Interaction of the beta adrenergic receptor antagonist bucindolol with serotonergic receptors

Bucindolol is a nonselective beta-adrenergic receptor antagonist that has a dditional vasodilating properties. Because some beta-adrenergic receptor an tagonists such as cyanopindolol are used as 5-HT1A/5-HT1B receptor antagoni sts, we tested the hypothesis that bucindolol can interact with 5-HT recept ors. Both in vitro and in vivo methods were used to examine the interaction of bucindolol with 5-HT receptors relevant to the cardiovascular system-th e 5-HT1A, 5-HT1D, 5-HT2A and 5-HT2B receptors-and with alpha(1)-adrenergic receptors. In binding studies, bucindolol displayed high affinity for the 5 -HT1A receptor (K-i, 11 nM), modest affinity for the 5-HT2A receptor (K-i 3 82 nM), and no measurable affinity for the 5-HT1D receptor; binding affinit y for the 5-HT2B receptor was not studied. Bucindolol also displayed signif icant binding affinity (K-i, 69 nM) for the alpha(1)-adrenergic receptors. alpha(1)-Adrenereic receptor antagonist activity was confirmed by the abili ty of bucindolol (1 mg/kg) to act as a competitive antagonist against 0.01- 30 mu g/kg phenylephrine-induced presser responses in conscious rats. In co nscious permanently instrumented rats, bucindolol (0.1-3.0 mg/kg, i.v.) did nor cause bradycardia similar to that elicited by the 5-HT1A-receptor agon ist 8-OH-DPAT (3-300 mu g/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 PGF(2 alpha)-contracted, endothelium-intact porcine coron ary artery, nor did bucindolol (10(-5) M) block 5-HT-induced coronary arter y relaxation, indicating that bucindolol does not have significant interact ions at the 5-HT1D receptor. Bucindolol also displayed no agonist activity at the 5-HT2A and 5-HT2B receptor (endothelium-denuded rat thoracic aorta a nd 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 (-l og K-B [M] = 7.8 +/- 0.1). Thus, these data suggest that bucindolol lacks t he ability to activate the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptor, but can block alpha(1)-adrenergic receptors and act as a weak 5-HT2A- and 5-HT 2B-recepror antagonist, The relevance of these serotoninergic effects as it pertains to the mechanism of bucindolol-induced vasodilation is unknown.