Relationship between cytosolic calcium concentration and force in the papaverine-induced relaxation of medial strips of pig coronary artery.
1. The mechanisms of vasorelaxation induced by papaverine were investigated using front-surface fluorometry and fura-2-loaded medial strips of the pig coronary artery. 2. In the presence of extracellular Ca2+ (1.25 x 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. 3. 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 x 10(-2) M caffeine, contractions were inhibited. 4. For a given level of [Ca2+]i, the force developed with the cumulative application of histamine(10-7 M-10-1 M) was greater than that observed with the cumulative application of extracellular Ca2+(0-7.5 x 10-3 M) during high K+ depolarization. Papaverine (10-7 M-10-5M) 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.5. 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.
Aoki
H
H
Division of Molecular Cardiology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Nishimura
J
J
Kobayashi
S
S
Kanaide
H
H
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005456:Fluorescent Dyes; D016257:Fura-2; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010208:Papaverine / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D013552:Swine
D005456:Fluorescent Dyes; D002110:Caffeine; D006632:Histamine; D010208:Papaverine; D011188:Potassium; D002118:Calcium; D016257:Fura-2