Archives internationales de pharmacodynamie et de therapie最新文献

The difference between the responses of phenylephrine (1 microM)-precontracted vascular (endothelium-denuded rat or rabbit aortic strips) and nonvascular (rat anococcygeus muscle) smooth muscles to acetylcholine (0.1-100 microM) was investigated when they were mounted co-axially inside the tracheas isolated from normal or ovalbumin-sensitized guinea-pigs. Acetylcholine produced concentration-dependent relaxations in both types of bioassay tissues. These relaxations, previously shown to be due to the release of airway epithelium-derived relaxing factor(s), were significantly attenuated when the epithelial layer of the tracheas was removed mechanically (as confirmed by histological examination). There were no significant differences in responsiveness to acetylcholine between vascular strips mounted inside the epithelium-intact normal or sensitized tracheas. The phenylephrine-induced precontraction was significantly more pronounced in rat anococcygeus muscles mounted inside sensitized tracheas as compared to tissues mounted inside control tracheas. The acetylcholine-induced relaxations were significantly decreased but this effect disappeared when the concentration of phenylephrine was reduced to obtain a similar precontraction level as in tissues mounted inside control tracheas. The responsiveness of both vascular strips and anococcygeus muscles to acetylcholine was attenuated when they were mounted inside sensitized tracheas and incubated with ovalbumin for 20 min, which may be explained by the epithelial damage induced by ovalbumin challenge. This attenuation was absent when co-axial pairs, utilizing normal tracheas, were used. These results indicate a difference in response patterns of the rat anococcygeus muscle and vascular strips in ovalbumin-sensitized tracheas, which should be taken into consideration in co-axial bioassay studies.

The association between torsade de pointes and experimentally induced early afterdepolarizations in isolated fibres is well documented. The effect of eight beta-adrenoceptor-blocking drugs (sotalol, nifenalol, acebutolol, dichloroisoproterenol, propranolol, oxprenolol, pindolol, atenolol), and of amiodarone, was studied in isolated spontaneously beating guinea-pig Purkinje fibres by the intracellular microelectrode technique. Phase 3 early afterdepolarizations were initiated by nifenalol hydrochloride (n = 18; 10 mumol/l: 0/18, 40 mumol/l: 3/18, 80 mumol/l: 8/18, 160 mumol/l: 11/18), rac.-(+/-)-sotalol hydrochloride (n = 28; 20 mumol/l: 0/28, 40 mumol/l: 9/28, 80 mumol/l: 20/28), (R)(+)-sotalol hydrochloride (n = 12; 40 mumol/l: 1/12, 80 mumol/l: 4/12), and (S)(-)-sotalol hydrochloride (n = 10, 40 mumol/l: 1/10, 80 mumol/l: 4/10). The arrhythmogenic effect was reversible after a washout period of one hour and early after-depolarizations could be terminated by tetrodotoxin (0.4-1.6 mumol/l, n = 6). Amiodarone only induced early afterdepolarizations at a low extracellular potassium concentration of [K+]o = 1.35 mmol/l (n = 5; 150 mumol/l: 0/5, 300 mumol/l: 1/5). The initiation of early after-depolarizations by sotalol and nifenalol might be induced by an imbalance of sodium inward current and potassium outward currents, and early afterdepolarizations are blocked by tetrodotoxin.

The present study explored the role of the dopaminergic transmission in the mouse writhing test analgesia by examining the relative analgesic activity of indirect dopaminergic agonists (amphetamine and cocaine), a mixed D1/D2 direct agonist (apomorphine), and a direct D1 (SKF38393) and D2 (bromocriptine) dopaminergic agonist. Amphetamine (1, 3 and 10 mg/kg, s.c.), cocaine (3 and 10 mg/kg, s.c.), apomorphine (0.3, 1 and 3 mg/kg, s.c.) and bromocriptine (30 mg/kg, s.c.) induced a significant decrease of the number of writhes. SKF38393 (1, 3, 10 and 30 mg/kg, s.c.) had no effect on writhing. The antinociceptive effect of amphetamine and cocaine was not reversed by naltrexone, haloperidol or SCH23390. The apomorphine- and bromocriptine-induced analgesia was not reduced by naltrexone or SCH23390 but was attenuated by haloperidol; the apomorphine-induced analgesia was not modified by domperidone. The present results suggest an involvement of the dopaminergic transmission in visceral nociception. This dopaminergic component appears to involve exclusively the central D2 receptor system, and does not seem to be influenced by opioid mechanisms.

