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 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.
Chiu
C C
CC
Department of Cardiovascular Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
Lin
Y T
YT
Tsai
C H
CH
Liang
J C
JC
Chiang
L C
LC
Wu
J R
JR
Chen
I J
IJ
Yeh
J L
JL
D000317:Adrenergic alpha-Antagonists / Q000032:analysis / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000032:analysis / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001262:Atenolol / Q000032:analysis / Q000494:pharmacology; D001547:Benzaldehydes / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000032:analysis / Q000494:pharmacology; D007741:Labetalol / Q000032:analysis / Q000494:pharmacology; D008464:Mecamylamine / Q000032:analysis / Q000494:pharmacology; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D011433:Propranolol / Q000032:analysis / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D012044:Regression Analysis; D013268:Stimulation, Chemical; D014665:Vasodilator Agents / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D001547:Benzaldehydes; D002317:Cardiovascular Agents; C435583:N-(4-(2-hydroxy-3-(2-methoxy-1-oxyethylaminobenzene)propoxy))benzaldehyde; D014665:Vasodilator Agents; D001262:Atenolol; D008464:Mecamylamine; D011433:Propranolol; D007545:Isoproterenol; D007741:Labetalol