Does failure to maintain low ADP concentration contribute to diastolic dysfunction in hypertrophied rat hearts?
Increased intracellular ADP contributes to diastolic dysfunction in left ventricular hypertrophy, likely due to slowed cross-bridge cycling and decreased creatine kinase reaction capacity.
BACKGROUND: Mechanisms in addition to diastolic calcium overload may contribute to diastolic dysfunction in hypertrophied hearts. In this study, we tested the hypothesis that failure to maintain a low ADP concentration in hypertrophied hearts contributes to diastolic dysfunction by inhibiting the rate of cross-bridge cycling. METHODS AND RESULTS: By perfusing isolated rat hearts with pyruvate and 2-deoxyglucose (2DG), we were able to perturb ADP with minimal changes in ATP and inorganic phosphate or the contribution of glycolytic ATP to ATP synthesis. The effects of 2DG were compared in aortic-banded (LVH, n=5) and sham-operated (control, n=5) rat hearts. 31P NMR spectroscopy was used to measure the concentrations of phosphorus-containing compounds. We found a threefold increase of left ventricular end-diastolic pressure (LVEDP) in LVH during 2DG perfusion, and this increase was concomitant with a threefold increase in intracellular free ADP. The ADP in the control hearts was maintained <40 micromol/L, and no change in LVEDP was observed. A linear relationship between increases in ADP and LVEDP was found (r2=.66, P=.001). Furthermore, the capacity of the creatine kinase reaction, a major mechanism for maintaining a low ADP, was decreased in LVH (P=.0001). CONCLUSIONS: Increased ADP contributes to diastolic dysfunction in LVH, possibly due to slowed cross-bridge cycling. Decreased capacity of the creatine kinase reaction to rephosphorylate ADP is a likely contributing mechanism to the failure to maintain a low ADP in LVH.
Tian et al. (Tue,) studied this question.