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 beta(1)/beta(2)-
adrenoceptor competitive antagonist. 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 that
KMUP 880723 was a nonselective beta-
adrenoceptor blocker. In thoracic aorta experiments,
KMUP 880723 also produced a competitive antagonism of
norepinephrine-induced contraction with a pA(2) value of 7.14+/-0.06. In isolated 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 [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 alpha/beta-
adrenoceptor blocking activities of
KMUP 880723 reported in the functional studies. We conclude that
KMUP 880723 is a nonselective
beta-adrenoceptor antagonist with alpha-
adrenoceptor blocking-associated
vasorelaxant activity.