title: Serotonin-induced contraction in porcine coronary artery: use of ergolines to support vascular 5-hydroxytryptamine2-receptor heterogeneity.
abstract: Serotonin-induced contraction in porcine coronary artery was studied in ring segments of coronary artery without endothelium. 5-hydroxytryptamine (5-HT), 5-methoxytryptamine (5-MeOT) and alpha-methyl-5-HT (alpha Me-5-HT) concentration-dependently contracted vessels with similar maximal force. The agonist rank order potency was 5-HT > alpha Me-5-HT > 5-MeOT. Neither prazosin (1 microM) nor tetrodotoxin (0.3 microM) significantly altered 5-HT-induced contraction, ruling out activation of alpha-1 adrenoceptors and sodium channels in the contractile response, respectively. Using 5-MeOT as the prototype agonist, cyanopindolol blocked contraction with an antagonist dissociation constant lower than expected for 5-HT1-receptor blockade and ICS 205-930 (10 microM) did not affect 5-MeOT-induced contraction. Five structurally distinct 5-HT2-receptor antagonists (ketanserin, cisapride, spiperone, MDL11939, ICI169369) blocked 5-HT-induced contraction with antagonist dissociation constants similar to reported 5-HT2-receptor affinities. Two ergoline-based 5-HT2-receptor antagonists, LY53857 and sergolexole, blocked 5-HT-induced contraction with antagonist dissociation constants lower than expected for vascular 5-HT2-receptor blockade. Based on the agonist profile and the fact that ICS 205-930 and cyanopindolol were not potent antagonists, the 5-HT receptor-mediating contraction does not represent either the 5-HT1A/B/C/D, 5-HT3 or 5-HT4 receptor. Rather, based on the affinity of several established 5-HT2-receptor antagonists, a 5-HT2 receptor mediates contraction in porcine coronary artery. However, the low antagonist affinity of the ergolines (i.e., LY53857 and sergolexole) suggests that heterogeneity of 5-HT2 receptors may exist among species.
authors.affiliation: Cardiovascular Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: D J
authors.initials: DJ
authors.lastname: Cushing
authors.forename: M L
authors.initials: ML
authors.lastname: Cohen
mesh_terms: D008735:5-Methoxytryptamine / Q000494:pharmacology; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000502:physiology; D004873:Ergolines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008237:Lysergic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013552:Swine
chemical_list: D004873:Ergolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C042390:alpha-methylserotonin; D012701:Serotonin; D008735:5-Methoxytryptamine; D008237:Lysergic Acid; C054583:sergolexole; C032663:LY 53857