title: Potentiation by endothelin-1 of 5-hydroxytryptamine-induced contraction in coronary artery of the pig.
abstract: 1. 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. 2. Isometric tension and cytosolic Ca2+ concentration ([Ca2+]i) in a ring segment of porcine coronary artery loaded with fura-2 were measured simultaneously. 3. 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 radio-receptor 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. 4. 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. 5. 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.6. 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.7. 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.
authors.affiliation: Department of Pharmacology, University of Shizuoka, School of Pharmaceutical Sciences, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakayama
authors.forename: Y
authors.initials: Y
authors.lastname: Ishigai
authors.forename: H
authors.initials: H
authors.lastname: Uchida
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; 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*; D012701:Serotonin / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013552:Swine
chemical_list: D002121:Calcium Channel Blockers; D016232:Endothelins; D012701:Serotonin; D002118:Calcium