Archives internationales de pharmacodynamie et de therapie最新文献

Pressor responses to [Ile5]-Angiotensin II and [Val5]-Angiotensin II were measured following single intravenous doses of 0.0075, 0.075, 0.375, 0.75 and 7.5 micrograms/kg b.w. in anesthetised rats. [Val5]-Angiotensin II was significantly (10 per cent) more potent than [Ile5]-angiotensin II when log dose was plotted against the increase in carotid arterial pressure. Doses of 0.075 microgram/kg b.w. or more of each of the two peptides gave a full pressor response within 30 seconds. However, only at the highest and, probably, nonphysiological dose of [Ile5]-Angiotensin II (7.5 micrograms/kg b.w.) was there a significant increase in noradrenaline and adrenaline concentrations measured using a radioenzymatic assay. [Val5]-Angiotensin II was more potent than [Ile5]-Angiotensin II insofar as plasma noradrenaline increased significantly (p < 0.05) following doses of 0.75 and 7.5 micrograms/kg b.w.; adrenaline at the higher dose only. Plasma dopamine was unresponsive to both peptides.

KW-5092 ([1-[2-[[[5-(piperidinomethyl)-2-furanyl]- methyl]amino]ethyl]-2-imidazolidinylidene]propanedinitrile fumarate) is a novel gastroprokinetic agent with acetylcholinesterase inhibitory and acetylcholine release facilitatory activity. The present study examined the effects of KW-5092 on the defecation and colonic motor activity in rats. KW-5092, at 1 to 30 mg/kg, p.o., dose-dependently increased the fecal pellet output. In the in vitro study, KW-5092, at 10(-6) M to 10(-5) M, evoked contraction of the isolated distal colonic preparation. In the in vivo study, KW-5092, at 1 to 10 mg/kg, p.o., induced an increase in the distal colonic motor index, which was dose-dependently inhibited by atropine (0.1 to 1 mg/kg, i.v.). The present results suggest that KW-5092 induces the defecation in rats by enhancing the distal colonic motor activity via its acetylcholinesterase inhibitory activity and/or acetylcholine release facilitatory activity. KW-5092 may be a useful drug in the treatment of constipation.

bis-Quaternary amines, which are acetal analogues of hemicholinium-3, were synthesized and several compounds were potent chemicals to antagonize toxicity induced by the organophosphate, paraoxon. Structural requirements were specific and included two oxygen atoms (bis-acetal substitution) within 6 or 7 atom heterocyclic rings, oxygen atoms spaced 2-carbon atoms from the quaternary nitrogen, and carbonyl substitutions adjacent to the spacing moieties, either bicyclohexyl or biphenyl. Biological testing showed a positive potency correlation between the chemicals when data from the following tests were compared: antagonism in mice of paraoxon-induced motor impairment using the incline screen and toxicity, and ability to induce contractions of guinea-pig isolated ilea. The compounds were compared with the often used protective antagonist of organophosphate-induced toxicity, pyridostigmine. One compound, MFS-3, was seven times more efficacious and possessed a much higher therapeutic index. Possible mechanisms of action for these chemicals are discussed.

Pergolide, along with bromocriptine and lisuride, is one of the most active dopamine receptor agonists. To determine whether or not pergolide protects against dopaminergic neuronal damage, via its activity on monoamine metabolism, we studied the effects of pergolide pretreatment on changes in monomaines and their metabolites in the mouse striatum after intracerebroventricular injection of 6-hydroxydopamine with pretreatment of desipramine. After intracerebroventricular administration of 6-hydroxydopamine (40 micrograms) in mice, the levels of dopamine and its metabolites (DOPAC, HVA) in the striatum rapidly decreased to 49%, 29% and 68%, respectively, of the naive controls at week 1 but then gradually recovered to control levels at weeks 2 and 4. Repeated pretreatment with pergolide (0.5 mg/kg, i.p.) for 7 days before administration of 6-hydroxydopamine, almost completely protected against reduction in striatal dopamine and its metabolites 1 week after injection of 6-hydroxydopamine. Therefore, pergolide could normalize the decreased dopamine synthesis or storage, and has a neuroprotective effect against dopaminergic dysfunction induced by the neurotoxin, 6-hydroxydopamine. Although we found that pergolide did not show radical scavenging activity in an in vitro system that generated hydroxyl radicals, it has been reported in vivo that pergolide treatment may induce Cu/Zn superoxide dismutase in the rat striatum. Considering these findings, pergolide may well be protective to dopaminergic neurons, largely because of its effects on presynaptic autoreceptors and on its induction of Cu/Zn superoxide dismutase. Further research on the neuroprotective effects of pergolide in Parkinson disease models, by injection of 6-hydroxydopamine, is needed to clarify its mechanism of action on dopaminergic indices.

The effect of ambrein, a major constituent of ambergris, was studied on the sexual behavior of male rats. The rats were administered ambrein in doses of 100 and 300 mg/kg body weight. Male sexual activities were assessed by recording the erectile responses (penile erection) and homosexual mountings in the absence of female. The copulatory studies were carried out by caging males with receptive females brought into estrus with subcutaneous injections of estradiol benzoate and progesterone. The copulatory pattern of treated male rats (mountings, intromissions, ejaculations and refractory period), the pendiculations (yawns/stretches) and orientation activities towards females, the environment and themselves, were recorded. Ambrein produced recurrent episodes of penile erection, a dose-dependent, vigorous and repetitive increase in intromissions and an increased anogenital investigatory behavior, identifying the drug used in the present study as a sexual stimulant. It is conceivable from the present results that the ambrein-modified masculine sexual behavior in male rats supports the folk use of this drug as an aphrodisiac.

