Archives internationales de pharmacodynamie et de therapie最新文献

We investigated the expression of prostaglandin H synthase-2 in rats subjected to endotoxic shock. The prostaglandin H synthase activities were assessed by measuring the plasma prostaglandins (PGE2 and 6-keto-PGF1 alpha) after arachidonic acid administration (3 mg/kg, i.v.). The plasma prostaglandin concentrations increased immediately after administration of arachidonic acid, reached a peak at 30-60 seconds, and then rapidly decreased. Lipopolysaccharide (1 mg/kg, i.v.) also increased the plasma prostaglandin concentrations, reached a peak 1 hour after administration, and then gradually decreased to normal levels. The production of plasma prostaglandin, induced by administration of arachidonic acid, was markedly enhanced in the lipopolysaccharide-treated rats. A low dose of acetylsalicylic acid (3 mg/kg, i.v.) blocked the prostaglandin production in the nontreated rats but not in the lipopolysaccharide-treated rats. In the latter group of rats, a high dose of acetylsalicylic acid (30 mg/kg, i.v.), given 10 to 30 minutes before administration of arachidonic acid, completely blocked the prostaglandin production, but recovery of this production was seen with acetylsalicylic acid (30 mg/kg) treatment at 1 to 2 hours before administration of arachidonic acid. These data suggest that pretreatment with lipopolysaccharide enhances the prostaglandin production by forming newly synthesized prostaglandin H synthase. Immunoblots of the levels of enzyme protein from rat aorta endothelial cells were analyzed. The enzyme protein cross-reacting with antibody against prostaglandin H synthase-2 was increased by lipopolysaccharide treatment in endothelial cells, and was constitutively expressed in the stomach, kidney and liver, but not in the lung and the intestine. The induction of prostaglandin H synthase-2 by lipopolysaccharide treatment was observed only in endothelial cells. The enhancement of the prostaglandin production in lipopolysaccharide-treated rats was blocked by pretreatment with dexamethasone, prior to administration of lipopolysaccharide, this suppression is apparently the result of a decrease of the prostaglandin H synthase-2 protein in endothelial cells, as determined by Western blotting. The enhanced production of prostaglandin, induced by lipopolysaccharide, seems to be due to the in vivo expression of prostaglandin H synthase-2.

The effect of atropine and of the bispyridinium oximes, HI6 and HLö 7, on the electrocardiographic pattern was investigated in acutely nerve agent-poisoned guinea-pigs. The electrocardiographic, circulatory and respiratory parameters were recorded in female urethane-anaesthetized Pirbright-white guinea-pigs. After base line measurements, the animals received pyridostigmine (0.05 mumol/kg) and, 30 min later, tabun (5xLD50), sarin (5xLD50), soman (5xLD50 or 10xLD50) or VX (10xLD50 or 20xLD50), followed by saline or atropine (10 mg/kg) or atropine plus HI 6 or or HLö 7 (30 mumol/kg) 2 minutes later. Nerve agent poisoning resulted in respiratory arrest within 2-3 minutes, followed by circulatory arrest a few minutes later in nontreated animals. Antidote treatment rapidly restored heart rate and mean arterial pressure and improved the respiratory function to various extent. The nerve agent injection caused a marked sinus bradycardia and a subsequent complete atrioventricular block within 1-2 minutes, followed by idioventricular rhythm. No ventricular tachyarrhythmias were observed in these groups just before death. Atropine and atropine plus oxime administration immediately restored sinus rhythm which persisted in animals with sufficient respiration > 50% of base line) throughout the observation period (60 minutes). In guinea-pigs with depressed respiratory function ( < 50%), intermittent ST-T wave alterations and second degree atrioventricular block were observed. In some cases, especially in tabun and soman (10xLD50) poisoning, sinus rhythm converted to deleterious ventricular tachycardia within 1 minute after treatment. These results suggest that atropine-containing antidote combinations may induce lethal arrhythmias in nerve agent poisoning, which may be of clinical importance during intravenous treatment of severe inhalative intoxications.

The effects of 12 compounds, structurally related to the indolocarbazole bacterial metabolite staurosporine, on caffeine-induced contractions in rabbit renal arteries were studied. Eight of these compounds are effective protein kinase C inhibitors, the others are inactive towards the enzyme. The results show a link between the protein kinase C inhibitory activity and the inhibition of vascular smooth muscle contraction. However, a strong inhibition of protein kinase C is required to observe the vasorelaxant effect.

