Circulation, Vol 90, 1141-1153, Copyright © 1994 by American Heart Association
AJ Kaumann, M Frenken, H Posival and AM Brown
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.
ARTICLES
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
Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge University, England.
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