Effects of nifedipine derivatives on smooth muscle cells and neuromuscular transmission in the rabbit mesenteric artery.

Abstract

The effects of nifedipine and its derivatives, nisoldipine, nimodipine and nitrendipine, on smooth muscle cells and neuromuscular transmission were investigated in the rabbit mesenteric artery. These agents in concentrations of up to 2 X 10(-7) M modified neither the membrane potential nor the membrane resistance, yet did inhibit the spike potential evoked by direct muscle stimulation in the presence of TTX or by perivascular nerve stimulation. The inhibitory action of nitrendipine was weaker than that of the other derivatives. These agents had no effect on the miniature excitatory junction potentials (m.e.j.ps) and e.j.ps evoked by the first stimuli and after completion of the facilitation in a train stimulation. Nifedipine and its derivatives had no effect on the K-induced depolarization but did have a marked effect on the K-induced contraction. Nisoldipine showed the highest inhibitory potency for the K-induced contraction [IC50 was 1.2 X 10(-9) M for the 128 mM (K)o-induced contraction]. Noradrenaline depolarized the membrane (greater than 5 X 10(-7 M) and produced contraction (greater than 3 X 10(-7) M). The contraction evoked by high concentrations of noradrenaline was inhibited by these agents to a greater extent than that evoked by low concentrations. The contraction evoked by perivascular nerve or direct muscle stimulation was partly inhibited by nifedipine and its derivatives. The contraction elicited by Na-free solution was inhibited by these agents but the noradrenaline- or caffeine-induced contraction in Ca-free solution was not. These results indicate that in smooth muscle cells of the rabbit mesenteric artery, nifedipine and its derivatives inhibit the voltage dependent Ca-influx which occurs during the spike potential and in response to K-, electrically- or noradrenaline-induced depolarization. These derivatives appear to have no effect on the adrenoceptor operated Ca increase in myoplasm which occurs in the absence of depolarization at low noradrenaline concentrations. The derivatives act as Ca antagonists with a quantitative difference in potency, i.e. the strongest action was observed with nisoldipine and the weakest with nitrendipine.