title: Interaction of the beta adrenergic receptor antagonist bucindolol with serotonergic receptors.
abstract: Bucindolol is a nonselective beta-adrenergic receptor antagonist that has additional vasodilating properties. Because some beta-adrenergic receptor antagonists such as cyanopindolol are used as 5-HT1A/5-HT1B receptor antagonists, we tested the hypothesis that bucindolol can interact with 5-HT receptors. Both in vitro and in vivo methods were used to examine the interaction of bucindolol with 5-HT receptors relevant to the cardiovascular system-the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptors-and with alpha1-adrenergic receptors. In binding studies, bucindolol displayed high affinity for the 5-HT1A receptor (Ki, 11 nM), modest affinity for the 5-HT2A receptor (Ki, 382 nM), and no measurable affinity for the 5-HT1D receptor; binding affinity for the 5-HT2B receptor was not studied. Bucindolol also displayed significant binding affinity (Ki, 69 nM) for the alpha1-adrenergic receptors. Alpha1-Adrenergic receptor antagonist activity was confirmed by the ability of bucindolol (1 mg/kg) to act as a competitive antagonist against 0.01-30 microg/kg phenylephrine-induced pressor responses in conscious rats. In conscious permanently instrumented rats, bucindolol (0.1-3.0 mg/kg, i.v.) did not cause bradycardia similar to that elicited by the 5-HT1A-receptor agonist 8-OH-DPAT (3-300 microg/kg, i.v.), nor did bucindolol (1 mg/kg) block the 8-OH-DPAT-induced bradycardia. Bucindolol (10(-9)-10(-5) M) did not cause relaxation in the PGF2alpha-contracted, endothelium-intact porcine coronary artery, nor did bucindolol (10(-5) M) block 5-HT-induced coronary artery relaxation, indicating that bucindolol does not have significant interactions at the 5-HT1D receptor. Bucindolol also displayed no agonist activity at the 5-HT2A and 5-HT2B receptor (endothelium-denuded rat thoracic aorta and rat stomach fundus, respectively), but did act as a weak 5-HT2A-receptor antagonist (-log K(B) [M] = 5.4+/-0.1) and 5-HT2B-receptor antagonist (-log K(B) [M] = 7.8+/-0.1). Thus, these data suggest that bucindolol lacks the ability to activate the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptor, but can block alpha1-adrenergic receptors and act as a weak 5-HT2A- and 5-HT2B-receptor antagonist. The relevance of these serotoninergic effects as it pertains to the mechanism of bucindolol-induced vasodilation is unknown.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824-1317, USA. wattss@pilot.msu.edu
authors.forename: S W
authors.initials: SW
authors.lastname: Watts
authors.forename: G D
authors.initials: GD
authors.lastname: Fink
authors.forename: P J
authors.initials: PJ
authors.lastname: Silver
authors.forename: D J
authors.initials: DJ
authors.lastname: Cushing
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects; D005748:Gastric Fundus / Q000187:drug effects / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D011412:Propanolamines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013237:Stereoisomerism; D013552:Swine
chemical_list: D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D018340:Receptors, Adrenergic, alpha-1; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D010656:Phenylephrine; C024307:bucindolol