Comparative effects of T-type and L-type Ca2+-antagonists against noradrenaline-induced contractions of human vas deferens

OBJECTIVE To investigate the effects of the relatively selective T-type Ca2+-antagonists, mibefradil and flunarizine, and the L-type Ca2+-antagonist, nifedipine, on the contractions of longitudinal and circular muscles of human vas deferens, to elucidate the possible involvement of T-type voltage-gated Ca2+ channels (VOCs) in the contractile function of the tissue. MATERIALS AND METHODS Human vas deferens specimens from elective vasectomies were cut into strips of longitudinal muscle or transversely into rings of circular muscle. These were set up for tension recording and superfused with Krebs' medium (36 degrees C). Contractions were evoked by noradrenaline or high [K+](o) (in the presence of the L-type Ca2+ agonist, FPL 64176) and the effects of Ca2+ antagonists were determined. RESULTS Noradrenaline (0.1-100 mu mol/L) evoked rhythmic and tonic contractions of longitudinal and circular muscles, which were potently inhibited by nifedipine (< 0.1 mu mol/L). Mibefradil (1-10 mu mol/L) inhibited the contractions but was comparatively more effective in longitudinal than circular muscle. Flunarizine was ineffective except against contractions to low concentrations of noradrenaline. The drugs' potencies as antagonists of L-type VOCs were determined against contractions to high K+ (120 mmol/L in the presence of FPL 64176, 1 mu mol/L). The contractions in longitudinal and circular muscle had different times to peak and decline but were inhibited comparably by nifedipine (50% inhibitory concentration, IC50, longitudinal and circular muscle, approximate to 2 nmol/L) or by mibefradil (IC50 longitudinal muscle, 1.1 mu mol/L; circular muscle, 2.4 mu mol/L) and were less sensitive to flunarizine (up to 30 mu mol/L). CONCLUSION These results indicate that noradrenaline-induced contractions of human vas deferens depend primarily on nifedipine-sensitive L-type VOCs, as opposed to mibefradil/flunarizine-sensitive T-type VOCs. The effects of mibefradil and flunarizine, at concentrations found to be effective against noradrenaline-induced contractions, involve the blockade of L-type VOCs. The modest differential effect of mibefradil in longitudinal and circular muscle is discussed in relation to factors that modulate activation and drug-sensitivity of L-type VOCs.