Intralipid, a clinically safe compound, protects the heart against ischemia-reperfusion injury more efficiently than cyclosporine-A.

Abstract

BACKGROUND:

We have recently shown that postischemic administration of intralipid protects the heart against ischemia-reperfusion injury. Here we compared the cardioprotective effects of intralipid with cyclosporine-A, a potent inhibitor of the mitochondrial permeability transition pore opening.

METHODS:

In vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with intralipid (0.5%, 1% and 2% ex-vivo, and 20% in vivo), cyclosporine-A (0.2 μM, 0.8 μM, and 1.5 μM ex- vivo and 10 mg/kg in vivo), or vehicle. The hemodynamic function, infarct size, calcium retention capacity, mitochondrial superoxide production, and phosphorylation levels of protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) were measured. The values are mean ± SEM.

RESULTS:

Administration of intralipid at reperfusion significantly reduced myocardial infarct size compared with cyclosporine-A in vivo (infarct size/area at risk)%: 22.9 ± 2.5% vs. 35.2 ± 3.5%; P = 0.030, n = 7/group). Postischemic administration of intralipid at its optimal dose (1%) was more effective than cyclosporine-A (0.8 μM) in protecting the ex vivo heart against ischemia-reperfusion injury, as the rate pressure product at the end of reperfusion was significantly higher (mmHg · beats/min: 12,740 ± 675 [n = 7] vs. 9,203 ± 10,781 [n = 5], P = 0.024), and the infarct size was markedly smaller (17.3 ± 2.9 [n = 7] vs. 29.2 ± 2.7 [n = 5], P = 0.014). Intralipid was as efficient as cyclosporine-A in inhibiting the mitochondrial permeability transition pore opening (calcium retention capacity = 280 ± 8.2 vs. 260.3 ± 2.9 nmol/mg mitochondria protein in cyclosporine-A, P = 0.454, n = 6) and in reducing cardiac mitochondrial superoxide production. Unlike intralipid, which increased phosphorylation of Akt (6-fold) and GSK-3β (5-fold), cyclosporine-A had no effect on the activation of these prosurvival kinases.

CONCLUSIONS:

Although intralipid inhibits the opening of the mitochondrial permeability transition pore as efficiently as cyclosporine-A, intralipid is more effective in reducing the infarct size and improving the cardiac functional recovery.

• Authors: Jingyuan Li, Andrea Iorga, Salil Sharma, Ji-Youn Youn, Rod Partow-Navid, Soban Umar, Hua Cai, Siamak Rahman, Mansoureh Eghbali
• Journal: Anesthesiology (Anesthesiology) Vol. 117 Issue 4 Pg. 836-46 (Oct 2012) ISSN: 1528-1175 [Electronic] United States
• PMID: 22814384 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cardiotonic Agents
• Emulsions
• Fat Emulsions, Intravenous
• Immunosuppressive Agents
• Phospholipids
• Reactive Oxygen Species
• soybean oil, phospholipid emulsion
• Soybean Oil
• Cyclosporine
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Gsk3b protein, rat
• Oncogene Protein v-akt
• Glycogen Synthase Kinase 3
• Calcium

Topics

• Animals
• Anterior Wall Myocardial Infarction (pathology)
• Blotting, Western
• Calcium (metabolism, pharmacology)
• Cardiotonic Agents
• Coronary Vessels (physiology)
• Cyclosporine (pharmacology)
• Dose-Response Relationship, Drug
• Electron Spin Resonance Spectroscopy
• Emulsions (pharmacology)
• Fat Emulsions, Intravenous (pharmacology)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Heart Function Tests
• Immunosuppressive Agents (pharmacology)
• In Vitro Techniques
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria, Heart (drug effects)
• Myocardial Reperfusion Injury (pathology, prevention & control)
• Necrosis
• Oncogene Protein v-akt (metabolism)
• Permeability
• Phospholipids (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (analysis, metabolism)
• Soybean Oil (pharmacology)