BLOCKADE OF BIOCHEMICAL AND PHYSIOLOGICAL RESPONSES OF CARDIAC MUSCLE TO NOREPINEPHRINE BY N-tert.-BUTYLMETHOXAMINE (BUTOXAMINE)

¹ Divisions of Pharmacology and Pediatric Cardiology, Departments of Medicine and Pediatrics, University of California, San Diego, La Jolla, California, and Department of Pharmacology, Emory University, Atlanta, Georgia

Methoxamine congeners have been described as beta₂ adrenergic blocking agents with little effect on cardiac adrenergic responses and also as having the capacity to block the formation of cardiac adenosine 3', 5'-monophosphate (cyclic AMP) but not contractile force in response to norepinephrine. The purpose of the present experiments was to evaluate the effectiveness of N-tert.-butylmethoxamine (butoxamine) as a cardiac adrenergic blocking agent in vivo and in vitro. Norepinephrine (1 µg/kg) administered to open-chest anesthetized dogs increased cardiac cyclic AMP 2-fold in 7 to 10 seconds. which preceded the increase in right ventricular contractile force (2.4-fold in 15 seconds) and formation of phosphorylase a (13-fold in 15 seconds). Butoxamine (2.5-15 µg/kg iv.) produced a dose-dependent blockade of phosphorylase a formation; 10 mg/kg reduced the contractile, phosphorylase and cyclic AMP responses to norepinephrine by two-thirds. Butoxamine alone depressed contractile force and cyclic AMP content. Repeated administration of norepinephrine reversed the blockade of contractile force and phosphorylase. Augmentation of isometric tension of isolated cat papillary muscles by norepinephrine was blocked competitively by 3 x 10^-5 M butoxamine. The EC50 of norepinephrine was increased from 4 x 10^-7 M to 3 x 10^-6 M. The chronotropic effect on cat isolated right atria was blocked in what appeared to be a semicompetitive fashion. Butoxamine alone (> 3 x 10^-5 M) depressed both parameters. We conclude that while butoxamine is a relatively weak antagonist, it blocks biochemical and physiological cardiac responses to adrenergic stimulation and does not dissociate cyclic AMP formation from augmentation of contractile force.