β3 Adrenergic Stimulation of the Cardiac Na+ -K+ Pump by Reversal of an Inhibitory Oxidative Modification

Background-Inhibition of L-type Ca2+ current contributes to negative inotropy of beta(3) adrenergic receptor (beta(3) AR) activation, but effects on other determinants of excitation-contraction coupling are not known. Of these, the Na+ -K+ pump is of particular interest because of adverse effects attributed to high cardiac myocyte Na+ levels and upregulation of the beta(3) AR in heart failure. Methods and Results-We voltage clamped rabbit ventricular myocytes and identified electrogenic Na+ -K pump current (I-p) as the shift in holding current induced by ouabain. The synthetic beta(3) AR agonists BRL37344 and CL316,243 and the natural agonist norepinephrine increased I-p. Pump stimulation was insensitive to the beta(1)/beta(2) AR antagonist nadolol and the protein kinase A inhibitor H-89 but sensitive to the beta(3) AR antagonist L-748,337. Blockade of nitric oxide synthase abolished pump stimulation and an increase in fluorescence of myocytes loaded with a nitric oxide-sensitive dye. Exposure of myocytes to beta(3) AR agonists decreased beta(1) Na+ -K+ pump subunit glutathionylation, an oxidative modification that causes pump inhibition. The in vivo relevance of this was indicated by an increase in myocardial beta(1) pump subunit glutathionylation with elimination of beta(3) AR-mediated signaling in beta(3) AR(-/-) mice. The in vivo effect of BRL37344 on contractility of the nonfailing and failing heart in sheep was consistent with a beneficial effect of Na+ -K+ pump stimulation in heart failure. Conclusions-The beta(3) AR mediates decreased beta(1) subunit glutathionylation and Na+ -K+ pump stimulation in the heart. Upregulation of the receptor in heart failure may be a beneficial mechanism that facilitates the export of excess Na+. (Circulation. 2010;122:2699-2708.)