The main neurotransmitter of the mouse urinary bladder is ATP, which is hydrolyzed to AMP and adenosine; the latter compound, in contrast to ATP, relaxes the smooth muscle. Diazepam also relaxes the urinary bladder and, since some peripheral and central effects of the benzodiazepines are thought to be induced by inhibition of adenosine uptake or by inhibiting calcium channels, the effects of diazepam, adenosine, R-phenylisopropyladenosine, cyclohexyladenosine, and of the calcium channel antagonists, diltiazem, verapamil and nifedipine, were studied on the contractile responses of the mouse isolated urinary bladder. The contractile responses of the bladder's smooth muscle were elicited by transmural stimulation and by application of ATP or acetylcholine. All drugs mentioned decreased the contractile responses of the bladder. The inhibitory effect of diazepam was similar to that induced by adenosine, R-phenylisopropyladenosine, cyclohexyladenosine, and nifedipine. 8-Phenyltheophylline, an adenosine receptor antagonist, did not decrease the relaxatory response of diazepam, which might exclude a P1 purinoceptor-mediated mechanism in the response studied. Diazepam did not significantly change the inhibitory effects of diltiazem and nifedipine on the contractile response to acetylcholine. The similar patterns of relaxant effects, exerted by diazepam, adenosine analogues and calcium channel antagonists, suggest the interference of benzodiazepine, and adenosine and its analogues on calcium channels of the urinary bladder smooth muscle. The inability of diazepam to further increase the effects of diltiazem and nifedipine on the responses to acetylcholine, reinforces the hypothesis that diazepam is acting through a common mechanism with calcium antagonists.

Acute treatments with synthetic atrial natriuretic peptides induce hypotension, in which several mechanisms, including renal effects, are involved. The implication of the renal vasculature and the excretory capacities in the hypotensive action of atrial natriuretic peptides are not ascertained as yet. To address this issue, the rapid time sequence of the acute effects of atrial natriuretic peptides upon renal blood flow, mean arterial pressure, heart rate, and salt and water excretion, as well as a dose-response analysis, were investigated in 38 anesthetized euvolemic rats. Doses varying from 0.25 to 2.50 micrograms of atrial natriuretic peptide were injected i.v. in 30 sec. Each dose induced a brisk and transient increase in renal blood flow, which was maximal (13%) above 1 microgram of atrial natriuretic peptide. A small reduction in mean arterial pressure, timely related to renal vasodilation, occurred at first. It was followed by a second reduction in mean arterial pressure, which was concomitant to the maximal increases in diuresis and natriuresis. It persisted over a longer period of time. The maximal hypotensive effect (-15 mmHg) was observed above 1.5 micrograms of atrial natriuretic peptide. All effects were dose-dependent. There were no changes in heart rate. In conclusion, atrial natriuretic peptides transiently induced dose-dependent increases in renal blood flow and salt and water excretion, while the mean arterial pressure decreased stepwisely. The biphasic hypotensive effect was time-related to the renal vasodilator and diuretic effects, respectively.

The acute actions of cyclosporin A and its solvent Cremophor-EL on the rise of perfusion pressure induced by periarterial stimulation were studied in the rabbit isolated kidney. Thirty-second stimulations were used and the parameters were 1-25 Hz, 5 msec duration, and 15 V. The responses to periarterial stimulation were frequency-dependent. Noradrenaline (0.01-20 microgram) induced similar effects when given into the renal artery. Clonidine (10(-7)M), added to the perfusion medium, inhibited the responses to periarterial stimulation without altering the effect of noradrenaline. Cyclosporin A (10(-7)-4 x 10(-5)M), added to the perfusion medium, potentiated the responses both to periarterial stimulation and exogenously given noradrenaline and restored the responses to clonidine (10(-7)M). The effects of cyclosporin A and Cremophor-EL on the responses to various contractile agonists (potassium chloride, phenylephrine, serotonin and angiotensin II) were also studied in the rabbit isolated renal artery. The results suggest that cyclosporin A may exert a direct action on the vasculature rather than an action on the vascular adrenergic neurotransmission of the rabbit kidney.

