Potentiation by endothelin‐1 of 5‐hydroxytryptamine‐induced contraction in coronary artery of the pig

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Abstract
In order to elucidate the physiological and potential pathological roles of endothelin‐1 (ET‐1) in coronary artery contraction and relaxation, we undertook the present study to examine the action of ET‐1 itself, and the combined effects of ET‐1 with vasoconstrictor agonists such as acetylcholine (ACh), histamine, and 5‐hydroxytryptamine (5‐HT), all of which have been implicated in the genesis of coronary spasm. Isometric tension and cytosolic Ca2+ concentration ([Ca2+]i) in a ring segment of porcine coronary artery loaded with fura‐2 were measured simultaneously. ET‐1 contracted the artery in a concentration‐dependent manner; and nisoldipine, a Ca2+ channel blocking drug of the 1,4‐dihydropyridine type, antagonized the ET‐1 action non‐competitively. A radioreceptor binding assay also indicated the mutually exclusive binding of ET‐1 and (+)‐[3H]‐PN200–110, a Ca2+ channel ligand, to the membrane fraction of porcine coronary artery. ET‐1 (10–100 pm) increased tension and [Ca2+]i in a parallel manner, while at higher concentrations (1–10 nm) it produced further contraction with a small increase in [Ca2+]i. ET‐1 (30–100 pm) selectively potentiated the 5‐HT‐induced contraction 1.5 to 2 times over the control without causing a significant increase in [Ca2+]i, which seems to be qualitatively similar to a tumour promoting phorbol ester, 12‐deoxyphorbol 13‐isobutylate (DPB). Bay K 8644 (10 nm), on the other hand, potentiated the contraction in response to practically all agonists used and affected a concomitant increase in [Ca2+]i. A Ca2+ channel blocking drug such as diltiazem abolished the increase in [Ca2+]i and partially attenuated the mechanical potentiation produced by a small amount of ET‐1 in combination with 5‐HT. The results suggest that ET‐1 and 5‐HT interact functionally at the cellular or subcellular level and modulate the Ca2+ sensitivity of the contractile elements through the possible activation of protein kinase C.

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