Triglycerides impair postischemic recovery in isolated hearts: roles of endothelin-1 and trimetazidine.
There is growing evidence that hypertriglyceridemia exacerbates ischemic injury. We tested the hypothesis that triglycerides impair myocardial recovery from low-flow ischemia in an ex vivo model and that such an effect is related to endothelin-1. Hyperglycemic (glucose concentration = 12 mmol/l) and hyperinsulinemic (insulin concentration = 1.2 micromol/l) isolated rat hearts were perfused with Krebs-Henseleit buffer (PO(2) = 670 mmHg, pH 7.4, 37 degrees C) added with increasing triglycerides (0, 1,000, 2,000, and 4,000 mg/dl, 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 that increasing triglycerides impaired both the diastolic (P < 0.005) and systolic (P < 0.02) recovery. The release of endothelin-1 during reperfusion increased linearly with triglyceride concentration (P = 0.0009). Elevated triglycerides also increased the release of nitrite and nitrate (NO(x)), the end products of nitric oxide, up to 6 micromol/min. Trimetazidine (1 micromol) further increased NO(x) release, blunted endothelin-1 release, and protected myocardial function during recovery. We conclude that high triglyceride levels impair myocardial recovery after low-flow ischemia in association with endothelin-1 release. The endothelium-mediated effect of triglycerides on both contractile recovery and endothelin-1 release is prevented by 1 microM trimetazidine.
Monti
L D
LD
Divisione di Medicina, Universita' Vita-Salute, 20132 Milan, Italy. lucilla.monti@hsr.it
Allibardi
S
S
Piatti
P M
PM
Valsecchi
G
G
Costa
S
S
Pozza
G
G
Chierchia
S
S
Samaja
M
M
D000818:Animals; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism; D006946:Hyperinsulinism / Q000150:complications / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D014280:Triglycerides / Q000378:metabolism / Q000494:pharmacology*; D014292:Trimetazidine / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D019332:Endothelin-1; D007328:Insulin; D014280:Triglycerides; D014665:Vasodilator Agents; D005947:Glucose; D014292:Trimetazidine