A possible mechanism for relaxation of rat uterine smooth muscle by nicardipine hydrochloride (YC-93), a new potent vasodilator.

Abstract

A new potent vasodilator, nicardipine hydrochloride, inhibited oxytocin-induced contraction of rat uterus dose-dependently with an increase in the intracellular cAMP level at the onset of relaxation. Dibutyryl cAMP and papaverine, an inhibitor of cAMP phosphodiesterase (PDEase), also inhibited the contraction. Nicardipine competitively inhibited PDEase in homogenates of rat uterus which exhibited apparently 2 Km values for cAMP (3.6 .mu.M and 67.3 .mu.M) with the Ki [inhibition constant] of 5.3 .mu.M and 13.2 .mu.M, respectively, but had no effect on adenylate cyclase. Nicardipine enhanced Ca uptake by rat uterine microsomes, at concentrations which inhibited oxytocin-induced contraction in the same manner as cAMP. The maximal stimulation by nicardipine of the microsomal Ca uptake was identical substantially to that by cAMP, and both were not additive. cAMP was also accumulated during the uptake reaction in the presence of nicardipine. Neither myosin ATPase nor microsomal Ca2+-dependent ATPase was inhibited directly by nicardipine. The inhibition of oxytocin-induced contraction of rat uterus by nicardipine may be due to enhancement of microsomal Ca uptake, mediated by cAMP accumulated through the inhibition of PDEase.