The Inotropic Effects of the Calcium Ionophore X-537A in the Anesthetized Dog

Abstract

The ability of ion permeability-inducing agents (ionophores) to complex and transport cations and amines across membranes has provided a novel approach for the pharmacological modification of biological systems. Of particular interest is X-537A, since it not only transports alkali ions but compared to most of the known ionophores it is unusually efficient in transporting calcium as well as catecholamines. The cardiovascular effects of this agent were studied in normal anesthetized dogs. X-537A produced a dramatic augmentation of myocardial contractility with up to 210% increases in max dP/dt after intravenous doses of 1.0-1.5 mg/kg. The moderate dose of 0.5-0.75 mg/kg X-537A induced significant increases in max dP/dt (68%, P < .001), isometric ventricular segmental tension (IVST) (79%, P < .01), peak dT/dt (65%, P < .05), cardiac output (44%, P < .001), aortic systolic (18%, P < .001) and diastolic (15%, P < .001) pressures, pulse pressure (28%, P < .001), left ventricular systolic pressure (18%, P < .001), and decrease in total peripheral resistance (23%, P < .05) without significant changes in heart rate and atrioventricular conduction. Beta-blockade with large doses of propranolol showed 20% suppression of the cardiac inotropism of X-537A. The action of X-537A is typically rapid with a smooth continuous progression until maximal response is attained in 10-15 minutes, sustained for about one hour, then gradually subsides during the third hour. Such ideal cardiovascular effects of X-537A portend a profound therapeutic potential in cases of cardiac decompensation and circulatory compromise. X-537A may also prove to be a valuable tool for probing the complex factors influencing myocardial contractility.