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.

Cyclosporine before PCI in Patients with Acute Myocardial Infarction

“…The vehicle of Sandimmune (Cremophor EL [polyoxyethylated castor oil]) differs from that of CicloMulsion (lipid emulsion), and both have been shown to alter mitochondrial respiration and PTP opening in a different manner, possibly influencing infarct size. 22,23 Whether the vehicles contributed to the discrepancy between the two studies remains to be clarified. However, unpublished data from our group indicate that CicloMulsion is associated with a significant reduction in infarct size in the mouse heart.…”

The Importance of Intralipid in Heart Protection: A Brief Review

“…In vivo dose of intralipid (at 5ml/kg) in their work was within recommended range by American Society of Regional Anesthesia and Pain Medicine for rescuing bupivacaine cardiotoxicity in patients. They concluded that according to their results intralipid can introduce as a new beneficial agent for acute myocardial infarction patients [6] . Rahman et al, showed that intralipid can protect the heart against ischemia/reperfusion injury as well as bupivacaine induced cardiotoxicity [9] and then their group also examined the effect of intralipid on the heart protection against bradycardia on wild type female mice C57/Bl6 (2 -4 month old).The recorded results showed that the heart rates at the baseline before inducing bradycardia was 224 ± 7 beats/min and the left ventricular pressures was 64 ± 4 mmHg.…”

“…Li et al have presented a report about post ischemic treatment with intralipid in 2012 as the first safe fat emulsion for human use. The authors stated that such an emulsion can improve the cardiac functional recovery of isolated Langendorff-perfused mouse hearts by ~ 4 fold and outcomes in 70% reduction in the myocardial infarct size [6] . In this review the importance of intralipid have presented.…”

MRI Investigation of New Approach to Improve the Recovery of Myocardial Ischemia Reperfusion Injury by Treatment with Intralipid<sup>®</sup>

“…The cardioprotective mechanisms of Intralipid ® are not totally understood. It has been shown that Intralipid ® can inhibit mitochondrial permeability transition pore opening [24] and reduce mitochondrial superoxide production, and increase pro-survival kinases such as Akt and GSK-3 [23] among other effects [4] [6] [7] [25] [26]. However, the effect of Intralipid ® on post-MI inflammatory MØs has not been investigated.…”