Role of MgADP in the development of diastolic dysfunction in the intact beating rat heart

J Clin Invest. 1997 Feb 15;99(4):745-51. doi: 10.1172/JCI119220.

Abstract

Sarcomere relaxation depends on dissociation of actin and myosin, which is regulated by a number of factors, including intracellular [MgATP] as well as MgATP hydrolysis products [MgADP] and inorganic phosphate [Pi], pHi, and cytosolic calcium concentration ([Ca2+]c). To distinguish the contribution of MgADP from the other regulators in the development of diastolic dysfunction, we used a strategy to increase free [MgADP] without changing [MgATP], [Pi], or pHi. This was achieved by applying a low dose of iodoacetamide to selectively inhibit the creatine kinase activity in isolated perfused rat hearts. [MgATP], [MgADP], [Pi], and [H+] were determined using 31P NMR spectroscopy. The [Ca2+]c and the glycolytic rate were also measured. We observed an approximately threefold increase in left ventricular end diastolic pressure (LVEDP) and 38% increase in the time constant of pressure decay (P < 0.05) in these hearts, indicating a significant impairment of diastolic function. The increase in LVEDP was closely related to the increase in free [MgADP]. Rate of glycolysis was not changed, and [Ca2+]c increased by 16%, which cannot explain the severity of diastolic dysfunction. Thus, our data indicate that MgADP contributes significantly to diastolic dysfunction, possibly by slowing the rate of cross-bridge cycling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Diphosphate / physiology*
  • Animals
  • Calcium / metabolism
  • Diastole*
  • Dose-Response Relationship, Drug
  • Glycolysis
  • Iodoacetamide / pharmacology
  • Magnetic Resonance Spectroscopy
  • Male
  • Myocardial Reperfusion
  • Myocardium / enzymology
  • Rats
  • Ventricular Dysfunction, Left / etiology*
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / physiopathology*

Substances

  • Adenosine Diphosphate
  • Calcium
  • Iodoacetamide