The cellular mechanisms of abnormal calcium regulation and excitation - contraction coupling in relation to glucose metabolism in the hypertrophied heart are not well understood. The present study evaluated the myocardial mechanics of 6-7-week-old pressure overload hypertrophied rabbit hearts in response to dobutamine by (1) serial echocardiograms in vivo and (2) isolated Langendorff perfusion. Cytosolic Ca
2+([Ca
2+]
i) and sarcoplasmic reticulum Ca
2+-ATPase (SERCA2) expression were measured by fluorescence spectroscopy and Western immunoblotting, respectively. The effect of glycolytic inhibition by 2-deoxy-D-glucose ± pyruvate was also evaluated. Both systolic and diastolic [Ca
2+]
i tended to be higher and diastolic calcium removal (τ
Ca) significantly slower in the hypertrophied heart. The myocardial response to dobutamine was blunted and dobutamine insignificantly improved τ
Ca. The SERCA2 protein level was higher in early hypertrophy, but was significantly reduced by 6 weeks of age, with progressive contractile failure. Inhibition of glycolysis or SERCA2 caused an increase in [Ca
2+]
i as well as a slower τ
Ca. Pyruvate completely preserved myocardial function and [Ca
2+]
i handling during glycolytic inhibition. It was concluded that in this model of advanced pressure overload hypertrophy, contractile failure and inotrope insensitivity are associated with increased [Ca
2+]
i, slower τ
Ca and reduced sensitivity of the contractile proteins to Ca
2+. These changes occur in association with downregulation of the SERCA2, probably caused by impaired glucose metabolism. (
Jpn Circ J 2001;
65: 1064 - 1070)
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