THE RELAXANT 5-HT RECEPTOR IN THE DOG CORONARY-ARTERY SMOOTH-MUSCLE -PHARMACOLOGICAL RESEMBLANCE TO THE CLONED 5-HT(7) RECEPTOR SUBTYPE

1 The relaxant effect of 5-hydroxytryptamine (5-HT) in the dog isolate d coronary artery deprived of endothelium is mediated by a receptor un related to the 5-HT1, 5-HT2, 5-HT3 or 5-HT4 types. Based upon the phar macological characteristics of this relaxant 5-HT receptor and those r eported for the new members of the 5-HT receptor family, the present s tudy explored the possibility that the relaxant 5-HT receptor referred to above, corresponds to the cloned 5-ht(7) subtype. Thus, the relaxi ng and/or blocking effects of several 5-HT receptor drugs as well as s ome typical and atypical antipsychotic drugs with high affinity for th e cloned 5-ht(7) receptor in precontracted ring segments were analyzed . 2 5-HT, 5-carboxamidotryptamine (5-CT) and 5-methoxytryptamine, but not 8-OH-DPAT or sumatriptan, produced concentration-dependent relaxat ions in endothelium-denuded canine coronary artery rings precontracted with prostaglandin F-2 alpha (2 mu M). Clozapine (1 mu M) produced in some cases a small relaxing effect and antagonized 5-HT- and 5-CT-ind uced relaxation suggesting a partial agonist effect. In the presence o f the 5-HT1D receptor antagonist, GR127935 (100 nM), the rank order of agonist potency was 5-CT>5-HT>clozapine greater than or equal to 5-me thoxytryptamine. 8-OH-DPAT and sumatriptan remained inactive as agonis ts. 3 In GR127935-treated preparations, methiothepin (3 nM) and mianse rin (1 mu M), as well as the antipsychotics, clozapine (1 mu M), pimoz ide (300 nM), risperidone (3 nM) and spiperone (1 mu M), failed to ind uce a significant relaxation in prostaglandin F-2 alpha-precontracted vessels, but produced significant rightward displacements of the conce ntration-response curves to 5-HT and 5-CT without significantly reduci ng the E(max). In a final set of experiments with 5-CT, metergoline (1 00 nM) and mesulergine (300 nM) behaved as competitive antagonists. In contrast, lisuride (3 nM) noncompetitively antagonized 5-CT-induced r elaxation. The estimated affinity (apparent pK(B) values) of the above antagonist drugs for the relaxant 5-HT receptor significantly correla ted with their reported affinity at the cloned 5-ht(7) receptor. 4 Tak en together, the above pharmacological data may suggest that the relax ant 5-HT receptor in the smooth muscle of the canine coronary artery i s similar to the cloned 5-ht(7) receptor subtype.