The relaxant 5-HT receptor in the dog coronary artery smooth muscle: Pharmacological resemblance to the cloned 5-ht7 receptor subtype

Abstract

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-ht7 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-ht7 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(2α) (2 μM). Clozapine (1 μM) 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-HT(1D) receptor antagonist, GR127935 (100 nM), the rank order of agonist potency was 5-CT > 5-HT > clozapine ≤ 5-methoxytryptamine. 8-OH-DPAT and sumatriptan remained inactive as agonists. 3. In GR127935-treated preparations, methiothepin (3 nM) and mianserin (1 μM), as well as the antipsychotics, clozapine (1 μM), pimozide (300 nM), risperidone (3 nM) and spiperone (1 μM), failed to induce a significant relaxation in prostaglandin F(2α)-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-ht7 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-ht7 receptor subtype.