Characterization of an endothelial 5-hydroxytryptamine (5-HT) receptor mediating relaxation of the porcine coronary artery

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Abstract
The pharmacological properties of the endothelial 5-hydroxytryptamine (5-HT) receptors involved in relaxation of vascular smooth muscle were determined in rings of pig coronary artery contracted with 10 nmol/1 of the thromboxane A2 receptor agonist 9,11-dideoxy-11α,9α-epoxy-methano-prostaglandin F2α (U 46619). (1) In the presence of 10 μmol/l ketanserin, relaxation was obtained with: 5-HT (apparent pD2 value 7.00), 5-carboxamidotryptamine (5-CONH2-T; 6.42), 5-aminotryptamine (5-NH2-T; 5.96), 5-methoxytryptamine (5-OCH3-T; 5.92), tryptamine, 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo(1,2-a)quinoxaline maleate (CGS 12066 A) and 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU 24969). The maximum relaxation obtainable with the agonists was about 40–60% of the U 46619-induced contraction and the concentration-response curves for 5-HT, 5-NH2-T and 5-OCH3-T were bell-shaped. The endothelium-dependence of this effect (i. e. the failure to relax the artery in endothelium-denuded preparations) was demonstrated for 5-HT, 5-CONH2-T, RU 24969, CGS 12066A and tryptamine. (2) 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 4-hydroxytryptamine, quipazine and yohimbine were ineffective in decreasing the tension of arteries with or without endothelium. Ipsapirone elicited full relaxation of U 46619-induced contraction, but this effect was not endothelium-dependent. (3) Metitepine (0.03-1 μmol/l), 6-chloro-2-(1-piperazinyl)pyrazine (MK 212; 10 μmol/l), methysergide (1 gmol/l) and cyanopindolol (0.1 μmol/l) antagonized the relaxing effect of 5-HT in a non-surmountable manner, whereas metergoline (0.1 μmol/l), quipazine (10 μmol/l), yohimbine (1 μmol/l), propranolol (1 μmol/l) and (3α-tropanyl)-1H-indole-3-carboxylic acid ester (ICS 205-930; 0.1 μmol/l) did not. However, spiroxatrine (0.1 μmol/l) and mesulergine (10 μmol/l) enhanced the 5-HT-induced relaxation. The endothelium-dependent relaxation induced by 5-CONH2-T was also inhibited by metitepine 1 gmol/l. (4) The 5-HT-induced relaxation was probably mediated by release of an endothelium-derived relaxing factor (EDRF). Gossypol, an inhibitor of EDRF, virtually abolished the 5-HT-induced relaxation while indometacin, an inhibitor of cyclooxygenase and accordingly of PGI2 formation, did not. In conclusion, the failure of ketanserin and ICS 205–930 to counteract the relaxant effect of 5-HT receptor agonists excludes the involvement of 5-HT2 and 5-HT3 receptors, respectively, in the endothelium-dependent relaxation of the porcine coronary artery. The rather high potency of 5-CONH2-T and the ability of certain 5-HT receptor antagonists, such as metitepine, methysergide and cyanopindolol, to counteract the effect of 5-HT are compatible with a “5-HT1” character of the endothelial receptor. However, on the basis of the present data, no final classification, in particular with respect to the known “5-HT1” receptor subtypes, is possible. Classification is also hampered by the bell-shaped character of the concentration-response curves for 5-HT receptor agonists and by their property to produce only partial relaxation.