Pharmacological effects of an aldehyde type alpha/beta-adrenoceptor blocking agent with vasodilating properties

KMUP 880723 (0.5. 1.0, and 3.0 mg/kg, iv) produced dose-dependent hypotensi ve and bradycardia responses in pentobarbital-anesthetized Wistar rats. KMU P 880723 (1.0 mg/kg, iv) also markedly inhibited both the tachycardia effec ts induced by (-)isoproterenol and arterial pressor responses induced by ph enylephrine. In the isolated Wistar rat right atria, left atria, and guinea pig tracheal strips, KMUP 880723 competitively antagonized the (-)isoprote renol-induced positive chronotropic effects, inotropic effects, and trachea l relaxation effects in a concentration-dependent manner. The parallel shif t to the right of the concentration-response curve of (-)isoproterenol sugg ested that KMUP 880723 was a beta (1)/beta (2)-adrenoceptor competitive ant agonist. The apparent pA(2) values were 6.89 +/-0.10 in the right atria, 7. 02 +/-0.09 in the left atria, and 6.59 +/-0.11 in the trachea, indicating t hat KMUP 880723 was a nonselective beta-adrenoceptor blocker. In thoracic a orta experiments, KMUP 880723 also produced a competitive antagonism of nor epinephrine-induced contraction with a pA(2) value of 7.14 +/-0.06. In isol ated rat thoracic aorta, KMUP 880723 more potently relaxed the contractions induced by norepinephrine (3 x 10(-6) M) than those by high K- (75 mM). In the radioligand-binding assay, the pK(i) values of [H-3]CGP-12177 binding to rat ventricle and lung membranes were 6.56 and 6.40, respectively, and t he value of [H-3]prazosin binding to rat brain membranes was 6.66. These re sults further confirmed the alpha/beta-adrenoceptor blocking activities of KMUP 880723 reported in the functional studies. We conclude that KMUP 88072 3 is a nonselective beta-adrenoceptor antagonist with alpha-adrenoceptor bl ocking-associated vasorelaxant activity. (C) 2001 Elsevier Science Inc. All rights reserved.