The cardiovascular effects of intracerebroventricular (i.c.v.) injections of low doses of CPU-23, a substituted tetrahydroisoquinoline, were investigated and compared with those of nifedipine in pentobarbital-anaesthetized Sprague-Dawley rats. CPU-23, in doses of 0.2 to 0.5 mg/kg (i.c.v.), which did not elicit any significant cardiovascular responses when injected intravenously, caused a clear-cut and long-lasting decrease of mean arterial pressure (MAP) and heart rate (HR) in a dose-dependent manner. The effects of CPU-23, in a dose of 0.05 mg/kg, were similar to those of nifedipine, a prototype L-type calcium antagonist. The hypotensive effects of CPU-23 were significantly attenuated by bilateral cervical vagotomy. The results strongly suggest that a central component may be involved in the cardiovascular effects of CPU-23 and that dihydropyridine receptor sites in the brain may be involved in the central control of cardiovascular functions.

Using Rb+ as a K+ tracer and atomic absorption spectrophotometry for measuring the Rb+ stable isotope, we studied K+ transport systems and their regulation by protein kinase C in nontransformed and spontaneously transformed rat liver epithelial cells. Ouabain-sensitive Na+/K(+)-ATPase and the furosemide-sensitive Na+/K+/Cl- cotransport had comparable activity ratios in both cell types (0.92 and 1 in nontransformed and transformed rat liver epithelial cells, respectively). The protein kinase C activators, dioctanoylglycerol and phorbol myristate acetate, partly inhibited the Na+/K+/Cl- cotransport in both cell types but their effect was stronger in nontransformed cells, suggesting that, in transformed cells, the Na+/K+/Cl- cotransport had partly lost the ability to be inhibited by protein kinase C. In both cell types, phorbol myristate acetate had little and dioctanoylglycerol had no inhibitory effect on Na+/K(+)-ATPase. Furosemide (1 mM) partly inhibited the [3H]thymidine incorporation in both cell types, suggesting an involvement of the Na+/K+/Cl- cotransport in rat liver epithelial cell growth.

The results of the present study show that the down-regulation of beta-adrenoceptors of rat brain, induced by subacute administration of sertraline, is facilitated when this selective serotonin reuptake inhibitor was co-administered with the serotonin releaser, norfenfluramine, or the serotonin terminal autoreceptor antagonist, methiothepin. The respective drug combination produced a reduction in Bmax of [3H]dihydroalprenolol binding to cortical membranes of treated rats at a dose of the releaser, release enhancer, or sertraline, which was ineffective when administered alone. In a similar manner, the 5-HT1A agonists, gepirone and 8-OH-DPAT, were found to facilitate the downregulation of beta-adrenoceptors induced by sertraline. The 5-HT1B agonist, 3-trifluoromethylphenylpiperazine, and the 5-HT2 antagonist, ritanserin, showed neither facilitation nor antagonism of sertraline, but the 5-HT3 antagonist, ondansetron, attenuated the decrease of Bmax of [3H]dihydroalprenolol binding elicited by sertraline. Agents that putatively increase the serotoninergic activity facilitated the down-regulation of beta-adrenoceptors induced by sertraline, suggesting that the enhancement of serotonin transmission, expected of the selective serotonin reuptake inhibitor itself, may play a role in this effect of sertraline. Whether the downregulation of brain beta-adrenoceptors by sertraline plays any role in its antidepressant activity cannot be deduced from these experiments.

The hepatoprotective effect of SY-640 on Propionibacterium acnes and lipopolysaccharide-induced liver injury in mice and its protective mechanism were examined. Oral administration of SY-640, 150 mg/kg once daily for 7 days, significantly inhibited Propionibacterium acnes and lipopolysaccharide-induced liver injury, but a single administration was without effect. Liver-infiltrating cells (T-lymphocytes and macrophages) play an important role in Propionibacterium and lipopolysaccharide-induced liver injury and express a higher level of leukocyte function-associated antigen-1. SY-640 inhibited the number of liver-infiltrating cells and attenuated the increased expression of leukocyte function-associated antigen-1 on these cells. Tumor necrosis factor-alpha mediated Propionibacterium acnes and lipopolysaccharide-induced liver injury, and SY-640 inhibited the elevation of the serum tumor necrosis factor-alpha concentration after injection of lipopolysaccharide in Propionibacterium acnes-primed mice. The putative effects of SY-640 are inhibitory effects on infiltration into the liver and on activation of T-lymphocytes and macrophages after Propionibacterium acnes-priming, and attenuation of expression of cell adhesion molecules such as leukocyte function-associated antigen-1. The immunological effect of SY-640 is likely to be closely related to the inhibition of Propionibacterium and lipopolysaccharide-induced liver injury.

Release of neuropeptides from sensory nerves causes an increase in vascular permeability, plasma extravasation and edema. The sensory nerves in the airways can be activated by electrical stimulation of the vagus nerve or by application of chemical and mechanical irritants, such as capsaicin, hypertonic saline, isocapnic hyperpnea and cigarette smoke. In rodent airways, the neurogenic plasma extravasation is mediated by tachykinins released from the capsaicin-afferent nerve fibres, and involves activation of neurokinin-1 tachykinin receptors. In peripheral guinea-pig airways, neurokinin-2 tachykinin receptors have also been implicated in the neurogenic plasma exudation. The tachykinins can increase vascular permeability by both a direct effect on venular endothelium, and indirect mechanisms involving mast cell activation and serotonin release. Tachykinins and their receptors are present in the human airways. Release of tachykinins, following antigen challenge, has been demonstrated in the nose and lower airways. In humans, tachykinins have been shown to increase plasma exudation in the nasal mucosa, but whether neurogenic inflammation also occurs in the lower airways still remains to be proven.