Regulation of beta-adrenergic receptors: impaired desensitization in myocardial ischemia.
The dynamic regulation of the adrenergic system plays an important role in the adaptation of the cardiovascular system in health and in disease. In myocardial infarction, large quantities of catecholamines are presynaptically released. The mechanisms of adaptive regulation of the beta-adrenergic receptors to beta-agonist stimulation involves functional uncoupling of the beta-adrenergic receptors from stimulatory guanine nucleotide binding protein Gs by local sequestration with the domain of the plasma membranes and by internalization of the beta-adrenergic receptors. During this course of adaptive regulation, also called desensitization, the beta-adrenergic receptors become phosphorylated by the newly discovered beta-adrenergic receptorkinase in a cAMP-independent process. In myocardial infarction, however, large quantities of beta-adrenergic agonists are contrasted by an increased number of functionally coupled beta-adrenergic receptors. The increase of functionally coupled beta-adrenergic receptors is dependent on the loss of high energy phosphates like ATP. This loss occurring in myocardial ischemia can be mimicked by the perfusion of isolated hearts with cyanide. The perfusion with cyanide results in an increase of functionally coupled receptors, additionally demonstrating that the loss of high energy phosphates is responsible for the increase of the beta-adrenergic receptors in acute myocardial ischemia. For the first time it could be demonstrated that in myocardial ischemia the processes of beta-agonist-induced receptor uncoupling and internalization are abolished. They lead to the functional sensitization of the beta-adrenergic system and are at least in part responsible for the occurrence of malignant arrhythmias in myocardial infarction.
Strasser
R H
RH
Department of Internal Medicine and Cardiology, University of Heidelberg, F.R.G.
Krimmer
J
J
Marquetant
R
R
D000818:Animals; D003327:Coronary Disease / Q000378:metabolism*; D006801:Humans; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D011943:Receptors, Adrenergic, beta