Relationship between cytosolic calcium concentration and force in the papaverine‐induced relaxation of medial strips of pig coronary artery

Abstract

The mechanisms of vasorelaxation induced by papaverine were investigated using front‐surface fluorometry and fura‐2‐loaded medial strips of the pig coronary artery. In the presence of extracellular Ca2+ (1.25 × 10−3 m), histamine (10−4 m) induced abrupt elevations of cytosolic calcium concentration, [Ca2+]i reaching a peak within 12 s (the first phase); after making a slight shoulder, [Ca2+]i declined gradually to reach sustained levels (the second phase). Force rapidly rose to reach maximum levels in 3 min, then gradually declined. Papaverine (10−7–10−5 m) inhibited both the first and the second phases of [Ca2+]i elevation and the development of force induced by histamine, in a concentration‐dependent manner. In the absence of extracellular Ca2+, histamine (10−4 m) induced a transient increase in [Ca2+]i and force, both of which were inhibited in a concentration‐dependent manner by papaverine (10−7–10−5 m). When papaverine was washed out, a second application of 10−4 m histamine also induced transient increases in [Ca2+]i and force. The smaller the first response, the greater was the second response. The total amount of [Ca2+]i released from intracellular stores by the first and second application of histamine in the presence of papaverine was smaller than in its absence, thereby indicating a reduction of Ca2+ in the histamine‐sensitive store. However, while papaverine (10−5 m) did not affect the transient increase in [Ca2+]i induced by 2 × 10−2 m caffeine, contractions were inhibited. For a given level of [Ca2+]i, the force developed with the cumulative application of histamine (10−7 m–10−4 m) was greater than that observed with the cumulative application of extracellular Ca2+ (0–7.5 × 10−3 m) during high K+ depolarization. Papaverine (10−7 m–10−5 m) suppressed, in a concentration‐dependent manner, the increase in [Ca2+]i and the force induced by cumulative applications of both histamine and extracellular Ca2+ during high K+ depolarization. The [Ca2+]i‐force curve obtained by depolarization with K+, but not that obtained during histamine application, was shifted to the right by papaverine. Diltiazem, 10−7 m, a concentration causing a similar degree of relaxation to 10−5 m papaverine, did not shift the [Ca2+]i‐force curve obtained with high K+. Nitroglycerin (10−6 m) and isoprenaline (10−6 m) shifted the [Ca2+]i‐force curve to the right to a greater extent than did 10−5 m papaverine. These findings suggest that papaverine relaxes medial strips of the porcine coronary artery by two mechanisms. The first is mainly due to a decrease in [Ca2+]i, not only through inhibiting Ca2+ influx through either voltage‐dependent or receptor‐operated Ca2+ channels, but also by inhibiting agonist‐induced intracellular Ca2+ release. This occurs presumably by interference with the signal transduction pathway for histamine and by a depletion of Ca2+ in histamine‐sensitive stores. Secondly, the [Ca2+]i‐sensitivity of certain contractile mechanisms may be minimally decreased. 1994 British Pharmacological Society