Amplification of sumatriptan-induced contractions with phenylephrine, histamine and KCl in the isolated human mesenteric artery: in-vitro evidence for sumatriptan-induced mesenteric ischaemia.
Sumatriptan, a 5-HT(1B/1D/1F) receptor agonist, is used to relieve migraine headache. Sumatriptan contracts some arteries either directly or after modest precontraction with non-serotonergic agonists. Sumatriptan can cause myocardial ischaemia and myocardial infarction. While previous in-vitro studies have shown that sumatriptan has no or only weak contractile activity in human omental arteries, recent clinical studies suggest that sumatriptan may induce mesenteric ischaemia. The aim of this study was to investigate the presence of contractile 5-HT(1B) receptors in the human mesenteric artery and to establish whether the weak sumatriptan-induced contractions are amplified by precontraction with various contractile substances. The study was performed in organ baths using endothelium-denuded isolated human mesenteric arteries. Sumatriptan induced concentration-dependent contractions in some mesenteric arteries [ E(max) 61+/-10% of the maximum contraction induced by 80 mM KCl, pD(2) (-log(10)EC(50)) 6.56+/-0.20, n=9]. In the other mesenteric arteries, sumatriptan induced only very weak ( E(max) <5%) or no contraction ( n=13). GR127935 (3 nM), a selective 5-HT(1B) receptor antagonist, antagonized sumatriptan-induced contractions insurmountably in sumatriptan-sensitive arteries. When the resting tension of the arterial rings was increased moderately by threshold concentrations (EC(10)-EC(20) of maximum contraction induced by 80 mM KCl) with the non-5-HT receptor agonists phenylephrine (10-100 nM), histamine (100 nM-1 microM) or the depolarizing agent KCl (4-10 mM), 5-HT(1B) receptor-mediated responses were amplified in sumatriptan-insensitive arteries (with phenylephrine E(max) 82+/-17%, pD(2) 6.64+/-0.20, n=7; with histamine E(max) 107+/-26%, pD(2) 6.16+/-0.14, n=6; with KCl E(max) 78+/-16%, pD(2) 6.45+/-0.15, n=7). These results show that sumatriptan induced concentration-dependent contractions in sumatriptan-sensitive mesenteric arteries and that 5-HT(1B) receptors were present and active in these vessels. However, in sumatriptan-insensitive arteries, precontraction is required for sumatriptan to induce concentration-dependent contractions. These findings suggest that sumatriptan may induce ischaemia in human mesenteric vasculature directly or in the presence of precontractile risk factors.
Gul
Husamettin
H
Gülhane Military Medical Academy, School of Medicine, Department of Pharmacology, 06018 Etlik, Ankara, Turkey.
Yildiz
Oguzhan
O
D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007511:Ischemia / Q000139:chemically induced; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000633:toxicity*; D014662:Vasoconstrictor Agents / Q000633:toxicity*
C470302:HTR1B protein, human; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D011189:Potassium Chloride; D006632:Histamine; D018170:Sumatriptan