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-hydroxytryptamine (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-HT 1D 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 mumol/L) and ketanserin-resistant receptors with methiothepin (0.1 mumol/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, f1 and f2, were estimated in arteries from 28 patients: f1 (0.71 +/- 0.20, mean +/- SD) was significantly larger than f2 (0.29 +/- 0.20) (P < .0001). Using [3H]-serotonin to label transfected and expressed receptors, we verified that ketanserin has lower affinity for 5-HT1D beta (pKi [-log Ki, mol/L] less than 5.0) than for 5-HT1D alpha (pKi = 7.1 +/- 0.1) receptors. A concentration of ketanserin (1 mumol/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 f1 and was equipotent with 5-HT through 5-HT1-like receptors (8 patients). No systematic influence of disease, atheroma, or therapy on f1 and f2 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.