Total ischemia III: Effect of inhibition of anaerobic glycolysis

Robert B. Jennings, Keith A. Reimer, Charles Jr Steenbergen, Jutta Schaper

Research output: Contribution to journalArticle

Abstract

The effect of inhibition of glycolysis with sodium iodoacetate (IAA) on the changes induced by total ischemia was studied in canine left ventricle. Hearts were excised from phenobarbital anesthetized dogs and the circumflex (LCC) and anterior descending (LAD) branches of the left coronary artery were perfused in order to expose the LCC region to 48 μmol of IAA (about 1·5 μmol/g wet wt). The LAD regions of the same hearts served as untreated control myocardium. Hearts then were subjected to total ischemia in vitro at 37°C. Metabolites, ultrastructure, and the capacity of thin incubated slices of heart to maintain volume and ion gradients were studied in the control and IAA-treated regions. Depletion of ATP to levels of 3-4% of control occurred in only 4-5 min of ischemia in the IAA-treated myocardium, but similar depletion required 90 min of total ischemia in untreated myocardium. These low levels of ATP were associated with marked contracture-rigor. Depletion of ATP in the IAA treated region was accompanied by a marked increase in adenosine levels in the tissue at the onset of rigor (∼5 min); at this time, as much as 50% of the adenine nucleotide pool (ΣAd) was in the form of adenosine. In contrast, inosine was the predominant catabolite at 5 min in control myocardium, and only composed 16% of the ΣAd pool. Thus, pretreatment with IAA produced an enormous acceleration in the rate at which the ΣAd pool was consumed in totally ischemic myocardium. Lactate, the principal glycolytic intermediate which accumulates in totally ischemic tissue, was not formed in the IAA-treated heart. Moreover, IAA treatment did not accelerate the rate at which ultrastructural evidence of lethal injury developed in the poisoned myocytes. Thus, in a setting in which lactate accumulation did not occur, totally ischemic myocytes tolerated a very low level of high energy phosphate for a longer period of time than did untreated tissue before ultrastructural signs of cell death developed. The results indicate that marked ATP depletion, pe se, does not necessarity cause prompt sarcolemmal disruption.

Original languageEnglish (US)
Pages (from-to)37-54
Number of pages18
JournalJournal of Molecular and Cellular Cardiology
Volume21
Issue numberSUPPL. 1
DOIs
StatePublished - 1989
Externally publishedYes

Fingerprint

Iodoacetates
Glycolysis
Ischemia
Myocardium
Adenosine Triphosphate
Adenosine
Muscle Cells
Lactic Acid
Iodoacetic Acid
Inosine
Adenine Nucleotides
Contracture
Phenobarbital
Heart Ventricles
Canidae
Coronary Vessels
Cell Death
Phosphates
Dogs
Ions

Keywords

  • Glycolytic inhibition
  • Iodoacetate poisoning
  • Sarcolemmal damage
  • Total ischemia

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Total ischemia III : Effect of inhibition of anaerobic glycolysis. / Jennings, Robert B.; Reimer, Keith A.; Steenbergen, Charles Jr; Schaper, Jutta.

In: Journal of Molecular and Cellular Cardiology, Vol. 21, No. SUPPL. 1, 1989, p. 37-54.

Research output: Contribution to journalArticle

Jennings, Robert B. ; Reimer, Keith A. ; Steenbergen, Charles Jr ; Schaper, Jutta. / Total ischemia III : Effect of inhibition of anaerobic glycolysis. In: Journal of Molecular and Cellular Cardiology. 1989 ; Vol. 21, No. SUPPL. 1. pp. 37-54.
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AB - The effect of inhibition of glycolysis with sodium iodoacetate (IAA) on the changes induced by total ischemia was studied in canine left ventricle. Hearts were excised from phenobarbital anesthetized dogs and the circumflex (LCC) and anterior descending (LAD) branches of the left coronary artery were perfused in order to expose the LCC region to 48 μmol of IAA (about 1·5 μmol/g wet wt). The LAD regions of the same hearts served as untreated control myocardium. Hearts then were subjected to total ischemia in vitro at 37°C. Metabolites, ultrastructure, and the capacity of thin incubated slices of heart to maintain volume and ion gradients were studied in the control and IAA-treated regions. Depletion of ATP to levels of 3-4% of control occurred in only 4-5 min of ischemia in the IAA-treated myocardium, but similar depletion required 90 min of total ischemia in untreated myocardium. These low levels of ATP were associated with marked contracture-rigor. Depletion of ATP in the IAA treated region was accompanied by a marked increase in adenosine levels in the tissue at the onset of rigor (∼5 min); at this time, as much as 50% of the adenine nucleotide pool (ΣAd) was in the form of adenosine. In contrast, inosine was the predominant catabolite at 5 min in control myocardium, and only composed 16% of the ΣAd pool. Thus, pretreatment with IAA produced an enormous acceleration in the rate at which the ΣAd pool was consumed in totally ischemic myocardium. Lactate, the principal glycolytic intermediate which accumulates in totally ischemic tissue, was not formed in the IAA-treated heart. Moreover, IAA treatment did not accelerate the rate at which ultrastructural evidence of lethal injury developed in the poisoned myocytes. Thus, in a setting in which lactate accumulation did not occur, totally ischemic myocytes tolerated a very low level of high energy phosphate for a longer period of time than did untreated tissue before ultrastructural signs of cell death developed. The results indicate that marked ATP depletion, pe se, does not necessarity cause prompt sarcolemmal disruption.

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