Energetic basis for reduced contractile reserve in isolated rat hearts

To study the relationship between myocardial energetics and contractile reserve, we acutely and selectively inhibited creatine kinase (CK) activity in isolated perfused rat hearts, using increasing doses of iodoacetamide. P-31 nuclear magnetic resonance spectroscopy was used to measure intracellular pH and the concentrations of ATP, phosphocreatine, and inorganic phosphate. Contractile reserve was assessed as the increase of rate-pressure product (RPP) from baseline during high-calcium perfusion. Contractile reserve was reduced by 9, 35, and 72% in hearts with 26, 6, and 1% CK activity, respectively. An inverse linear relationship between RPP and the free energy release from ATP hydrolysis (\Delta G(similar to P\)) was shown for all groups. Furthermore, the maximal RPPs of all hearts were achieved at the same level of \Delta G(similar to P)\ (52-53 kJ/mol), which is equal to the free energy requirement of sarcoplasmic reticulum Ca2+ adenosine 5'-triphosphatase (ATPase). We suggest that inhibition of the CK reaction caused a decrease of \Delta G(similar to P)\ which, in turn, limits the Ca2+-handling capacity of sarcoplasmic reticulum Ca2+ ATPase. In this way, the ability of the heart to increase its contractile performance is restricted.