Insulin Preconditioning Elevates p-Akt and Cardiac Contractility after Reperfusion in the Isolated Ischemic Rat Heart

Abstract

Insulin induces cardioprotection partly via an antiapoptotic effect. However, the optimal timing of insulin administration for the best quality cardioprotection remains unclear. We tested the hypothesis that insulin administered prior to ischemia provides better cardioprotection than insulin administration after ischemia. Isolated rat hearts were prepared using Langendorff method and divided into three groups. The Pre-Ins group (Pre-Ins) received 0.5 U/L insulin prior to 15 min no-flow ischemia for 20 min followed by 20 min of reperfusion. The Post-Ins group (Post-Ins) received 0.5 U/L insulin during the reperfusion period only. The control group (Control) was perfused with KH buffer throughout. The maximum of left ventricular derivative of pressure development (dP/dt(max)) was recorded continuously. Measurements of TNF-α and p-Akt in each time point were assayed by ELISA. After reperfusion, dP/dt(max) in Pre-Ins was elevated, compared with Post-Ins at 10 minutes after reperfusion and Control at all-time points. TNF-α levels at 5 minutes after reperfusion in the Pre-Ins were lower than the others. After 5 minutes of reperfusion, p-Akt was elevated in Pre-Ins compared with the other groups. Insulin administration prior to ischemia provides better cardioprotection than insulin administration only at reperfusion. TNF-α suppression is possibly mediated via p-Akt leading to a reduction in contractile myocardial dysfunction.

Glycemia and the cardioprotective effects of insulin pre-conditioning in the isolated rat heart

“…[14, 15] Cardiomyocytes perfused with insulin had elevated p-Akt levels prior to ischemia compared with those that did not receive insulin [3]. Similarly, in the present study, insulin pre-conditioning was associated with increased myocardial p-Akt concentrations.…”

“…Pharmacological options include the pre-emptive administration of volatile anesthetics, adenosine, nicorandil, delta opioids and nitroglycerin [2]. Recently, insulin also demonstrated cardioprotective qualities when given prior to an ischemic insult [3, 9]. …”

“…Hyperglycemia itself further exacerbates inflammatory and oxidative responses, potentially initiating a vicious cycle [17, 18]. In contrast to the results of a previous study [3], tissue TNF-α, a known inhibitor of insulin-induced IRS-1 tyrosine phosphorylation and myocardial contractility [19], was not affected by insulin pre-conditioning. In our previous protocol, insulin had decreased the release of TNF-α into the coronary efferent fluid 5 min after reperfusion, while no effect was seen 15 min later [3].…”

“…The mechanisms responsible for these beneficial effects in cardiac surgery involve specific modifications of cell surface receptors, mitochondrial components, and signaling kinases [1]. We recently demonstrated that insulin pre-conditioning improves cardiac contractility and that this cardioprotective influence is associated with the activation of the myocardial phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling system [1, 3]. …”

Obesity induced by high fat diet attenuates postinfarct myocardial remodeling and dysfunction in adult B6D2F1 mice

“…A large body of evidence indicates that insulin increases the tolerance to ischemia/reperfusion [44][45][46]. Different experimental [47,48] and clinical studies [49][50][51] observed a beneficial effect of glucoseinsulin-potassium (GIK) infusion against myocardial reperfusion injury.…”