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Endothelium-dependent relaxation of porcine pulmonary arteries via 5-HT1C-like receptors

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Summary

In PGF2α-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 precontracted pulmonary arteries was probably mediated by release of an endothelium-derived relaxing factor (EDRF). Preincubation of the arteries with methylene blue or NG-nitro-Lrarginine (200 μmol/l) attenuated the relaxant effect. The 5-HT-induced relaxation was accompanied by an increase in cGMP. Indomethacin (3 μmol/l) 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 α-methyl-5HT was as potent as 5-HT in inducing relaxation. The rank order of relaxant potency of the agonists investigated was α-methyl-5-HT > 5-HT > 5-methoxytryptamine > tryptamine > ω-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 μmol/l) 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 μmol/l, each) induced a parallel shift to the right of the concentration-response curve for the relaxation induced by a-methyl-5-HT or 5-HT. Spiperone (0.3 μmol/l) exerted weak inhibitory effects on relaxation and contraction. The most potent (noncompetitive) antagonist against relaxant responses was metitepine (0.1-1.0 μmol/l) 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.

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Authors and Affiliations

  1. Institut fur Pharmakologie und Toxikologie, Medizinische Hochschule Erfurt, Nordhauser Strasse 74, 0-5010, Erfurt, Federal Republic of Germany

    Erika Glusa & Manfred Richter

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  1. Erika Glusa
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  2. Manfred Richter
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Correspondence to E. Glusa at the above address

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Glusa, E., Richter, M. Endothelium-dependent relaxation of porcine pulmonary arteries via 5-HT1C-like receptors. Naunyn-Schmiedeberg's Arch Pharmacol 347, 471–477 (1993). https://doi.org/10.1007/BF00166737

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  • DOI: https://doi.org/10.1007/BF00166737

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