Serotonin and Serotonin Antagonism in Cardiovascular and Non‐Cardiovascular Disease

Abstract

Serotonin, or 5-hydroxytryptamine, is a naturally-occurring vasoactive substance found primarily in the brain, enterochromaffin tissue, and blood platelets. It has diffuse cardiophysiologic effects. The multiple effects of serotonin on blood vessels can be explained by the existence of 2 serotonergic receptor subtypes (the S1 receptor mediates vasodilation, and the S2 receptor vasoconstriction). Serotonin via the S2 receptor also augments the actions of several other vasoconstricting substances. Serotonin may be responsible for causing, or at least perpetuating, some forms of systemic hypertension through peripheral and central nervous system (CNS) actions. Ketanserin is a highly selective S2-serotonergic antagonist with additional alpha-adrenergic blocking activity, which has been proposed as a therapy for various cardiovascular diseases including hypertension. It has been shown to be more effective than placebo in treating hypertension and comparable in effectiveness to other antihypertensive drugs. Its major side effects relate to the CNS, and prolongation of the electrocardiogram QT interval has been described. Caution must be used when using ketanserin in patients receiving potassium- and magnesium-losing agents, because of the risk of torsades de pointes. Ketanserin has potential utility in the treatment of eclampsia, peripheral vascular disease, carcinoid syndrome, and "shock lung." The drug is not yet approved for clinical use in the United States.

PRX-08066, a Novel 5-Hydroxytryptamine Receptor 2B Antagonist, Reduces Monocrotaline-Induced Pulmonary Arterial Hypertension and Right Ventricular Hypertrophy in Rats

“…As the LV filling decreases, there is less systemic cardiac output, and this was observed in the MCT-induced PAH rats that became systemically hypotensive. Contrary to previous reports with the 5HT2A receptor blocker ketanserin, which caused systemic hypotension (Frishman et al, 1995;Frishman and Grewall, 2000), our experiment demonstrated no significant change in the LV pressure between the treatment groups and the PBS controls, suggesting less peripheral vasodilatation with more selective vasodilatation of the pulmonary vasculature.…”

Affinity of Serotonin Receptor Antagonists and Agonists to Recombinant and Native α1-Adrenoceptor Subtypes

“…Pharmacological studies have revealed several subtypeselective agents: for example, 5-methylurapidil, KMD-3213, RS-17053 and nigludipine for the a1a-subtype (6 -9); spiperone for the a1b-subtype (10); and BMY7378 for the a1d-subtype (11, 12). Among them, 5-methylurapidil, spiperone and BMY7378 were originally categorized in serotonin (5-HT) receptor agonists and / or antagonists.Many 5-HT receptor antagonists have been developed and some of them are now clinically used as anticoagulants, antihypertensive drugs and antipsychotic drugs (13,14). Such therapeutic diversity of 5-HT antagonists may be related to their wide spectrum for not only 5-HT receptor family but also for heterogeneous receptors such as dopamine receptors and a1-adrenoceptors (15, 16).…”

“…Many 5-HT receptor antagonists have been developed and some of them are now clinically used as anticoagulants, antihypertensive drugs and antipsychotic drugs (13,14). Such therapeutic diversity of 5-HT antagonists may be related to their wide spectrum for not only 5-HT receptor family but also for heterogeneous receptors such as dopamine receptors and a1-adrenoceptors (15, 16).…”

Serotonin Increases Interleukin-6 Synthesis in Human Vascular Smooth Muscle Cells

“…In the vascular system, multiple effects of 5-HT are mediated primarily by 5-HT 1 and 5-HT 2 receptors. 16 5-HT induces VSMC proliferation, contraction, migration, and platelet aggregation. [17][18][19][20][21][22] 5-HT also participates in vascular inflammation associated with atherosclerosis.…”