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

Rong Tian, Michael E. Christe, Matthias Spindler, James C.A. Hopkins, Jessica M. Halow, S. Albert Camacho, Joanne S. Ingwall

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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], pH(i), 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 pH(i). 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.

Original languageEnglish (US)
Pages (from-to)745-751
Number of pages7
JournalJournal of Clinical Investigation
Volume99
Issue number4
DOIs
StatePublished - Feb 15 1997
Externally publishedYes

Keywords

  • ATP
  • calcium
  • cross-bridge cycling
  • inorganic phosphate
  • relaxation

ASJC Scopus subject areas

  • Medicine(all)

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