The aim of the present study was to investigate the mechanism of the biphasic blood pressure response to the 5-hydroxytryptamine2 (5-HT2) receptor agonist, alpha-methyl-5-HT (alpha-Me-5-HT) in anaesthetized rats. In conscious rats, 5-HT (2.5-15 micrograms/kg, i.v.) produced typical triphasic blood pressure responses at the higher doses. In anaesthetized rats, 5-HT produced only hypotensive responses at all doses. In conscious rats, i.v. injections of alpha-Me-5-HT (5-125 micrograms/kg) produced dose-dependent increases in mean arterial pressure with concomitant bradycardia. However, in inactin-anaesthetized rats, alpha-Me-5-HT produced biphasic blood pressure responses consisting of an initial pressor response followed by a longer lasting depressor phase. In anaesthetized rats, the 5-HT1A antagonist, spiroxatrine (1 mg/kg), and the 5-HT3 receptor antagonist, MDL72222 (0.3 mg/kg), selectively diminished the hypotensive phase without affecting the pressor phase. The 5-HT1/5-HT2 antagonist, methysergide (0.5 mg/kg), and the selective 5-HT2 antagonist, ketanserin (50 micrograms/kg), completely abolished all responses to alpha-Me-5-HT. Pretreatment with the 5-HT-selective uptake inhibitor, fluoxetine (1 mg/kg), produced a significant attenuation of the hypotensive response whilst enhancing the pressor response. Pretreatment with the 5-HT depletor, p-chlorophenylalanine (3 x 100 mg/kg/day), produced an attenuation of the hypotensive phase while the pressor response was augmented. The selective 5-HT2/5-HT2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2- amino-propane (5-200 micrograms/kg, i.v.), produced dose-dependent pressor responses in anaesthetized rats but no hypotensive responses were observed. The results show that the 5-HT2 agonist, alpha-Me-5-HT, produces a biphasic blood pressure response in anaesthetized rats which is not seen in conscious rats. The hypotensive response is due to a nonselective activation of 5-HT1 and 5-HT3 receptors through release of 5-HT.

The potencies and intrinsic activities on cyclic AMP accumulation and lipolysis of various selective beta 3-adrenoceptor agonists were studied in brown adipocytes and compared to those of the nonselective, (-)-isoprenaline, and conventional beta 1- (dobutamine) and beta 2-adrenoceptor (salbutamol) agonists. (-)-Isoprenaline, dobutamine and salbutamol were more potent stimulants of lipolysis than of cyclic AMP accumulation, while the selective beta 3-adrenoceptor agonists had similar potencies for these two functions. Apparent pA2 values of the selective beta 1-(CGP20712A) and beta 2-adrenoceptor (ICI118551) antagonist for inhibition of adenylyl cyclase stimulation by (-)-isoprenaline and the beta 3-adrenoceptor agonists, BRL37344, SR58611A, and ICI215001, indicated that (-)-isoprenaline can stimulate the enzyme through a relevant beta 1-adrenergic component, while the other drugs activate the enzyme mainly by acting on the beta 3-adrenoceptors. On the contrary, antagonism of the lipolysis yielded apparent pA2 values for CGP20712A and ICI118551, suggesting that (-)-isoprenaline, like all the beta 3-adrenoceptor agonists, stimulated the brown adipose tissue lipid metabolism mainly through an action on beta 3-adrenoceptors.

The effects of the 5-hydroxytryptamine1A agonists, 8-OH-DPAT, buspirone and flesinoxan, on the delayed hyperactivity and on the ensuing neuronal degeneration induced by transient global cerebral ischaemia, were studied. In normothermic, male Mongolian gerbils, subjected to 3 min bilateral carotid artery ligation, the locomotor activity was measured 1 day after ischaemia. The neuronal damage was quantified 7 days later using an image analysis system. Buspirone (3 and 10 mg/kg, i.p.) and flesinoxan (1 and 3 mg/kg, i.p.), administered twice a day for 3 days both in pre- and post-ischaemic conditions, failed to significantly protect the CA1 zone of the hippocampus against neuronal damage. In contrast, 8-OH-DPat (1 and 3 mg/kg, i.p.) significantly reduced the neuronal degeneration. All compounds abolished the hyperactivity but there was no correlation between this parameter and the extent of the reduction in neuronal damage. The ineffectiveness of buspirone and flesinoxan was not the result of too low a dose - as evidenced by the complete inhibition of hyperactivity with both compounds and by the appearance of a serotonin behavior syndrome with flesinoxan - but is possibly related to a partial agonist activity at the 5-hydroxytryptamine1A receptor, as reported for buspirone. Further studies are necessary to explain the differences between these agonists.

The effects of the antimalarial agent, mefloquine, and its derivatives on Ca2+ uptake and release by crude microsomes from the rabbit skeletal muscle were investigated using a spectrophotometric method. These compounds diminished the rate of Ca2+ uptake and inhibited the Ca2+ pump ATPase activity of the microsomes. Except for quinine, they appear to have negligible effects on Ca2+ release channels. Of the compounds investigated, mefloquine had the most pronounced effect on Ca2+ uptake and was also the most potent (noncompetitive) inhibitor of Ca(2+)-ATPase (Ki: 53 microM). The ability of mefloquine to interfere with Ca2+ sequestration into the sarcoplasmic reticulum via inhibition of the Ca2+ pump ATPase, may explain some of its actions on the isolated skeletal muscle (relaxation, inhibition of twitch responses, diminution of caffeine contractures) observed in earlier studies. However, its contractile effects are less readily explained. The novel finding that mefloquine inhibits the Ca2+ pump ATPase of the skeletal muscle, suggests that it may have similar effects on the Ca(2+)-ATPases of other tissues.