5-hydroxytryptamine contracts human coronary arteries predominantly via 5-HT2 receptor activation

doi:10.1016/0014-2999(89)90184-2

European Journal of Pharmacology

Volume 161, Issue 1, 14 February 1989, Pages 91-94

https://doi.org/10.1016/0014-2999(89)90184-2 Get rights and content

Abstract

5-Hydroxytryptamine (5-HT) caused contractions of human isolated epicardial coronary arteries which were markedly antagonised by ketanserin (10 nM-1 μM). The antagonism was not competitive. The selective 5-HT₁-like receptor agonist, GR43175, caused only small, ketanserin-resistant contractions. These results suggest that the predominant contractile effect of 5-HT in human isolated large coronary arteries is mediated via 5-HT₂ receptors but that, in addition, 5-HT₁-like receptors contribute to some degree to this response in vitro.

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Cited by (154)

Vasoconstrictor 5-HT receptors in the smooth muscle of the rat middle cerebral artery
2012, European Journal of Pharmacology
Citation Excerpt :
The recent confirmation of the vasodilator mechanism of migraine without aura (Asghar et al., 2011) can renew the interest in developing 5-HT1B agonist vasoconstrictor drugs for the treatment of migraine. However, a serious limitation to this attempt is that triptans may provoke serious side effects by causing pulmonary and coronary vasoconstriction in patients, in which the 5-HT1B receptors are up-regulated (MacLean et al., 1996; Connor et al., 1989). In conclusion, 5-HT and 5-HT agonist drugs can mediate vasoconstrictions in the rat middle cerebral artery via activation of the 5-HT1B and 5-HT2A receptors located on the vascular smooth muscle cells similarly to the situation in the human cerebral vasculature.
Serotonin (5-HT) can constrict cerebral arteries via activation of 5-HT_1B and 5-HT_2A receptors. Our goal was to reveal the importance and relative contribution of the two 5-HT receptor subtypes to the serotonin-induced vasoconstriction in the rat middle cerebral artery. The vasoconstrictor effects of 5-carboxamidotryptamine, sumatriptan and 5-HT were measured without and with pre-treatment with SB 216641 (5-HT_1B antagonist), or ritanserin, (5-HT_2A antagonist), in endothelium-denuded arteries, in vitro. All agonists caused vasoconstrictions. The order of potency (EC₅₀) of the compounds was: 5-carboxamidotryptamine (14±3 nM)>5-HT (270±30 nM)>sumatriptan (5.8±1.9 μM). The concentration–response curve of 5-carboxamidotryptamine resembled the sum of two sigmoid curves (EC₅₀ 14±3 nM and 15±7 μM), and SB 216641 and ritanserin antagonized its low and high concentration components, respectively. Vasoconstrictions evoked by 5-HT at low and high concentrations were also fully antagonized by SB 216641 and ritanserin, respectively. Sumatriptan constricted the middle cerebral artery exclusively via 5-HT_1B receptors. The efficacy of 5-carboxamidotryptamine and sumatriptan was low in comparison to the maximum contractile force elicited by 120 mmol/l KCl, reaching only 18–23% for 5-HT_1B and 14% for 5-HT_2A receptor activation. In conclusion, 5-HT produced small vasoconstrictions in the rat middle cerebral artery that were mediated by 5-HT_1B receptors with high potency and by 5-HT_2A receptors with low potency. Thus, 5-HT may have a minor physiological role in blood flow regulation via 5-HT_1B receptor activation while 5-HT_2A receptors seem to have a pathophysiological role in this vessel.
Sumatriptan provokes coronary artery spasm in patients with variant angina: Possible involvement of serotonin 1B receptor
2007, International Journal of Cardiology
Citation Excerpt :
This drug causes chest symptoms, including chest oppression, tightness, and pain, often mimicking angina pectoris in about 5–15% of patients [25]. Although extracardiac mechanisms such as esophageal spasm may be involved, SMT has been reported to cause myocardial ischemia and ischemic ventricular arrhythmia due to CAS [26–28]. It was also reported that chest pain after subcutaneous use of SMT could result in an acute myocardial infarction [29,30].
Serotonin (5HT) can induce coronary artery spasm (CAS) in patients with variant angina (VA). We have previously reported that 5HT_1B and 5HT_2A receptors gene were expressed in human coronary arterial smooth muscle cells and that isolated coronary artery from a patient with VA showed the supersensitivity to sumatriptan (SMT), a 5HT_1B/1D receptor agonist. The aim of the present study was to determine whether SMT can provoke CAS directly or indirectly through platelet aggregation in patients with VA.
We evaluated the effects of intracoronary infusion of graded concentrations of SMT on coronary arteries in 9 patients, including 5 documented VA and 4 participants with atypical chest pain as control.
SMT provoked CAS in all patients with VA. SMT could not induce CAS in control. SMT (10^− 4 M) caused significant contractions (%diameter of baseline; median [interquartile range], 0 [0–18.4]% in VA, as compared with control (proximal segments; 92.6 [77.9–118.9]%, p < 0.05 vs. VA, distal segments; 92.9 [65.3–158.5]%, p < 0.01 vs. VA). In control, minor dilation occurred at SMT concentration up to 10^− 5 M. SMT could induce in vitro platelet aggregation neither in healthy subjects nor in patients with VA.
These findings suggest that activation of 5HT_1B receptor by SMT can induce CAS directly in patients with VA without platelet activation. This is the first report directly demonstrating the effect of 5HT_1B receptor activation on human coronary arteries in vivo.
5-Hydroxytryptamine receptors in the human cardiovascular system
2006, Pharmacology and Therapeutics
