Rat cardiac contractile dysfunction induced by Ca2+ overload: possible link to the proteolysis of alpha-fodrin

The aim of the present study was to examine the mechanisms of Ca2+ overload -induced contractile dysfunction in rat hearts independent of ischemia and acidosis. Experiments were performed on 30 excised cross-circulated rat hea rt preparations. After hearts were exposed to high Ca2+, there was a contra ctile failure associated with a parallel downward shift of the linear relat ion between myocardial O-2 consumption per beat and systolic pressure-volum e area (index of a total mechanical energy per beat) in left ventricles fro m all seven hearts that underwent the protocol. This result suggested a dec rease in O-2 consumption for total Ca2+ handling in excitation-contraction coupling. In the hearts that underwent the high Ca2+ protocol and had contr actile failure, we found marked proteolysis of a cytoskeleton protein, a-fo drin, whereas other proteins were unaffected. A calpain inhibitor suppresse d the contractile failure by high Ca2+, the decrease in O-2 consumption for total Ca2+ handling, and membrane alpha -fodrin degradation. We conclude t hat the exposure to high Ca2+ may induce contractile dysfunction possibly b y suppressing total Ca2+ handling in excitation-contraction coupling and de gradation of membrane alpha -fodrin via activation of calpain.