A comparison of the effects of the calcium entry blockers, verapamil, diltiazem and flunarizine against contractions of the rat isolated aorta and portal vein

Abstract

The actions of the chemically distinct calcium entry blockers, verapamil (Ver), diltiazem (Dlz) and flunarizine (Flu) have been compared in rat isolated aorta and portal vein. KCl-induced contractions of the rat aorta depend exclusively upon extracellular Ca2+, whereas, those induced by noradrenaline (NA) rely upon Ca2+ from intra- and extracellular sources. The NA-induced contraction was pharmacologically dissected under Ca2+-free conditions revealing a contraction dependent upon intracellular Ca2+ (EGTA-resistant response) or a low concentration of prazosin which left a contraction which was mediated by extracellular Ca2+ (prazosin-resistant response). The portal vein produced spontaneous rhythmic contractions and a sustained contraction to NA and KCl; however, all responses appeared to depend exclusively upon extracellular Ca2+. In the aorta, contractions which might be expected to depend upon Ca2+-entry through voltage-operated channels (KCl-induced contraction) showed similar sensitivities to Ver, Dlz and Flu whereas, marked differences in the sensitivity to these agents was noted against contractions which appear to depend upon Ca2+-entry through receptor-operated channels (prazosin-resistant response). Only Dlz reduced contractions mediated by intracellular Ca2+ (EGTA-resistant response). In the portal vein Ver and Dlz caused similar pronounced reductions of spontaneous and NA or KCl-induced contractions. In contrast, these contractions of the portal vein were unaffected by Flu except at a concentration of 10 .mu.M. However, contractions induced by addition of Ca2+ (0-14 mM) to previously depolarized portal veins could be reduced by Flu (100 nM-10 .mu.M). The present study indicates that in the rat aorta, contractions mediated by intracellular Ca2+ and depolarization or receptor-activated Ca2+ entry can be pharmacologically dissected and that these processes show different sensitivities to calcium entry blockade. Of the agents tested, Ver displays the properties most commonly associated with an ideal calcium entry blocker. Ca2+-activation mechanisms in the portal vein differ from those in the aorta resulting in a different spectrum of selectivity of the calcium entry blockers studied.