Effects of mibefradil on uterine contractility.

Mibefradil, a benzimidazolyl tetralol derivative, is a new Ca(2+) channel antagonist which is structurally distinct from other Ca(2+) channel antagonists such as nifedipine, verapamil and diltiazem. It is a very effective antihypertensive agent that is thought to achieve its action via a higher affinity block for low-voltage activated (T) than for high-voltage-activated (L) Ca(2+) channels. Nevertheless, it blocks L-type Ca(2+) channels in several tissues. In the present study, the effects of mibefradil on spontaneous rhythmic contractions and on contractions elicited by CaCl(2) (K(+)-depolarized preparations) and oxytocin (in low Ca(2+)/Ca(2+)-free solutions) were investigated on uterus strips from pregnant and non-pregnant rats. Mibefradil (10(-8)-3 x 10(-6) M) caused concentration-dependent inhibition of spontaneous contractions of uterus strips from pregnant and non-pregnant rats with the IC(50) values of 8.83 x 10(-7) M; 5.94 x 10(-7) M (amplitude) and 1.03 x 10(-6) M; 5.48 x 10(-7) M (frequency), respectively. Mibefradil (3 microM) caused a rightward shift in the concentration-response curves for CaCl(2) in K(+) (40 mM)-depolarized uterus strips taken from both pregnant and non-pregnant rats. Mibefradil (3 microM) was, however, more potent for antagonising CaCl(2) responses in uterus strips obtained from pregnant rats than in those from non-pregnant rats. Mibefradil (3 microM) had no effect on oxytocin-induced contraction in Ca(2+)-free physiological salt solution (PSS) on uterus strips from non-pregnant rats. However, it markedly inhibited oxytocin-induced contraction of pregnant rat uterus strips in Ca(2+)-free PSS. Thus, mibefradil probably antagonizes L-type Ca(2+) channels as well as interferes with the intracellular Ca(2+) release mechanism, which would be helpful in the development of a tocolytic agent.