Improving glucose metabolism and/or sarcoplasmic reticulum Ca2+-ATPase function is warranted for immature pressure overload hypertrophied myocardium

The cellular mechanisms of abnormal calcium regulation and excitation-contr action coupling in relation to glucose metabolism in the hypertrophied hear t are not well understood. The present study evaluated the myocardial mecha nics of 6-7-week-old pressure overload hypertrophied rabbit hearts in respo nse to dobutamine by ( 1) serial echocardiograms in vivo and (2) isolated L angendorff perfusion. Cytosolic Ca2+([Ca2+]i) and sarcoplasmic reticulum Ca 2+-ATPase (SERCA2) expression were measured by fluorescence spectroscopy an d Western immunoblotting, respectively. The effect of glycolytic inhibition by 2-deoxy-D-glucose +/- pyruvate was also evaluated. Both systolic and di astolic [Ca2+], tended to be higher and diastolic calcium removal (tau ca) significantly slower in the hypertrophied heart. The myocardial response to dobutamine was blunted and dobutamine insignificantly improved tau Ca. The SERCA2 protein level was higher in early hypertrophy, but was significantl y reduced by 6 weeks of age, with progressive contractile failure. Inhibiti on of glycolysis or SERCA2 caused an increase in [Ca2+]i as well as a slowe r tau ca. Pyruvate completely preserved myocardial function and [Ca2+]i han dling during glycolytic inhibition. It was concluded that in this model of advanced pressure overload hypertrophy, contractile failure and inotrope in sensitivity are associated with increased [Ca2+]i, slower tau ca and reduce d sensitivity of the contractile proteins to Ca2+. These changes occur in a ssociation with downregulation of the SERCA2. probably caused by impaired g lucose metabolism.