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 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.
Hirano
K
K
Research Institute of Angiocardiology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Kanaide
H
H
Abe
S
S
Nakamura
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003331:Coronary Vessels / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects* / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D005470:Fluorometry; D016257:Fura-2; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D013552:Swine
D006632:Histamine; D004110:Diltiazem; D002118:Calcium; D016257:Fura-2