Abstract
Cardiac alternans is a high risk indicator for cardiac arrhythmias, stroke and sudden cardiac death. The cardioactive peptide Urocortin 2 (Ucn2) exhibits beneficial effects in normal and failing hearts, and elicits PKA-dependent positive inotropic and lusitropic effects in normal myocytes. Thus, we investigated if Ucn2 protects against pacing-induced alternans and elucidated the underlying mechanism.Experiments were performed on single rabbit atrial and ventricular myocytes from normal and failing hearts. Chronic heart failure was induced by combined pressure and volume overload. Ca alternans was induced by incrementally increasing the pacing frequency until stable Ca alternans occurred at room temperature. Global Ca transients were measured with the fluorescent Ca indicators Fluo-4 or Indo-1 and monitored simultaneously with mechanical alternans (sarcomere length). In some experiments, cytosolic Ca alternans and intra-SR Ca alternans were simultaneously recorded with the Ca indicators Rhod-2 and Fluo-5N, respectively.The average alternans ratio (AR = 1-(small-amplitude/large-amplitude)) in atrial myocytes was 0.79, and in normal and failing ventricular myocytes the ARs were 0.69 and 0.64, respectively. Ucn2 (100 nM) completely abolished Ca and mechanical alternans (within 2-3 min) in atrial and ventricular myocytes from normal and failing hearts. An increased sarcoplasmic reticulum (SR) Ca content, together with an enhanced SR Ca release flux, suggested that Ucn2 normalized alternans through effects on SR Ca ATPase (SERCA). Ucn2 increased significantly the level of cyclic adenosine monophosphate (cAMP) in normal cells (∼12-fold), and enhanced phosphorylation of phospholamban (PLB) at Ser16 in normal myocytes (∼10-fold) and to a lesser extent (∼5-fold) in failing myocytes. These data demonstrate that Ucn2 rescues alternans presumably via increased SERCA activity in atrial and ventricular myocytes and thus protects normal and failing hearts from proarrhythmic alternans.
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