Abstract 2173: Bradycardiac Therapy Normalized Altered Calcium-handling Proteins in Chronic Heart Failure
Background: We previously showed that cilobradine (Cilo), a bradycardiac agent, decreases heart rate and improves cardiac function in chronic heart failure (CHF). However, the mechanisms of bradycardiac therapy responsible for its beneficial effects are not clear. We hypothesized that bradycardiac therapy might improve abnormal calcium hemeostasis via normalization of altered calcium-handling proteins in CHF. The objective of this study was to examine whether Cilo alteres three major calcium-handling protein levels (sarcoplasmic reticulum calcium-ATPase, SERCA2a; Ryanodine receptor, RyR2; Na+-Ca2+ exchanger, NCX1) in myocardium in a canine model of ischemic CHF.
Methods: Stable CHF was created by daily coronary embolizations via a chronically implanted coronary (LAD) catheter in 10 chronically instrumented dogs. After establishment of CHF, Cilo (1 mg/kg/day, n=5) or placebo (n=5) was orally given for 12 wks. Left ventricular (LV) tissue samples from these dogs and other 5 normal dogs were obtained for Western analysis (band intensities normalized to tubulin) in terminal experiments. RyR2 protein kinase A (PKA) phosphorylation was determined by back-phosphorylation assay.
Results: In CHF, SERCA2a was significantly decreased and NCX1 was markedly increased; the phosphorylated form of RyR2 was significantly increased while the total RyR2 protein levels were not changed. Bradycardiac therapy via administration of Cilo normalized protein levels of SERCA2a, NCX1 and restored PKA hyperphosphorylation of RyR2 companied with improved cardiac function (hemodynamic data are not shown). Data are summarized in table⇓ (Mean ± SE; * p<0.05 vs normal; # p<0.05 vs CHF).
Conclusion: We demonstrated normalized calcium-handling protein levels by bradycardiac therapy in CHF. Our results suggested that the mechanism responsible for the beneficial effects of bradycardiac therapy on cardiac function in CHF might be associated with normalized calcium homeostasis.