Evaluation of a new beta-adrenergic blocking agent, carteolol, based on metabolic responses in rats—II: Blockade by carteolol of the epinephrine- and isoproterenol-induced increases of tissue and blood cyclic AMP in vivo

Abstract

Intraperitoneal injection of epinephrine caused a slight but significant increase in cyclic AMP in the liver and skeletal muscle in 5–10 min. Likewise, there was a significant increase in cyclic AMP in the muscle and adipose tissue 5 min after the injection of isoproterenol. However, no change was detected in the cardiac muscle. Pretreatment of rats with theophylline was so effective in enhancing responses of tissue cyclic AMP as to make it possible to detect a 2- to 3-fold increase of cyclic AMP even in the heart. The maximal increases in tissue cyclic AMP induced by 500 μg/kg of isoproterenol or epinephrine were blocked by carteolol, a new beta-adrenergic blocking agent, at doses of 10–100 μg/kg, regardless of whether or not the rats had been treated with theophylline. In contrast, neither the increase of liver cyclic AMP by glucagon nor the increase of adrenal cyclic AMP by adrenocorticotropic hormone (ACTH) was affected by this agent. Blood cyclic AMP rose sharply after isoproterenol, the maximal response attaining 20- to 30-fold of the preinjection level. Based on this tremendous increase of blood cyclic AMP, the dose of isoproterenol and carteolol required for the half-saturation of the beta-adrenergic receptor was calculated as 20–30 and 0.5 μg/kg of body wt respectively. These values are in the same order as the respective values obtained from the response of carbohydrate and lipid metabolites in blood.