VARIABLE PARTICIPATION OF 5-HT1-LIKE RECEPTORS AND 5-HT2 RECEPTORS IN SEROTONIN-INDUCED CONTRACTION OF HUMAN - ISOLATED CORONARY-ARTERIES 5-HT1-LIKE RECEPTORS RESEMBLE CLONED 5-HT1D-BETA RECEPTORS

Background Serotonin may contract human large coronary arteries through two 5-hydroxtryptamine (5-HT) receptors, 5-HT1-like and 5-HT2. These 5-HT1-like receptors resemble both cloned 5-HT1D receptor subtypes, 5-HT1D alpha and 5-HT1D beta. Although these subtypes have similar pharmacology, 5-HT1D beta receptors appear to have lower affinity for ketanserin than 5-HT1D alpha receptors. We assessed the relative participation of 5-HT1-like and 5-HT2 receptors and attempted to identify whether vasoconstrictor 5-HT1-like receptors are 5-HT1D alpha or 5-HT1D beta. Methods and Results Epicardial coronary arteries were dissected from the hearts of 29 patients (including 1 healthy donor) undergoing heart transplant operation. Endothelium-denuded strips were set up to contract at 37 degrees C. To assess the relative contributions of 5-HT1-like and 5-HT2 receptors, we blocked the latter with ketanserin (0.1 to 1.0 mu mol/L) and ketanserin-resistant receptors with methiothepin (0.1 mu mol/L L). Concentration-effect curves for 5-HT, in the absence and presence of ketanserin, were analyzed by using a model for two receptor subtypes. The fractional contributions of 5-HT1-like and 5-HT2 receptors to the maximum effect of 5-HT, f(1) and f(2) were estimated in arteries from 28 patients: f(1), (0.71+/-0.20, mean+/-SD) was significantly larger than f(2) (0.29+/-0.20) (P<.0001). Using [H-3]-serotonin to label transfected and expressed receptors, we verified that ketanserin has lower affinity for 5-HT1D beta (pK(i) [-log K-i, mol/L] less than 5.0) than for 5-HT1D alpha (pK(i)=7.1+/-0.1) receptors. A concentration of ketanserin (1 mu mol/L) that would occupy more than 90% of 5-HT1D alpha receptors failed to block 5-HT-induced contractions (4 patients). The 5-HT1-like receptor stimulant sumatriptan evoked maximal contractions that matched f(1) and was equipotent with 5-HT through 5-HT1-like receptors (8 patients). No systematic influence of disease, atheroma, or therapy on f(1) and f(2) was detected. Conclusions Coronary artery contractile 5-HT1-like receptors resemble cloned 5-HT1D beta receptors and predominate over 5-HT2 receptors in mediating serotonin-evoked contractions. Sumatriptan contracts coronary arteries as a full agonist through 5-HT1-like receptors.