(Circulation. 1997;96:1313-1319.)
© 1997 American Heart Association, Inc.
Articles |
Failure to Maintain a Low ADP Concentration Impairs Diastolic Function in Hypertrophied Rat Hearts
From the NMR Laboratory for Physiological Chemistry, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School (R.T., L.N., J.S.I.), and the Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School (B.H.L.), Boston, Mass.
Correspondence to Rong Tian, MD, PhD, NMR Laboratory for Physiological Chemistry, Brigham and Women's Hospital, 221 Longwood Ave, Room 247, Boston, MA 02115. E-mail rong{at}bustoff.bwh.harvard.edu
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 µmol/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.
Key Words: hypertrophy • diastole • adenosine • creatine kinase
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