EFFECTS OF DILTIAZEM ON CALCIUM CONCENTRATIONS IN THE CYTOSOL AND ON FORCE OF CONTRACTIONS IN PORCINE CORONARY ARTERIAL STRIPS

1. Using front-surface fluorometry with fura-2-loaded porcine coronary artery strips, we simultaneously measured effects of a Ca2+ antagonist, diltiazem, on cytosolic Ca2+ concentrations ([Ca2+](i)) and on tension development. 2. In the presence of extracellular Ca2+ (1.25 mM), histamine concentration-dependently induced abrupt (the first component) and then sustained (the second component) elevations of [Ca2+](i). In the absence of extracellular Ca2+, histamine induced transient elevations of [Ca2+](i), and the time course was similar to that of the first component observed in the presence of extracellular Ca2+. Histamine caused a greater contraction for a given change in [Ca2+](i) than did potassium, at [Ca2+](i) over 300 nM. 3. Diltiazem, 10-8 M to 10-5 M, concentration-dependently inhibited the second component of [Ca2+](i) elevation and tension development induced by histamine (10-5 M). Only at higher concentrations (over 10-5 M) did diltiazem inhibit the first component of increases in [Ca2+](i) and tension development induced by histamine, both in the presence and absence of extracellular Ca2+. 4. Diltiazem (10-6 M) inhibited increases in [Ca2+](i) and tension development induced by cumulative applications of extracellular Ca2+ during K+-depolarization. The curve of [Ca2+](i) against tension of these Ca2+-induced contractions obtained in diltiazem-treated strips overlapped with that obtained in untreated strips. This suggests that diltiazem has no direct effects on contracted elements. 5. In contrast, the histamine-induced Ca2+-tension curve (second component) was shifted in parallel to the left by diltiazem. 6. We conclude that diltiazem, at therapeutic concentrations, specifically inhibits extracellular Ca2+-dependent increases in [Ca2+](i), with no effects on the release of Ca2+ from intracellular store sites or on Ca2+-sensitivity of the contractile elements involved in the contractions induced by elevations of [Ca2+](i).