Excessive ATP hydrolysis in ischemic myocardium by mitochondrial F1F0-ATPase: effect of selective pharmacological inhibition of mitochondrial ATPase hydrolase activity.

Abstract

Mitochondrial F(1)F(0)-ATPase normally synthesizes ATP in the heart, but under ischemic conditions this enzyme paradoxically causes ATP hydrolysis. Nonselective inhibitors of this enzyme (aurovertin, oligomycin) inhibit ATP synthesis in normal tissue but also inhibit ATP hydrolysis in ischemic myocardium. We characterized the profile of aurovertin and oligomycin in ischemic and nonischemic rat myocardium and compared this with the profile of BMS-199264, which only inhibits F(1)F(0)-ATP hydrolase activity. In isolated rat hearts, aurovertin (1-10 microM) and oligomycin (10 microM), at concentrations inhibiting ATPase activity, reduced ATP concentration and contractile function in the nonischemic heart but significantly reduced the rate of ATP depletion during ischemia. They also inhibited recovery of reperfusion ATP and contractile function, consistent with nonselective F(1)F(0)-ATPase inhibitory activity, which suggests that upon reperfusion, the hydrolase activity switches back to ATP synthesis. BMS-199264 inhibits F(1)F(0) hydrolase activity in submitochondrial particles with no effect on ATP synthase activity. BMS-199264 (1-10 microM) conserved ATP in rat hearts during ischemia while having no effect on preischemic contractile function or ATP concentration. Reperfusion ATP levels were replenished faster and necrosis was reduced by BMS-199264. ATP hydrolase activity ex vivo was selectively inhibited by BMS-199264. Therefore, excessive ATP hydrolysis by F(1)F(0)-ATPase contributes to the decline in cardiac energy reserve during ischemia and selective inhibition of ATP hydrolase activity can protect ischemic myocardium.

• Authors: Gary J Grover, Karnail S Atwal, Paul G Sleph, Feng-Li Wang, Hossain Monshizadegan, Thomas Monticello, David W Green
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 287 Issue 4 Pg. H1747-55 (Oct 2004) ISSN: 0363-6135 [Print] United States
• PMID: 15371268 (Publication Type: Journal Article)

Chemical References

• Aurovertins
• BMS199264
• Enzyme Inhibitors
• Imidazoles
• Oligomycins
• Uncoupling Agents
• oligomycin B
• aurovertin B
• Adenosine Triphosphate
• Proton-Translocating ATPases

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Aurovertins (chemistry, pharmacology)
• Cell Survival (physiology)
• Enzyme Inhibitors (pharmacology)
• Hydrolysis
• Imidazoles (chemistry, pharmacology)
• Male
• Mitochondria (enzymology)
• Myocardial Ischemia (metabolism)
• Myocardium (cytology, metabolism)
• Oligomycins (chemistry, pharmacology)
• Proton-Translocating ATPases (antagonists & inhibitors, metabolism)
• Rats
• Rats, Sprague-Dawley
• Uncoupling Agents (chemistry, pharmacology)