title: Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA. rong@bustoff.bwh.harvard.edu
authors.forename: R
authors.initials: R
authors.lastname: Tian
authors.forename: L
authors.initials: L
authors.lastname: Nascimben
authors.forename: J S
authors.initials: JS
authors.lastname: Ingwall
authors.forename: B H
authors.initials: BH
authors.lastname: Lorell
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D017379:Hypertrophy, Left Ventricular / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018754:Ventricular Dysfunction / Q000209:etiology*; D017725:Ventricular Pressure / Q000187:drug effects / Q000502:physiology
chemical_list: D000963:Antimetabolites; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D003402:Creatine Kinase