Carvedilol restore cardiac calcium release channel structure and function in heart failure

The ryanodine receptor (RyR2) on cardiac sarcoplasmic reticulum is the key calcium release channel required for excitation-contraction coupling. In failing hearts, the stoichiometry and function of the RyR2 macromolecular complex is altered.

In the present study, we used a well-characterized canine model of pacing-induced HF to show that Carvedilol both restores the normal stoichiometry of the RyR2 macromolecular complex and normalizes the function of the channel.

A rapid cardiac pacing regimen that results in severe HF was used. Animals were assigned to 1 of 4 groups: (1) normal without heart instrumentation (n=6), (2) HF (n=6), (3) HF treated with Carvedilol (n=6), and (4) normal without heart instrumentation plus Carvedilol (n=6). In groups 2 and 3, after baseline measurements had been obtained, rapid left ventricular (LV) pacing was initiated at 210 bpm for 3 weeks, followed by an additional week of pacing at 240 bpm with an external pacemaker. Carvedilol was begun 2 weeks after initiation of pacing and continued for 2 weeks. Carvedilol was begun 2 weeks after baseline measurement for the control dogs with heart instrumentation. SR membranes were prepared from canine ventricular tissue, protein concentration was measured by Bradford assay.

Here, we show that systemic oral administration of Carvedilol reverses protein kinase A hyperphosphorylation of RyR2, restores the stoichiometry of the RyR2 macromolecular complex, and normalizes single-channel function in a canine model of heart failure.

These results may, in part, explain the improved cardiac function observed in heart failure patients treated with Carvedilol.