Differential classification of vascular smooth muscle and endothelial cell 5‐HT receptors by use of tryptamine analogues

Abstract

In ring preparations of the rabbit external jugular vein contracted with the thromboxane‐mimetic U‐46619, submicromolar concentrations of 5‐hydroxytryptamine (5‐HT) and chemically related analogues produced relaxations that were dependent on the integrity of the vascular endothelium. The receptor mediating endothelium‐dependent relaxations was evidently similar to previously described endothelial 5‐HT receptors since relaxation responses to α‐methyl‐5‐HT were not blocked by atropine, (±)‐propranolol, yohimbine, indomethacin, ketanserin or MDL‐72222, but were noncompetitively antagonized by methysergide, methiothepin and cyproheptadine. The activities of some tryptamine agonists and antagonists at the endothelial 5‐HT receptor in rabbit jugular vein were compared with their activities at the smooth muscle 5‐HT2‐receptor in rabbit aortic rings. Differences in the tryptamines' affinities and relative efficacies showed that the endothelial 5‐HT receptor was not of the 5‐HT2‐type. The high agonist potencies of 5‐HT and 5‐carboxamidotryptamine, the susceptibility to antagonism by both methiothepin and methysergide and the resistance to blockade by selective 5‐HT2 and 5‐HT3 (‘M’) receptor antagonists implies that the endothelial receptor belongs to the ‘5‐HT,‐like’ class. However, the agonist potency order 5‐HT = α‐methyl‐5‐HT > 5‐carboxamidotryptamine suggested that the receptor is not the same as the peripheral ‘5‐HT1‐like’ receptors reported to mediate directly contraction of the dog saphenous vein or relaxation of vascular and non‐vascular smooth muscles. At these receptors, the potency order is 5‐carboxamidotryptamine > 5‐HT > α‐methyl‐5‐HT. These results constitute preliminary evidence that peripheral ‘5‐HT1‐like’ receptors, like central 5‐HT1 recognition sites, are a heterogeneous population. Further comparative studies with a wider range of receptor probes are necessary to establish whether or not these receptors represent functional counterparts of the ligand binding sites in the brain. 1987 British Pharmacological Society