Triglycerides impair postischemic recovery in isolated hearts: roles of endothelin-1 and trimetazidine

There is growing evidence that hypertriglyceridemia exacerbates ischemic in jury. We tested the hypothesis that triglycerides impair myocardial recover y from low-flow ischemia in an ex vivo model and that such an effect is rel ated to endothelin-1. Hyperglycemic (glucose concentration = 12 mmol/l) and hyperinsulinemic (insulin concentration = 1.2 mu mol/l) isolated rat heart s were perfused with Krebs-Henseleit buffer (PO2 = 670 mmHg, pH 7.4, 37 deg reesC) added with increasing triglycerides (0, 1,000, 2,000, and 4,000 mg/d l, n = 6-9 rats/group). Hearts were exposed to 60 min of low-flow ischemia (10% of basal coronary flow), followed by 30 min of reperfusion. We found t hat increasing triglycerides impaired both the diastolic (P < 0.005) and sy stolic (P < 0.02) recovery. The release of endothelin-1 during reperfusion increased linearly with triglyceride concentration (P = 0.0009). Elevated t riglycerides also increased the release of nitrite and nitrate (NOx), the e nd products of nitric oxide, up to 6 mu mol/min. Trimetazidine (1 mu mol) f urther increased NOx release, blunted endothelin-1 release, and protected m yocardial function during recovery. We conclude that high triglyceride leve ls impair myocardial recovery after low-flow ischemia in association with e ndothelin-1 release. The endothelium-mediated effect of triglycerides on bo th contractile recovery and endothelin-1 release is prevented by 1 muM trim etazidine.