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 isolated coronary artery deprived of endothelium is mediated by a receptor unrelated to the 5-HT1, 5-HT2, 5-HT3 or 5-HT4 types. Based upon the pharmacological characteristics of this relaxant 5-HT receptor and those reported for the new members of the 5-HT receptor family, the present study explored the possibility that the relaxant 5-HT receptor referred to above, corresponds to the cloned 5-ht(7) subtype. Thus, the relaxing and/or blocking effects of several 5-HT receptor drugs as well as some typical and atypical antipsychotic drugs with high affinity for the 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 relaxations 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-induced relaxation suggesting a partial agonist effect. In the presence of 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-methoxytryptamine. 8-OH-DPAT and sumatriptan remained inactive as agonists. 3 In GR127935-treated preparations, methiothepin (3 nM) and mianserin (1 mu M), as well as the antipsychotics, clozapine (1 mu M), pimozide (300 nM), risperidone (3 nM) and spiperone (1 mu M), failed to induce a significant relaxation in prostaglandin F-2 alpha-precontracted vessels, but produced significant rightward displacements of the concentration-response curves to 5-HT and 5-CT without significantly reducing the E(max). In a final set of experiments with 5-CT, metergoline (100 nM) and mesulergine (300 nM) behaved as competitive antagonists. In contrast, lisuride (3 nM) noncompetitively antagonized 5-CT-induced relaxation. The estimated affinity (apparent pK(B) values) of the above antagonist drugs for the relaxant 5-HT receptor significantly correlated with their reported affinity at the cloned 5-ht(7) receptor. 4 Taken together, the above pharmacological data may suggest that the relaxant 5-HT receptor in the smooth muscle of the canine coronary artery is similar to the cloned 5-ht(7) receptor subtype.