Impairment of endothelium dependent relaxation in the diabetic rat heart: mechanisms and implications

An increased oxidative stress has been suggested to contribute to disturbances in the regulation of coronary flow and the increased cardiac risk in diabetes. Using the isolated perfused heart of streptozotocin-diabetic rats we could recently show [21] that the basal and the maximal coronary flow (tested by infusion of sodium nitroprusside) are not altered in diabetes, but that the 5-HT stimulated endothelial dependent increase in coronary flow becomes progressively impaired. This defect of the endothelium dependent vasodilatation was prevented by perfusion of the hearts with superoxide dismutase and pre-treatment of the diabetic rats with tocopherol-acetate. Perfusion of the hearts with indomethacin to inhibit the synthesis of vasoconstricting prostaglandin endoperoxides did not improve the disturbed 5-HT induced, endothelium dependent increase in coronary flow. Furthermore, acute variations of the glucose concentration in the perfusion medium did not affect the coronary flow significantly. In myocardium, the constitutive endothelial NO synthetase was nearly exclusively expressed with the highest activity in endothelium, as determined from experiments using isolated cardiac endothelial cells. The activity of NO synthetase determined by conversion of arginine to citrulline was significantly increased in diabetes. In line with this observation, the concentration of arginine in plasma was reduced, but that of citrulline elevated. Additionally, the renal elimination of nitrite was enhanced in diabetes. These data suggest that the impaired endothelium dependent relaxation observed in the diabetic myocardium is presumably not caused by a diminished synthesis and release of NO, but by an accelerated inactivation of NO by superoxide anions. We suggest that the increased NO generation reflects a compensatory mechanism to balance the enhanced inactivation of NO.