Antagonism of the effects of 5-hydroxytryptamine on the rabbit isolated vagus nerve by BRL 43694 and metoclopramide.
Depolarization and reduction in the C fibre compound action potential (C spike) in response to 5-HT were recorded simultaneously from rabbit isolated vagus nerve. 5-HT (0.1-100 mumol/l) was applied cumulatively and EC50 and IC50 values measured from individual concentration-response curves. Blockade of 5-HT responses by the 3-indazole carboxamide, BRL 43694, was investigated and compared with the blocking action of metoclopramide. BRL 43694 was a selective antagonist of 5-HT responses. A concentration of 10 nmol/l BRL 43694, which nearly abolished the depolarization and reduction of the C spike evoked by 5-HT (100 mumol/l), had no effect on similar responses evoked by DMPP (100 mumol/l) or GABA (100 mumol/l). Blockade of 5-HT responses by BRL 43694 (0.3 nmol/l) was slow in onset, a plateau blockade occurring after equilibrium of tissue with antagonist for 2 to 3 h. Metoclopramide induced a blockade of rapid onset. The maximal blockade was apparent within 30 min of application. Full recovery in the responsiveness of the tissue to 5-HT was observed within 30 min of washing out metoclopramide. BRL 43694 at concentrations of 0.3, 1, 3 and 10 nmol/l caused a progressive rightward shift of the concentration-response curves to 5-HT. At the highest concentration of antagonist, there was some depression of the maximal 5-HT response. The apparent pA2 estimated from the Schild equation was 10.03 +/- 0.09 (mean +/- SEM, n = 20) against 5-HT depolarization and 10.31 +/- 0.1 against C spike reduction. Schild plots had slopes not significantly different from 1.0.(ABSTRACT TRUNCATED AT 250 WORDS)
Elliott
P
P
Department of Physiology, University of Wales College of Cardiff, UK.
Seemungal
B M
BM
Wallis
D I
DI
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D005260:Female; D017829:Granisetron; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists; D014630:Vagus Nerve / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D004246:Dimethylphenylpiperazinium Iodide; D017829:Granisetron; D007191:Indazoles; D008787:Metoclopramide; D011720:Pyrazoles; D012701:Serotonin; D012702:Serotonin Antagonists; D005680:gamma-Aminobutyric Acid