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

Gen Pharmacol. 2000 Jun;34(6):391-400. doi: 10.1016/s0306-3623(01)00076-3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Antagonists / analysis
  • Adrenergic alpha-Antagonists / pharmacology*
  • Adrenergic beta-Antagonists / analysis
  • Adrenergic beta-Antagonists / pharmacology*
  • Animals
  • Aorta / drug effects
  • Atenolol / analysis
  • Atenolol / pharmacology
  • Benzaldehydes / pharmacology
  • Blood Pressure / drug effects
  • Cardiovascular Agents / pharmacology
  • Depression, Chemical
  • Dose-Response Relationship, Drug
  • Guinea Pigs
  • Heart Atria / drug effects
  • Heart Rate / drug effects
  • Isoproterenol / analysis
  • Isoproterenol / pharmacology
  • Labetalol / analysis
  • Labetalol / pharmacology
  • Mecamylamine / analysis
  • Mecamylamine / pharmacology
  • Models, Animal
  • Muscle, Smooth, Vascular / drug effects
  • Myocardial Contraction / drug effects
  • Propranolol / analysis
  • Propranolol / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Regression Analysis
  • Stimulation, Chemical
  • Vasodilator Agents / pharmacology

Substances

  • Adrenergic alpha-Antagonists
  • Adrenergic beta-Antagonists
  • Benzaldehydes
  • Cardiovascular Agents
  • N-(4-(2-hydroxy-3-(2-methoxy-1-oxyethylaminobenzene)propoxy))benzaldehyde
  • Vasodilator Agents
  • Atenolol
  • Mecamylamine
  • Propranolol
  • Isoproterenol
  • Labetalol