Effects of mibefradil on uterine contractility

Mibefradil, a benzimidazolyl tetralol derivative, is a new Ca2+ channel antagonist which is structurally distinct from other Ca2+ 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) Ca2+ channels. Nevertheless, it blocks L-type Ca2+ channels in several tissues. In the present study, the effects of mibefradil on spontaneous rhythmic contractions and on contractions elicited by CaCl2 (K+-depolarized preparations) and oxytocin (in low Ca2+/Ca2+-free solutions) were investigated on uterus strips from pregnant and nonpregnant 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 IC50 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. Mibefiradil (3 muM) caused a rightward shift in the concentration-response curves for CaCl2 in K+ (40 mM)-depolarized uterus strips taken from both pregnant and non-pregnant rats. Mibefradil (3 muM) was, however, more potent for antagonising CaCl2 responses in uterus strips obtained from pregnant rats than in those from non-pregnant rats. Mibefiradil (3 muM) had no effect on oxytocin-induced contraction in Ca2+-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 Ca2+-free PSS. Thus, mibefradil probably antagonizes L-type Ca2+ channels as well as interferes with the intracellular Ca2+ release mechanism, which would be helpful in the development of a tocolytic agent. (C) 2002 Elsevier Science B.V. All rights reserved.