Some aspects of heart beta adrenoceptor function.

Heart rate and force can be increased by noradrenaline and adrenaline through an interaction with both beta 1-adrenoceptors (beta 1AR) and beta 2-adrenoceptors (beta 2 AR). Several ionic currents (I) can flow upon beta AR activation: ICa (through either beta 1AR or beta 2AR), INa, IK, and ICl. Calcium currents (ICa) can be increased directly by the alpha s unit of a GTP binding protein, Gs, or by coupling of Gs to adenylyl cyclase with subsequent formation of cyclic AMP, release of the catalytic unit of cyclic AMP-dependent protein kinase, and phosphorylation of calcium channels and other proteins. Chronic exposure (days or months), but not acute exposure (hours), to a catecholamine downregulates human heart beta 1AR. Acute desensitization partially uncouples human heart beta AR from the adenylyl cyclase. Both acute and chronic desensitization reduce positive inotropic responses to catecholamines. In human heart, catecholamine-induced activation of one beta 2AR causes the production of at least four times more cyclic AMP than activation of one beta 1AR. Chronic treatment of patients with beta 1AR-selective blockers paradoxically induces selective inotropic beta 2AR hyperresponsiveness, presumably by increasing coupling of beta 2AR to Gs. Several partial agonists with high affinity for heart beta 1AR and beta 2AR cause stimulant effects that are resistant to blockade of beta 1AR and beta 2AR. Such nonconventional partial agonists could perhaps interact with beta AR that resemble beta 3 adrenoceptors.