TY - JOUR T1 - Role of Myocardial Nitric Oxide in Diabetic Ischemia-Reperfusion Dysfunction: Studies in Mice with Myocyte-Specific Overexpression of Endothelial Nitric-Oxide Synthase JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 729 LP - 738 DO - 10.1124/jpet.106.107854 VL - 319 IS - 2 AU - Beatriz Pozo-Navas AU - Heike Stessel AU - Gerald Wölkart AU - Friedrich Brunner Y1 - 2006/11/01 UR - http://jpet.aspetjournals.org/content/319/2/729.abstract N2 - We investigated the role of nitric oxide (NO) in myocardial ischemia-reperfusion injury of diabetic mice with myocyte-specific overexpression of endothelial NO synthase (NOS). Four weeks after diabetes induction with streptozotocin (blood glucose ∼29 mM), isolated isovolumic heart function and cellular NO metabolites in response to brief normothermic ischemia-reperfusion were determined. Under normoxic conditions transgenic (TG) hearts from nondiabetic and diabetic animals generated less leftventricular developed pressure compared with wild-type (WT) control hearts, and this abnormality was unaffected by NOS inhibition. During ischemia, the rise in end-diastolic pressure was less in the TG than WT group of nondiabetic hearts, whereas the transgene had no effect in the diabetic group. Similarly, the transgene also improved reperfusion systolic and diastolic function in nondiabetic but not in diabetic hearts. NOS inhibition worsened reperfusion function in diabetic hearts. Postischemic nitrite and cGMP formation were higher in nondiabetic TG than WT hearts, but in diabetic hearts cGMP was no longer elevated. The formation of reactive oxygen species (superoxide and peroxynitrite) during early reperfusion, measured by electron spin resonance spectroscopy, was similar in nondiabetic WT and TG hearts, but it was significantly higher in diabetic TG hearts. Stimulating endogenous NO production with 10 μM bradykinin more strongly reduced myocardial O2 consumption in diabetic TG than diabetic WT hearts perfused in normoxia, whereas there was no difference after ischemia-reperfusion. Thus, providing additional endogenous NO is sufficient to protect nondiabetic hearts against ischemia-induced injury, but for a similar protection in diabetic hearts, effective scavenging of reactive oxygen species is also important. The American Society for Pharmacology and Experimental Therapeutics ER -