Beta-blockers restore @entity460 release channel function and improve cardiac muscle performance in @entity1 XXXX .

@entity1 @entity712 @entity12573 @entity1405 @entity1406 @entity23963 @entity460 @entity1140 @entity141 @entity2165
BACKGROUND: Chronic beta-adrenergic receptor (beta-AR) blockade improves cardiac contractility and prolongs survival in @entity1 with @entity712 ; however, the mechanisms underlying these favorable responses are poorly understood. Stress-induced activation of the sympathetic nervous system results in protein kinase A (PKA)-mediated phosphorylation of the @entity460 ( @entity141 ) release channel/cardiac ryanodine receptor ( @entity23963 ), required for cardiac excitation-contraction (EC) coupling, activating the @entity23963 channel, and increasing cardiac contractility. The hyperadrenergic state of @entity712 results in leaky @entity23963 channels attributable to PKA hyperphosphorylation and depletion of the stabilizing @entity1140 binding protein, @entity12573 . We tested the hypothesis that improved cardiac muscle function attributable to beta-AR blockade is associated with restoration of normal @entity23963 channel function in @entity1 with @entity712 . METHODS AND RESULTS: We assessed the effects of beta-AR blockade on left ventricular volume using isolated perfused hearts and beta-agonist responsiveness using muscle strips from @entity1 undergoing transplantation. Twenty-four @entity1 hearts were examined, 10 from @entity1 with @entity712 treated with beta-AR blockers ( @entity1405 , @entity1406 , or @entity2165 ), 9 from @entity1 with @entity712 without beta-AR blocker treatment, and 5 normal hearts. @entity23963 PKA phosphorylation was determined by back-phosphorylation, @entity12573 in the @entity23963 macromolecular complex was determined by coimmunoprecipitation, and channel function was assayed using planar lipid bilayers. beta-AR blockers reduced left ventricular volume (reverse remodeling) and restored beta-agonist response in cardiac muscle from @entity1 with @entity712 . Improved cardiac muscle function was associated with restoration of normal @entity12573 levels in the @entity23963 macromolecular complex and @entity23963 channel function. CONCLUSIONS: Improved cardiac muscle function during beta-AR blockade is associated with improved cardiac @entity141 release channel function in @entity1 with @entity712 .
