The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis.

Abstract

BACKGROUND:

It is unclear how reperfusion of infarcting hearts with alternating cycles of coronary reperfusion/occlusion attenuates infarction, but prevention of mitochondrial permeability transition pore (MPTP) formation is crucial. Acidosis also suppresses MPTP formation. We tested whether postconditioning protects by maintaining acidosis during early reoxygenation.

METHODS AND RESULTS:

After 30-minute regional ischemia in isolated rabbit hearts, reperfusion with buffer (pH 7.4) caused 34.4+/-2.2% of the risk zone to infarct, whereas 2 minutes of postconditioning (6 cycles of 10-second reperfusion/10-second occlusion) at reperfusion resulted in 10.7+/-2.9% infarction. One minute (3 cycles) of postconditioning was not protective. Hypercapnic buffer (pH 6.9) for the first 2 minutes of reperfusion in lieu of postconditioning caused equivalent cardioprotection (15.0+/-2.6% infarction), whereas 1 minute of acidosis did not protect. Delaying postconditioning (6 cycles) or 2 minutes of acidosis for 1 minute aborted protection. Reperfusion with buffer (pH 7.7) blocked postconditioning protection, but addition of the MPTP closer cyclosporin A restored protection. Reactive oxygen species scavenger N-2-mercaptopropionyl glycine, protein kinase C antagonist chelerythrine, and mitochondrial K(ATP) channel closer 5-hydroxydecanoate each blocked protection from 2 minutes of acidosis as they did for postconditioning.

CONCLUSIONS:

Thus, postconditioning prevents MPTP formation by maintaining acidosis during the first minutes of reperfusion as reoxygenated myocardium produces reactive oxygen species that activate protective signaling to inhibit MPTP formation after pH normalization.

• Authors: Michael V Cohen, Xi-Ming Yang, James M Downey
• Journal: Circulation (Circulation) Vol. 115 Issue 14 Pg. 1895-903 (Apr 10 2007) ISSN: 1524-4539 [Electronic] United States
• PMID: 17389262 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Alkaloids
• Benzophenanthridines
• Buffers
• Decanoic Acids
• Free Radical Scavengers
• Hydroxy Acids
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• N-(2-mercaptoproprionyl)-glycine
• Potassium Channel Blockers
• Potassium Channels
• Sulfhydryl Compounds
• mitochondrial K(ATP) channel
• Carbon Dioxide
• 5-hydroxydecanoic acid
• chelerythrine
• Protein Kinase C
• Oxygen
• Glycine

Topics

• Acidosis (metabolism)
• Alkaloids (pharmacology)
• Animals
• Apoptosis
• Benzophenanthridines (pharmacology)
• Buffers
• Carbon Dioxide (administration & dosage)
• Catheterization
• Decanoic Acids (pharmacology)
• Free Radical Scavengers (pharmacology)
• Glycine (analogs & derivatives, pharmacology)
• Hydrogen-Ion Concentration
• Hydroxy Acids (pharmacology)
• Mitochondria, Heart (pathology)
• Mitochondrial Membrane Transport Proteins (antagonists & inhibitors, physiology)
• Mitochondrial Permeability Transition Pore
• Models, Cardiovascular
• Myocardial Infarction (pathology, physiopathology, therapy)
• Myocardial Reperfusion (methods)
• Oxygen (metabolism)
• Potassium Channel Blockers (pharmacology)
• Potassium Channels (drug effects)
• Protein Kinase C (antagonists & inhibitors)
• Rabbits
• Sulfhydryl Compounds (pharmacology)
• Time Factors