Role of MgADP in the development of diastolic dysfunction in the intact beating rat heart.
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.
Tian
R
R
NMR Laboratory for Physiological Chemistry, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. rong@bustoff.bwh.harvard.edu
Christe
M E
ME
Spindler
M
M
Hopkins
J C
JC
Halow
J M
JM
Camacho
S A
SA
Ingwall
J S
JS
D000244:Adenosine Diphosphate / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003971:Diastole; D004305:Dose-Response Relationship, Drug; D006019:Glycolysis; D007460:Iodoacetamide / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000201:enzymology; D051381:Rats; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*
D000244:Adenosine Diphosphate; D002118:Calcium; D007460:Iodoacetamide