrenoceptor agonist. The results of the present study suggest that the dihydropyridine, nifedipine, is more potent than the non-dihydropyridines, verapamil and diltiazem, in reducing the pulmonary vascular resistance and more effective in inhibiting the vasoconstrictor responses to the alpha-adrenoceptor agonists, to U46619 and to BAY K 8644 in the feline pulmonary circulation at the infusion rates which cause no or little hemodynamic changes.

After transient cerebral ischemia induced by bilateral ligation of carotid arteries, followed by 5 min reperfusion, concentrations of prostaglandin D2 and LTC4-like material increased with time in the gerbil brain. At least a 1 min occlusion time was necessary to elevate the eicosanoid concentrations significantly over the basal levels. Spontaneous tonic-clonic seizures of about 20 sec duration induced an increase in prostaglandin D2 and LTC4-like material comparable to the values found after a 2 min occlusion time. Following carotid artery occlusion, the eicosanoid levels were found to be elevated in midbrain, hypothalamus, striatum, hippocampus and cortex, i.e., those brain areas dependent upon the blood supply from the carotid arteries. In contrast, following spontaneous seizures, prostaglandin D2 concentrations were increased in the striatum, hippocampus and cortex only, and the LTC4-like material in the cortex. Hippocampus, striatum and cortex are brain areas which participate in the generation and propagation of seizures. It appears, therefore, unlikely that the seizure-induced eicosanoid synthesis is triggered off by a hypoxic event due to an impaired breathing caused by convulsions. The regional pattern of the eicosanoid synthesis following the seizures may rather depend on the intensity of the neuronal activity than on regional differences in the eicosanoid-synthesizing capacity.

The role of the L-arginine/nitric oxide pathway in mediating the central control of blood pressure and heart rate, has been investigated in chloralose-anaesthetized cats. L-arginine (10 micrograms to 10 mg), administered intracerebroventricularly into a lateral ventricle, produced a dose-dependent rise in mean blood pressure (7 to 28%) and heart rate (4 to 34%). D-arginine (1 mg), on the other hand, did not produce any change. The effect of L-arginine (100 micrograms) was dose-dependently inhibited by pretreatment with either L-NAME (1 mg) or methylene blue (400 micrograms). Sodium nitroprusside (1 microgram to 10 micrograms, intracerebroventricularly), a spontaneous source of nitric oxide, produced a dose-dependent fall in mean blood pressure (6 to 19%) with a moderate rise in heart rate (3 to 10%). The effect of nitroprusside was markedly inhibited by methylene blue, but not by L-NAME. The results suggest that the L-arginine/nitric oxide pathway in the central nervous system is involved in the blood pressure regulation in the cat.

Clozapine and its metabolite clozapine-N-oxide (0.5 mg/kg) were administered intraperitoneally to guinea-pigs. Significant amounts of clozapine were detected in plasma, liver, frontal cortex and caudate after clozapine-N-oxide administration. The amount of clozapine detected in plasma two hours post-administration of N-oxide was approximately 40% of the amount of clozapine after clozapine injection. Tissue concentrations of clozapine in liver, frontal cortex and caudate were greater than plasma concentrations. Clozapine concentrations were almost equivalent in the liver. Clozapine concentrations after N-oxide injection were approximately 40-50% lower compared to clozapine concentrations after clozapine administration in the frontal cortex and caudate. A single dose of clozapine-N-oxide was given to a schizophrenic patient. Clozapine plasma concentrations were detected after N-oxide administration. This study shows that clozapine is formed from its N-oxide metabolite and that a reversible metabolic pathway exists for clozapine and clozapine-N-oxide.

The contractions induced by the 5-hydroxytryptamine (5-HT) and 5-HT1-like receptor agonist sumatriptan in open ring segments of rabbit iliac, mesenteric and common carotid arteries were studied isometrically in vitro. The alteration of the responses by removal of the endothelium and by inhibitors of nitric oxide synthase and cyclooxygenase was investigated. 5-HT induced concentration-dependent contractions of all these three arterial segments. Sumatriptan did not induce any contraction of quiescent mesenteric and iliac arteries, but when a moderate tone was given with a threshold concentration of prostaglandin F2 alpha, it elicited contractions of both arteries (Emax values for sumatriptan in mesenteric and iliac arteries were 84.7% and 29.7% of the phenylephrine maximal effect and EC50 values were 0.22 +/- 0.14 and 0.33 +/- 0.06 microM, respectively). Sumatriptan had no contractile effect at all in carotid arteries in which 5-HT-induced contractions seemed to be mediated by 5-HT2 receptors only. Removal of the endothelium did not affect the responses to 5-HT in iliac, mesenteric and carotid arteries. The contractions induced by sumatriptan were not influenced by removal of the endothelium in the mesenteric artery, while sumatriptan responses were potentiated in the endothelium-denuded preparations of the iliac artery (Emax = 50.8% of the phenylphrine maximal effect; EC50 = 0.46 microM). L-NG-monomethyl arginine (100 microM), a nitric oxide synthase inhibitor, also potentiated the sumatriptan responses in the endothelium-intact segments of the iliac artery. Indomethacin (0.1 microM), a cyclooxygenase inhibitor, did not affect the sumatriptan responses. These results suggest that sumatriptan-induced contractions of the rabbit iliac, but not mesenteric artery, were depressed by itself through the release of nitric oxide upon stimulation of 5-HT1-like receptors located on the endothelium, whereas neither on vascular smooth muscle nor on endothelium, 5-HT1-like receptors were present in the rabbit carotid artery.