Physiologically tolerable insulin reduces myocardial injury and improves cardiac functional recovery in myocardial ischemic/reperfused dogs.

This study was designed to examine whether physiologically tolerable insulin, which maintains lower blood glucose, can protect the myocardium against ischemia/reperfusion (I/R) injury in a preclinical large animal model. Adult dogs were subjected to 50 minutes of myocardial ischemia (80% reduction in coronary blood flow) followed by 4 hours of reperfusion and treated with vehicle, glucose-insulin-potassium (GIK; glucose, 250 g/L; insulin, 60 U/L; potassium, 80 mmol/L), GK, or low-dose insulin (30 U/L) 10 minutes before reperfusion. Treatment with GIK exerted significant cardioprotective effects as evidenced by improved cardiac function, improved coronary blood flow, reduced infarct size, and myocardial apoptosis. In contrast, treatment with GK increased blood glucose level and aggravated myocardial I/R injury. It is interesting that treatment with insulin alone at the dose that reduced blood glucose to a clinically tolerable level exerted significant cardioprotective effects that were comparable to that seen in the GIK-treated group. This low-dose insulin had no effect on coronary blood flow after reperfusion but markedly reduced coronary reactive hyperemia and switched myocardial substrate uptake from fat to carbohydrate. Our results suggest that lower glucose supply to the ischemic myocardium at early reperfusion may create a "metabolic postconditioning" and thus reduce myocardial ischemia/reperfusion injury after prolonged reperfusion.

[Effects of insulin on cardiac function and coronary circulation in acute myocardial ischemia and reperfusion experiment with dogs].

OBJECTIVE: To study the effect of insulin on cardiac functional recovery, coronary blood flow (CBF), coronary arterial function and coronary vascular endothelial cell apoptosis following acute myocardial ischemia/reperfusion (MI/R). METHODS: In adult dogs, the left anterior descending coronary artery (LAD) was partially occluded (80% reduction in its blood flow) for 50 min and reperfused for 4 h. Vehicle (0.9% NaCl), GIK (glucose: 250 gxL(-1), insulin: 60 UxL(-1), potassium: 80 mmolxL(-1)), or GK (glucose: 250 gxL(-1), potassium: 80 mmolxL(-1)) were intravenously infused (2 mlxkg(-1)xh(-1)) 5 min before reperfusion, and CBF and left ventricular pressure were monitored. At the end of 4 h reperfusion period, coronary arteries were isolated, and the coronary vascular dysfunction, nitric oxide (NO) production and endothelial apoptosis were determined. RESULTS: During reperfusion, compared with the vehicle, GIK increased CBFLAD (19.2 ml/min +/- 2.2 ml/min) vs (14.6 ml/min +/- 1.8 ml/min) of vehicle at the end of reperfusion, P < 0.05, improved recovery of LVSP and +/- LVdP/dtmax. In vivo ischemia/reperfusion caused significant coronary vascular endothelial dysfunction as evidenced by reduced endothelium dependent vasorelaxation, decreased total NO production, and endothelial cell apoptosis as determined by TUNEL staining. Reperfusion with GIK, but not GK, markedly improved the endothelium-dependent vasorelaxation (80.3% +/- 3.8%) vs. vehicle (28.1% +/- 2.3%, P < 0.01) of coronary artery in response to ACh. GIK significantly increased total NO production (17.19 micromol/L +/- 2.18 micromol/L) versus vehicle (4.74 micromol/L +/- 2.01 micromol/L, P < 0.01) and inhibited apoptosis in coronary arterial endothelial cell (12% +/- 4%) vs vehicle (45% +/- 7%, P < 0.01). GK failed to show any significant vasculoprotection against MI/R-induced coronary vascular injury. CONCLUSION: These results demonstrate that insulin exerts cardioprotective effect by increasing CBF, reducing coronary artery injury and improving cardiac functional recovery during reperfusion, which may be partly attributable to the coronary vasculoprotective effect of insulin. The insulin-induced, NO-mediated anti-endothelial apoptotic effect may play a critical role in the insulin-induced coronary artery protective effect in MI/R.