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-1-AR) and beta-2-adrenoceptors (beta-2 AR). Several ionic currents (I) can flow upon beta-AR activation: I(Ca) (through either beta-1-AR or beta-2-AR), I(Na), I(K), and I(Cl). Calcium currents (I(Ca)) can be increased directly by the alpha-s, unit of a GTP binding protein, G(s), or by coupling of G(s) 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-1-AR. 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-2-AR causes the production of at least four times more cyclic AMP than activation of one beta-1-AR. Chronic treatment of patients with beta-1-AR-selective blockers paradoxically induces selective inotropic beta-2-AR hyperreponsiveness, presumably by increasing coupling of beta-2-AR to G(s). Several partial agonists with high affinity for heart beta-1-AR and beta-2-AR cause stimulant effects that are resistant to blockade of beta-1-AR and beta-2-AR. Such nonconventional partial agonists could perhaps interact with beta-AR that resemble beta-3 adrenoceptors.