Anti-spasmogenic and spasmolytic effects of BRL 34915: a comparison with nifedipine and nicorandil

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Abstract
BRL 34915, nifedipine and nicorandil were compared for anti-spasmogenic activity against field stimulation (frequency-response curves), noradrenaline and KCl (concentration-response curves), and for spasmolytic activity against tissues pre-contacted with 3 .times. 10-2 and 9 .times. 10-2 M KCl, in rabbit isolated mesenteric artery. BRL 34915 was an effective anti-spasmogenic agent (threshold concentration 10-8 M) against endogenous noradrenaline released by field stimulation, and slightly less effective (threshold concentration 10-7 M) against exogenous noradrenaline. Anti-spasmogenic activity of BRL 34915 against KCl was limited. BRL 34915 demonstrated spasmolytic activity against contractions to KCl 3 .times. 10-2 M (IC50 = 3.7 .times. 10-7 M) but not KCl 9 .times. 10-2 M. Nicorandil demonstrated anti-spasmogenic activity against all three contractile stimuli although relatively high concentrations (10-6-10-4 M) of the drug were required. Spasmolytic activity was greater against 3 .times. 10-2 M KCl contractions (IC50 = 1.0 .times. 10-5 M) than against 9 .times. 10-2 M KCl contractions (maximum relaxation of 18% at 10-4 M). Nifedipine (10-9-10-7 M) was a potent inhibitor of contractions over the entire KCl concentration range (1 .times. 10-2-9 .times. 10-2 M). Nifedipine was, however, much less effective against contractions to exogenous or endogenous noradrenaline. The results are consistent with the hypotheses that (a) the inhibitory activity of BRL 34915 may involve K+ channel activation, (b) the inhibition by nicorandil involves an additional mechanism(s) and (c) nifedipine is a Ca2+ channel blocker with selectivity for voltage-operated rather than receptor-operated Ca2+ channels.