The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology

beta-Adrenoceptor blocking agents ( beta-blockers) that at low concentrations antagonize cardiostimulant effects of catecholamines, but at high concentrations also cause cardiostimulation, have been appearing since the late 1960s. These cardiostimulant beta-blockers, coined non-conventional partial agonists, antagonize the effects of catecholamines through a high-affinity site (beta(1H)AR), but cause cardiostimulation mainly through a low-affinity site (beta(1L)AR) of the myocardial beta(1)-adrenoceptor. The experimental non-conventional partial agonist (-)-CGP12177 increases cardiac L-type Ca2+ current density and Ca2+ transients, shortens action potential duration but augments action potential plateau, increases heart rate and force, as well as causes arrhythmic Ca2+ transients and arrhythmic cardiocyte contractions. Other beta-blockers, which do not cause cardiostimulation, consistently have lower affinity for beta(1L)AR than beta(1H)AR. These sites were verified and the cardiac pharmacology of non-conventional partial agonists confirmed on recombinant beta(1)-adrenoceptors and on beta 1-adrenoceptors overexpressed into the heart. A targeted mutation of Asp138 to Glu138 virtually abolished the pharmacology of beta(1H)AR but left intact the pharmacology of beta(1L)AR. Non-conventional partial agonists may be beneficial for the treatment of peripheral autonomic neuropathy but probably due to their arrhythmic propensities, may be harmful for the treatment of chronic heart failure. (C) 2008 Elsevier Inc. All rights reserved.