The anorectic and behavioral effects of mazindol (2.5, 5 and 10 mg/kg) were determined. The experiments comprized acute and chronic administration to female rats, and the effects were compared with those produced by 2.5 mg/kg of methamphetamine. The following evaluation parameters were considered: food intake, body weight, motor activity, and stereotyped behavior. Acute administration of the three doses of mazindol, as well as of the methamphetamine dose, decreased food intake. Administered chronically to female rats, mazindol (5 and 10 mg/kg) and methamphetamine induced loss of body weight during the first fifteen days. However, weight was subsequently regained by the animals, indicating development of tolerance. Mazindol (10 mg/kg) and methamphetamine produced an increase in motor activity. This increase was, however, not observed after chronic treatment, suggesting development of tolerance. Additionally, mazindol induced noticeable dose-dependent effects, involving stereotyped behavior (sniffing, continuous licking, false bites), similar to those produced by methamphetamine. Verticalization, however, was only observed after administration of 2.5 and 5 mg/kg of mazindol, and was absent after administration of the higher dose of mazindol as well as of methamphetamine. Finally, it should be stressed that features of stereotyped behavior induced by both drugs, such as licking, false bites, sniffing and verticalization, were very similar.

The pharmacological characteristics of DQ-2511, a substituted benzamide (3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]methyl] amino-N-methylbenzamide), as a prokinetic agent were studied. Cholecystokinin-octapeptide, dopamine, and alpha-calcitonin gene-related peptide, all suppressed gastric emptying in mice. Reversal of the depressed emptying occurred when DQ-2511 was administered by the oral or intraperitoneal route. When the action of eight proposed metabolites of DQ-2511 on the mouse cholecystokinin-octapeptide model was investigated, the main metabolite in plasma, MA-2, showed no effect, although two minor metabolites ameliorated or aggravated the delayed gastric emptying. This finding implies that DQ-2511, as the parent compound itself, exerts the ameliorative action. In dogs treated with cisplatin or copper sulfate, DQ-2511 had no antiemetic activity, as assessed by the number of vomiting episodes. The concern that the mechanism of action of DQ-2511 was blockade of receptors for cholecystokinin-octapeptide, dopamine, serotonin, alpha-calcitonin gene-related peptide, nicotine or muscarine, was resolved by results of radioligand binding studies showing the absence of a DQ-2511 binding to any of these receptor types. Evidence is accumulating that the mechanism of the prokinetic action of DQ-2511 involves the intrinsic and extrinsic autonomic innervation.

Effects of diacetyl monoxime on the fast Na+ current were examined by the whole-cell voltage-clamp method in embryonic chick ventricular myocytes. Diacetyl monoxime (10-20 mM) decreased the duration and amplitude of the action potential and depressed the amplitude of the peak fast inward Na+ current by about 25 (10 mM)-45% (20 mM), without affecting other I-V parameters. Neither the activation and inactivation kinetics of the Na+ channels, such as the time to peak current and the time constant of inactivation, nor the steady state characteristics of the inactivation and activation were affected by diacetyl monoxime. It also did not alter the window conductance and the recovery kinetics from inactivation (reactivation). Hence, diacetyl monoxime suppresses the fast Na+ current, without affecting the time-dependent and voltage-dependent kinetics.

The radioactive microsphere technique was used to determine the contribution of acute changes in systemic hemodynamic variables to the lowering of blood pressure caused by substance P in rats anesthetized with urethane. Infusion of 0.74 nmol/kg/min of substance P caused a decrease of blood pressure, cardiac output, stroke volume and blood flow to most tissues. Total and regional vascular resistances were not affected. Heart rate was increased. These results suggest that the lowering of blood pressure caused by substance P occurs as a result of the decreased stroke volume and cardiac output. The most likely explanation for the decreased stroke volume is a decreased venous return. Several studies have shown that substance P has a direct effect to dilate peripheral arteries. Since substance P dilates arteries, one would expect a decrease of peripheral vascular resistance. The results of this study suggest, however, that counter-regulatory processes, elicited in response to the vasodilatation and direct effects of substance P on sympathetic ganglia to increase the sympathetic nervous system activity, offset the direct effect of substance P on arteries that would otherwise cause a decrease of peripheral vascular resistance.

