Pharmacological effects of an aldehyde type α/β-adrenoceptor blocking agent with vasodilating properties

KMUP 880723 (0.5, 1.0, and 3.0 mg/kg, iv) produced dose-dependent hypotensive and bradycardia responses in pentobarbital-anesthetized Wistar rats. KMUP 880723 (1.0 mg/kg, iv) also markedly inhibited both the tachycardia effects induced by (−)isoproterenol and arterial pressor responses induced by phenylephrine. In the isolated Wistar rat right atria, left atria, and guinea pig tracheal strips, KMUP 880723 competitively antagonized the (−)isoproterenol-induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in a concentration-dependent manner. The parallel shift to the right of the concentration–response curve of (−)isoproterenol suggested that KMUP 880723 was a β₁/β₂-adrenoceptor competitive antagonist. The apparent pA₂ 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 that KMUP 880723 was a nonselective β-adrenoceptor blocker. In thoracic aorta experiments, KMUP 880723 also produced a competitive antagonism of norepinephrine-induced contraction with a pA₂ value of 7.14±0.06. In isolated rat thoracic aorta, KMUP 880723 more potently relaxed the contractions induced by norepinephrine (3×10⁻⁶ M) than those by high K⁺ (75 mM). In the radioligand-binding assay, the pK_i values of [³H]CGP-12177 binding to rat ventricle and lung membranes were 6.56 and 6.40, respectively, and the value of [³H]prazosin binding to rat brain membranes was 6.66. These results further confirmed the α/β-adrenoceptor blocking activities of KMUP 880723 reported in the functional studies. We conclude that KMUP 880723 is a nonselective β-adrenoceptor antagonist with α-adrenoceptor blocking-associated vasorelaxant activity.