Effects of mibefradil on uterine contractility

Abstract

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 −8–3×10 −6 M) caused concentration-dependent inhibition of spontaneous contractions of uterus strips from pregnant and non-pregnant rats with the IC 50 values of 8.83×10 −7 M; 5.94×10 −7 M (amplitude) and 1.03×10 −6 M; 5.48×10 −7 M (frequency), respectively. Mibefradil (3 μM) 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 μM) 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 μM) 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.