Molecular Pharmacology, Vol 14, 562-574, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Cardiac Sites of Catecholamine Action: Diffusion Models for Soluble and Immobilized Catecholamine Action on Isolated Cat Papillary Muscles

¹ Department of Pharmacology and Therapeutics, State University of New York at Buffalo School of Medicine, Buffalo, New York 14214

Models for isoproterenol and polymer-immobilized isoproterenol diffusion into cat cardiac muscle have been developed by applying the diffusion rates in water and the tortuosity factor for cat cardiac muscle extracellular diffusion. The theoretical extent of drug diffusion into cardiac muscle with time has been compared with the kinetics of cyclic 3',5'-AMP formation and the development of the positive inotropic response to these agents. These studies indicate that peak cardiac inotropic responses may be obtained in cat papillary muscles when the majority of drug molecules are still at the muscle surface and less than 40% of the equilibrium concentration is present in the tissue. The maximum cyclic AMP response occurs with less than 15% of the equilibrium concentration of isoproterenol present and with the majority of the muscle cells exposed to subthreshold levels of drug. These findings suggest that under non-steady-state conditions soluble isoproterenol as well as immobilized catecholamines may cause increased contractility by propagation mechanisms. Biochemical events such as increases in the concentration of cyclic AMP may not reflect events occurring throughout the cardiac muscle. The diffusion arguments indicate that the common assumptions concerning a homogeneous distribution of drug-receptor interactions producing cardiac contractile events oversimplify the events that occur under actual experimental conditions. A model for glass bead-immobilized catecholamine action based on catecholamine leakage is also presented. It indicates that while massive drug leakage does not account for the biological responses of these agents, it may be impossible to elucidate the exact mode of drug action in the microenvironment enveloping the bead surface.