The low-affinity site of the beta1-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 Ca(2+) current density and Ca(2+) transients, shortens action potential duration but augments action potential plateau, increases heart rate and force, as well as causes arrhythmic Ca(2+) 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.