5-Hydroxytryptamine receptor profile in healthy and diseased human epicardial coronary arteries

Abstract

Study objective – The aim of the study was to investigate the receptor events that mediate the vascular effects of 5-hydroxytryptamine (5-HT) on human coronary arteries, since 5-HT has long been thought to play a role in coronary artery vasospasm. Design – Recently available selective receptor agonists and antagonists were used to examine the 5-HT receptor subtypes present in human epicardial coronary arteries using in vitro organ baths. Experimental material – 138 segments of coronary arteries were obtained from 21 patients aged 2-66 years undergoing heart transplantation. Measurements and main results – 5-HT produced only concentration dependent contractions of coronary artery segments. No evidence was obtained for 5-HT receptors mediating either endothelium dependent or endothelium independent vasorclaxation. In tissue from patients without ischaemic heart disease, 5-HT effects were mimicked by (±)-α-methyl-5-HT (α-me-5-HT), a selective agonist at 5-HT₂ receptors. In addition, the selective 5-HT₁-like receptor agonist GR43175 produced contractions which achieved 30% of the maximum response to 5-HT. Responses to α-me-5-HT were surmountably antagonised by the non-selective antagonist methiothepin (0.1 μmol·litre⁻¹) as well as the 5-HT₂ receptor antagonist ketanserin (0.1 μmol·litre⁻¹). In contrast GR43175 effects were resistant to blockade by ketanserin, but remained sensitive to methiothepin. Responses to the two agonists were not antagonised by the 5-HT₃ receptor antagonist MDL72222 (1.0 μmol·litre⁻¹). Vessel segments from ischaemic heart disease patients also contracted to α-me-5-HT and GR43175. Diseased arteries contracted with a decrease in the maximal response induced by both α-me-5-HT and by 90 mM K⁺ depolarisation compared to “normal” vessels, but the effect of GR43175 was preserved in the diseased arteries. Vascular rings adjacent to an atheromatous lesion were more reactive to GR43175 than serial segments taken distal to the lesion. Conclusions – These results show that both 5-HT₁-like and 5-HT₂ receptors mediate contraction of human epicardial coronary arteries and indicate that effects mediated by 5-HT₁-like receptors but not 5-HT₂ receptors are preserved in patients with ischaemic heart disease.