Journal de pharmacologie最新文献

Recent advances in the pharmacology of voltage-operated Ca++ channels (VOCs) are reviewed. It is proposed that three subgroups of calcium-antagonists exist and the pharmacology of the "subgroups" is compared at the level of ligand binding and functional (in vitro and in vivo) experiments. Recent electrophysiological experiments have indicated that there may be two populations of VOCs. The implications of these findings are discussed in the light of the different antagonist subgroups.

The solubilization of the serotonergic 5HT1 and 5HT3 sites was performed with digitonin and sodium cholate at 1% (final concentration). Two binding sites for [3H]5HT were observed on rat or horse brain synaptosomal membranes solubilized with these detergents. The corresponding dissociation constants (KD) were 1-3 nM and 13-30 nM respectively. These values were closely similar to those corresponding to 5HT1 and 5HT3 sites located in intact membranes. The solubilized sites specifically bound 5HT. The effect of GTP decreasing the binding to 5HT1 sites was lost on solubilized 5HT1 sites; it was recovered, however, by addition of phospholipids (asolectin 0,2%). The apparent molecular weights of these sites were determined using the gel filtration method (438 and 235 K daltons). The photoactivation of [3H]5HT by U.V. light was used to label 5HT1 and 5HT3 sites irreversively in membranes. The binding of [3H]5HT following U.V. irradiation was not dissociated after dilution; it was saturable and prevented by serotonergic drugs and not by adrenergic or dopaminergic antagonists. Moreover, GTP added prior to the irradiation reduced it markedly thus showing that 5HT1 sites were labelled. Electrophoretic and fluorographic analyses of the labelled material evidenced a 60 K dalton-band specifically labelled with [3H]5HT (5 or 20 nM). These results tend to indicate that the 60 K dalton-proteic band might represent a proteic subunit constituting part of 5HT1 and 5HT3 sites.

The effects of several cardiotonic agents (ARL-115, Amrinone, RMI 82-249, Milrinone, CI-914, RO 13-6438 and APP 201-533) were compared with those of ouabain on pig isolated coronary artery, guinea-pig isolated atria and guinea-pig perfused heart to compare vasodilatory and inotropic responses. Like ouabain, all compounds tested produce positive inotropic and chronotropic effects in isolated atria and on perfused heart, and induce relaxation in precontracted pig coronary artery and coronary vasodilation on perfused heart, except ouabain which induces vasoconstriction. The results indicate that non steroidal cardiotonics exert positive inotropic and coronary vasodilatory effects.

The human basophil degranulation test (HBDT) quantifies the apparent disappearance of basophils after contact with the sensitizing allergen. The inhibition of degranulation by pharmacological products can be appreciated by incubating beforehand the basophils with the substance concerned during various times. The inhibitory effect is evaluated by the difference of degranulation with or without it. EDTA, sodium cromoglycate, verapamil and bepridil have been tested at different concentrations and at 3 times of basophils preincubation (0,15 and 30 minutes). Results obtained confirm previous reports concerning cromoglycate which didn't inhibit degranulation of basophils. EDTA at 3.4*10(-2)M and 3.4*10(-3)M concentration has an inhibitory effect, not increasing with the time of preincubation. The inhibition with verapamil is of the same order at 1*10(-4)M for the 3 times of incubation and weaker, but significant, at 1*10-M5 after 30 minutes of preincubation. Bepridil inhibits at 1*10(-4)M, but this effect disappears if basophils are preincubated 30 minutes with the drug. The inhibition of the specific basophil degranulation by these drugs is probably du to their calcium antagonist property. However their effect is not quite similar when cells are preincubated at different times with the drug. On the other hand, one can study with HBDT the inhibitory effect of a new product, even if the therapeutic indications would have to be studied afterwards.

The effects of raubasine and tetrahydroalstonine (THA) on the vasopressor response to sympathetic nerve stimulation and to i.v. administration of noradrenaline were studied in the pithed rat to ascertain whether raubasine and THA would preferentially block pressor responses due to exogenous versus endogenous noradrenaline alpha-adrenergic receptor activation. Raubasine (0.5 to 4 mg/kg i.v.) was more effective in blocking the response due to sympathetic nerve stimulation than that due to i.v. noradrenaline. On the other hand THA (0.5 to 4 mg/kg i.v.) produced greater inhibition of the i.v. noradrenaline response than the sympathetic nerve stimulation response. THA (0.5, 1, 2 mg/kg i.v.) enhanced the nerve stimulation response, while at the 4 mg/kg dose the response was slightly reduced. This may be explained by a preferential block by THA at low doses, of presynaptic alpha 2-adrenoceptors. In pithed rat raubasine and THA showed dose-related blocking effects on the pressor response of phenylephrine and B-HT 933, respectively. This suggest that raubasine preferentially blocks alpha-1 and THA alpha 2-adrenoceptors. The results suggest that raubasine and THA preferentially block the pressor responses of post-synaptic alpha-adrenergic receptor activation due to endogenous and exogenous noradrenaline, respectively.

Systemic injection of kainic acid (KA, 11 mg/kg i.p.) to male albino Sprague-Dawley rats produced a sequence of behavioral events: stereotypies, convulsions, aphagia and aggressiveness in the form of sparring at artificial night fall, as well as a decline in brain-Gaba and brain-dopamine (DA)-levels followed by an increase in DA-levels on days 6 and 10 after treatment. No notable variations in serotonin (5-HT) was observed. Pretreatments of rats with GABA-mimetic drugs (gamma-vinyl GABA, 900 mg/kg i.p.; THIP, 1 microgram/1 microliter/rat, i.c.v.) prevented the occurrence of convulsion, aphagia and aggressiveness. Systemic injection of p-chlorophenylalanine (PCPA) (300 mg/kg i.p.) induced aggressiveness in the form of sparring at night fall. Treatment with PCPA followed by injection of KA shifted mild aggressive behavior to a violent one in the form of biting and killing familiar rats. The findings suggest that KA-neurotoxicity is due in part to its effects on GABA- and DA-neurotransmissions. It is shown also that convulsions are induced by a decline in GABA-level while sparring is provoked by an enhancement in DA-level. Violent aggressiveness is induced by the additive disruptive effects on GABA- and 5-HT-neurotransmissions in PCPA + KA treated animals.