Effects of diltiazem on calcium concentrations in the cytosol and on force of contractions in porcine coronary arterial strips

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Abstract
1 Using front-surface fluorometry with fura-2-loaded porcine coronary arterial 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 contractile 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.