Cardiac adenylate cyclase. II. Structure-activity relationships for the activation of rat ventricle adenylate cyclase by beta-adrenoceptor agonists.

The ability of phenylethylamine derivatives to stimulate adenylate cyclase activity of a sarcolemma fraction of rat ventricular muscle has been studied. The structure-activity relationships for maximal activation of adenylate cyclase activity showed that a phenylethylamine derivative required two adjacent hydroxyl groups at the 3 and 4 positions of the phenyl ring, a hydroxyl group on the asymmetric β-carbon of the ethylamine side chain and an isopropyi group on the amine. The configuration of the hydroxyl group on the β-carbon was critical since the laevo isomer of this amine (isoprenaline) was highly active whilst the dextro isomer was almost inactive. The activation of adenylate cyclase activity by (?)-isoprenaline was blocked by ( ? )-propranolol but not (+)-propranolol or phentolamine. These structure-activity relationships are identical with those found for the actions of β-agonists and antagonists on cardiac muscle and therefore strengthen the hypothesis that the β-adreno-receptor is a component of adenylate cyclase in cardiac muscle. The order of potency of catecholamine derivatives to stimulate adenylate cyclase activity in intact cubes of rat ventricles was similar to that found in homogenates of ventricles, although the relative sensitivity of catecholamines in cubes was approximately 50 times higher. It was concluded that homogenization and preparation of sarcolemma membranes alters the sensitivity of adenylate cyclase to activation by catecholamines.