Actions of serotonin antagonists on dog coronary artery

doi:10.1016/0014-2999(82)90346-6

European Journal of Pharmacology

Volume 81, Issue 4, 30 July 1982, Pages 569-576

https://doi.org/10.1016/0014-2999(82)90346-6 Get rights and content

Abstract

Serotonin released from platelets may initiate coronary vasopasm in patients with variant angina. If this hypothesis is correct, serotonin antagonists without constrictor activity may be useful in this form of angina. We have investigated drugs classified as serotonin antagonists on dog circumflex coronary artery ring segments in vitro. Ergotamine, dihydroergotamine, bromocriptine, lisuride, ergometrine, ketanserin, trazodone, cyproheptadine and pizotifen caused non-competitive antagonism of serotonin concentration-response curves. In addition, ketanserin, trazodone, bromocriptine and pizotifen inhibited noradrenaline responses in concentrations similar to those required for serotonin antagonism. All drugs with the exception of ketanserin, cyproheptadine and pizotifen showed some degree of intrinsic constrictor activity. Methysergide antagonized responses to serotonin competitively but also constricted the coronary artery. The lack of a silent competitive serotonin antagonist precludes a definite characterization of coronary serotonin receptors at this time. However, the profile of activity observed for the antagonist drugs in the coronary artery differs from that seen in other vascular tissues. Of the drugs tested, ketanserin may be the most useful in variant angina since it is a potent 5HT antagonist, lacks agonist activity and has α-adrenoceptor blocking activity.

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The vasoconstrictive effect is mainly mediated by serotonin 5-HT2A receptor, which is a Gq protein coupled receptor; to lesser extent, activation of serotonin 5-HT1B receptor, which is Gi coupled, also causes coronary artery constriction (Borton et al., 1990; Nilsson et al., 1999). Similar vasoconstrictive effects of serotonin on coronary artery have also been reported in bovine (Foy et al., 1992), porcine (Cushing and Cohen, 1992; Takenaka, 1959), canine (Brazenor and Angus, 1982; Cushing and Cohen, 1992; Lynch et al., 2009), monkey (Toda and Okamura, 1990), rabbit (Ellwood and Curtis, 1997), and rat (Lai et al., 1991). The coronary dilating effect is endothelium-dependent in human (Golino et al., 1991).
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Serotonin (5-hydroxytryptamine) is an important biogenic amine that fulfills the role of neurotransmitter and neuromodulator. It has been a focus of interest during the last decade. Its diversity of pharmacologic actions is related to a wide variety of receptors and effector mechanisms. Seven serotonin receptor families have been identified thus far. They are genetically different transmembrane proteins composed of several hundred amino acids. The majority of these are G-protein-coupled, except the 5-HT₃ receptors, which are directly ligand gated to fast ion channels. Serotonin is widely distributed in the body within the central and peripheral nervous systems, smooth muscles, and platelets, in particular. Consequently, its effects manifest mainly in these organs and influence a wide variety of neural, vascular, smooth muscle, and platelet functions. (Melatonin, a physiologically active metabolite of serotonin, is also instrumental in affecting many neural and hormonal functions.)
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Actions of serotonin antagonists on dog coronary artery

Abstract

Am. J. Cardiol.

Jap. J. Pharmacol.

Verapamil: A selective antagonist of constrictor substances in dog coronary artery: Implications for variant angina

Clin. Exp. Pharmacol. Physiol. Suppl.

Evidence for two types of excitatory receptors for 5-hydroxytryptamine in dog isolated vasculature

Br. J. Pharmacol.

Receptors for 5-hydroxytryptamine and noradrenaline in rabbit isolated ear artery and aorta

Br. J. Pharmacol.

Molecular Pharmacology

Ergometrine contracts isolated canine coronary arteries by a serotonergic mechanism: No role for α-adrenoceptors

J. Pharmacol. Exp. Ther.

The pharmacology of bromocriptine