beta-adrenergic mechanisms in cardiac diseases: a perspective.

Several lines of evidence show that neurohumoral systems, especially those involving catecholamines, play a crucial role in cardiac diseases. Changes in the beta-adrenergic receptor (beta-AR) system such as receptor down-regulation, uncoupling from G-proteins, receptor internalization and receptor degradation may account for some of the abnormalities of contractile function in this disease. Increases in the level of inhibitory G-protein subunits also appears to be involved in attenuating the beta-AR signal. Finally beta-AR signalling is strongly regulated by members of the G-protein-coupled receptor kinase family (GRKs), the best known of which is beta-adrenergic receptor kinase 1 (beta-ARK1). beta-ARK1 mRNA, protein level and enzymatic activity is increased in heart disease, further contributing to an attenuation in beta-AR signalling. The combination of these negative alterations are presumably related to the contractile dysfunction seen in human heart disease. The combination of biochemical, physiological and molecular biological studies bearing on the normal function and regulation of these various molecules should provide strategies for elucidating the pharmacological basis of the regulation of myocardial contractility in the normal and failing heart.