ENDOTHELIUM-DEPENDENT RELAXATION OF PORCINE PULMONARY-ARTERIES VIA 5-HT(1C)-LIKE RECEPTORS

In PGF2alpha-precontracted pulmonary arteries with intact endothelium, 5-hydroxytryptamine (5-HT, 1.0-100 nmol/l) caused a concentration-dependent reversible relaxation, at higher concentrations the contractile response prevailed. In endothelium-denuded vessels relaxation was absent. 5-HT-induced relaxation of pre-contracted pulmonary arteries was probably mediated by release of an endothelium-derived relaxing factor (EDRF). Preincubation of the arteries with methylene blue or NG-nitro-L-arginine (200 mumol/l) attenuated the relaxant effect. The 5-HT-induced relaxation was accompanied by an increase in cGMP. Indomethacin (3 mumol/1) did not influence the 5-HT-induced relaxation indicating that eicosanoids are not involved in the relaxant response to 5-HT. The 5-HT1C and 5-HT2 receptor agonist alpha-methyl-5-HT was as potent as 5-HT in inducing relaxation. The rank order of relaxant potency of the agonists investigated was alpha-methyl-5-HT > 5-HT > 5-methoxytryptamine > tryptamine > omega-methyl-5-HT > 5-carboxamidotryptamine > 2-methyl-5-HT > 5,6-dihydroxytryptamine > m-chlorophenylpiperazine > sumatriptan > 8-OH-DPAT. Phentolamine, pindolol and ICS 205-930 did not interfere with the relaxant effect. The 5-HT2 receptor antagonist ketanserin (1 mumol/1) inhibited the contractile response but did not alter vasodilatation. Apart from the blockade of the contractile effects, mesulergine, cyproheptadine and mianserin (0.1 - 3.0 mumol/l, each) induced a parallel shift to the right of the concentration-response curve for the relaxation induced by alpha-methyl-5-HT or 5-HT. Spiperone (0.3 mumol/1) exerted weak inhibitory effects on relaxation and contraction. The most potent (noncompetitive) antagonist against relaxant responses was metitepine (0.1-1.0 mumol/1) which markedly depressed the relaxant maximum effect of the agonists. The failure of ketanserin and ICS 205-930 to inhibit the relaxant effect of 5-HT receptor agonists suggests that classical 5-HT2 and 5-HT3 receptors are not involved in the endothelium-dependent relaxation. Comparison of the rank order of potencies of agonists and antagonists with their affinities for brain binding sites revealed that the endothelial 5-HT receptors are similar to the 5-HT1c receptor subtype. Furthermore, the endothelial receptors exhibit marked similarity to the recently cloned 5-HT receptor mediating contraction of the rat stomach fundus.