Regulation of cardiac alternans by β-adrenergic signaling pathways

Florea SM, Blatter LA. Regulation of cardiac alternans by beta-adrenergic signaling pathways. Am J Physiol Heart Circ Physiol 303: H1047-H1056, 2012. First published August 17, 2012; doi:10.1152/ajpheart.00384.2012.-In cat atrial myocytes, beta-adrenergic receptor (beta-AR) stimulation exerts profound effects on excitation-contraction coupling and cellular Ca2+ cycling that are mediated by beta(1)- and beta(2)-AR subtypes coupled to G proteins (G(s) and G(i)). In this study, we determined the effects of beta-AR stimulation on pacing-induced Ca2+ alternans. Ca2+ alternans was recorded from single cat atrial myocytes with the fluorescent Ca2+ indicator indo-1. Stable Ca2+ alternans occurred at an average pacing frequency of 1.7 Hz at room temperature with a mean alternans ratio of 0.43. Nonselective beta-AR stimulation as well as selective stimulation of beta(1)/G(s), beta(2)/G(s) + G(i), and beta(2)/G(s) coupled pathways all abolished pacing-induced Ca2+ alternans. beta(1)-AR stimulation abolished alternans through stimulation of PKA and Ca2+/calmodulin-dependent protein kinase II, whereas beta(2)-AR stimulation exclusively involved PKA and was mediated via G(s), whereas a known second pathway in cat atrial myocytes acting through G(i) and nitric oxide production was not involved in alternans regulation. Inhibition of various mitochondrial functions (dissipation of the mitochondrial membrane potential or inhibition of mitochondrial F-1/F-0-ATP synthase, mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter, and Ca2+ extrusion via mitochondrial Na+/Ca2+ exchange) enhanced Ca2+ alternans; however, beta-AR stimulation still abrogated alternans, provided that sufficient cellular ATP was available. Selective inhibition of mitochondrial or glycolytic ATP production did not prevent beta-AR stimulation from abolishing Ca2+ alternans. However, when both ATP sources were depleted, beta-AR stimulation failed to decrease Ca2+ alternans. These results indicate that in atrial myocytes, beta-AR stimulation protects against pacing-induced alternans by acting through parallel and complementary signaling pathways.