BOC-Tyr-Pro-Gly-Phe-Leu-Thr(OtBu) is a potent, highly delta-opioid receptor-selective competitive antagonist, the Ke values in the mouse vas deferens in vitro assay against [D-Ala2, D-Leu5]-enkephalin [D-Pen2, D-Pen5]enkephalin and deltorphin-II being 39.5, 38.7 and 27.3 nM, respectively, whereas those against [D-Ala2, MePhe4-Gly5-ol]enkephalin (DAMGO) and ethylketocyclazocine in the guinea-pig ileum are 368,000 and > 200,000 nM, giving a higher than 9000-fold delta- vs mu- and a higher than 5000-fold delta- vs kappa-selectivity ratio. The Ki values against various labeled delta-ligands in the rat brain receptor binding assay were in the 300-1000 nM range, whereas the Ki against [3H]-DAMGO was higher than 30,000 nM. The striking discrepancies between bioassay and receptor binding data show another aspect of already recognized differences of mouse vas deferens and rat brain delta-receptors. With the aim of producing a delta-selective affinity ligand, we synthesized the BOC-Mel1 derivative; however, there was a 175-fold loss of delta-receptor affinity in the bioassay and no indication of an irreversible interaction, but a delta-agonist effect appeared in spite of nonprotonated nitrogen. The corresponding BOC-Phe1 derivative had a 10 times higher affinity and, apparently, no agonist activity.

The role of 5-hydroxytryptamine (5-HT) in platelet thrombus formation and in the mechanisms of inhibition of thrombus formation by 5-HT2A antagonists was investigated using a turbidimetric method. Collagen-induced platelet aggregation occurred simultaneously with a release of 5-HT from the platelets. The supernatant of collagen-aggregated platelets induced a further aggregation volume-dependently. This supernatant-induced aggregation was inhibited by either 5-HT2A antagonists or adenosine-diphosphate (ADP) scavenging. 5-Hydroxytryptamine and a small amount of the supernatant shifted the dose-response curves of collagen to the left. The aggregation velocity and the onset of aggregation by collagen were significantly increased by the supernatant, but not by 5-HT. The 5-HT2A antagonists, ketanserin and MCI-9042, returned the dose-response curves of the maximum aggregation and of the aggregation velocity of collagen, which were already amplified by the supernatant, to the original values. The onset of aggregation was delayed by the antagonists, but was not completely returned to the original points. There were distinct differences between the effects of endogenous 5-HT, derived from platelets which were stimulated by collagen, and those of exogenous 5-HT on both extensive platelet activation and amplification of the collagen-induced aggregation. These findings suggest that endogenous 5-HT activates platelets in synergism with ADP. The 5-HT2A antagonists used, block the synergism via 5-HT2A receptors and lead to inhibition of a positive feedback loop of thrombus formation.

This article reviews critically the present status of lithium in the treatment and prophylaxis of manic-depressive illness compared to the two anticonvulsant drugs, carbamazepine and valproic acid. Lithium is used successfully in the prophylaxis and treatment of manic-depression. The mechanism by which it exerts its effects is still not very clear. There is much evidence to indicate that lithium may exert its therapeutic action by interfering with the metabolism of phosphoinositides which play an important role in synaptic transmission. Because of lithium's narrow therapeutic/toxic ratio, blood concentration monitoring is crucial. Published data suggest that, compared to lithium, carbamazepine is similar in its relative specificity in treating mania. It is often faster in achieving its antimanic effects and best established as an alternative for patients not responding or intolerant to lithium. Carbamazepine is a good substitute for lithium when severe renal problems exclude the use of lithium. The therapeutic profile of valproic acid in manic-depression, although less extensively studied, appears to be similar to that of carbamazepine. As carbamazepine, it seems to be best indicated in patients with rapid cycles. Whereas lithium inhibits myo-inositol monophosphatase, carbamazepine shows a stimulating effect and valproic acid has no effect on this biochemical target. The implication of the inositol pathway in the pathogenesis of adverse effects, such as neurotoxicity and dermatological irritation, is discussed. A further understanding of this pathway is important for the future development of new lithium-like compounds in order to maximize the therapeutic benefits without the adverse effects.