The human cardiovascular system is exposed to plasma 5-hydroxytryptamine (5-HT, serotonin), usually released from platelets. 5-HT can produce harmful acute and chronic effects. The acute cardiac effects of 5-HT consist of tachycardia (preceded on occasion by a brief reflex bradycardia), increased atrial contractility and production of atrial arrhythmias. Acute inotropic, lusitropic and arrhythmic effects of 5-HT on human ventricle become conspicuous after inhibition of phosphodiesterase (PDE) activity. Human cardiostimulation is mediated through 5-HT₄ receptors. Atrial and ventricular PDE3 activity exerts a protective role against potentially harmful cardiostimulation.
Chronic exposure to high levels of 5-HT (from metastatic carcinoid tumours), the anorectic drug fenfluramine and its metabolites, as well as the ecstasy drug 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA) are associated with proliferative disease and thickening of cardiac valves, mediated through 5-HT_2B receptors. 5-HT_2B receptors have an obligatory physiological role in murine cardiac embryology but whether this happens in humans requires research. Congenital heart block (CHB) is, on occasion, associated with autoantibodies against 5-HT₄ receptors.
Acute vascular constriction by 5-HT is usually shared by 5-HT_1B and 5-HT_2A receptors, except in intracranial arteries which constrict only through 5-HT_1B receptors. Both 5-HT_1B and 5-HT_2A receptors can mediate coronary artery spasm but only 5-HT_1B receptors appear involved in coronary spasm of patients treated with triptans or with Prinzmetal angina. 5-HT_2A receptors constrict the portal venous system including oesophageal collaterals in cirrhosis. Chronic exposure to 5-HT can contribute to pulmonary hypertension through activation of constrictor 5-HT_1B receptors and proliferative 5-HT_2B receptors, and possibly through direct intracellular effects.
Peptidergic and non-peptidergic innervation and vasomotor responses of human lenticulostriate and posterior cerebral arteries
2004, Peptides
The aim of the present study was to compare in man the innervation pattern and the functional responses to neuronal messengers in medium sized lenticulostriate and branches of the posterior cerebral arteries (PCA). The majority of the nerve fibers found were sympathetic and displayed specific immunoreactivity for tyrosine hydroxylase (TH) and neuropeptide Y (NPY). Only few nerve fibers displayed vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and substance P (SP) immunoreactivity. In both arteries, the contractions induced by noradrenaline (NA), NPY and 5-hydroxytryptamine (5-HT) and the relaxant responses induced by acetylcholine (ACh), VIP and pituitary adenylate cyclase activating peptide-27 (PACAP) as well as CGRP and SP were compared in vitro. In conclusion, there was no major difference in innervation pattern or vasomotor sensitivity (pEC₅₀ and pIC₅₀ values) between the two vessels. However, the general pattern indicates stronger vasomotor responses (E_max and I_max) in the PCA branches as compared to the lenticulostriate arteries which may lend support for the clinical observation of a difference in stroke expression between the two vascular areas.
Functions of 5-HT <inf>2A</inf> receptor and its antagonists in the cardiovascular system
2004, Pharmacology and Therapeutics
The serotonin (5-hydroxytryptamine, 5-HT) receptors have conventionally been divided into seven subfamilies, most of which have several subtypes. Among them, 5-HT_2A receptor is associated with the contraction of vascular smooth muscle, platelet aggregation and thrombus formation and coronary artery spasms. Accordingly, selective 5-HT_2A antagonists may have potential in the treatment of cardiovascular diseases. Sarpogrelate, a selective 5-HT_2A antagonist, has been introduced clinically as a therapeutic agent for the treatment of ischemic diseases associated with thrombosis. Molecular modeling studies also suggest that sarpogrelate is a 5-HT_2A selective antagonist and is likely to have pharmacological effects beneficial in the treatment of cardiovascular diseases. This review describes the above findings as well as the signaling linkages of the 5-HT_2A receptors and the mode of agonist binding to 5-HT_2A receptor using data derived from molecular modeling and site-directed mutagenesis.
5-HT<inf>1F</inf> Receptor Agonists: A New Treatment Option for Migraine Attacks?
2010, Neurotherapeutics
Citation Excerpt :
In contrast to cerebral arteries, vasoconstriction in coronary arteries is mainly mediated through 5-HT2 receptors. However, 5-HT1 receptors also participate to a smaller extent in cardiac vessel constriction,10 mostly through activation of the 5-HT1B receptor subtype.7 Because the vasoconstrictive potency of the triptans is low in cardiac vessels, it is unlikely that therapeutic plasma concentration can lead to myocardial ischemia in patients without coronary heart disease and normal coronary circulation.11

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Short communication5-hydroxytryptamine contracts human coronary arteries predominantly via 5-HT2 receptor activation

Abstract

Endothelium-dependent relaxation of coronary arteries by noradrenaline and serotonin

Nature

Contractions of isolated canine coronary arteries resistant to S2-serotonergic blockade

J. Pharmacol. Exp. Ther.

Quantitative pharmacologic responses of normal and atherosclerotic human epicardial coronary arteries

Circulation

Short communication
5-hydroxytryptamine contracts human coronary arteries predominantly via 5-HT₂ receptor activation

Contractions of isolated canine coronary arteries resistant to S₂-serotonergic blockade