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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 20, 2006; DOI: 10.1124/jpet.106.107854

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*Cardiomyopathy
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*NITRIC OXIDE
*STREPTOZOTOCIN


Received for publication May 16, 2006.
Revised July 19, 2006.
Accepted for publication July 19, 2006.

Role of Myocardial Nitric Oxide in Diabetic Ischemia- Reperfusion Dysfunction: Studies in Mice with Myocyte- Specific Overexpression of Endothelial Nitric Oxide Synthase

Beatriz Pozo Navas 1, Heike Stessel 1, Gerald Wolkart 1, Friedrich Brunner 1*

1 Karl-Franzens-Universitat Graz

* Address correspondence to: E-mail: friedrich.brunner{at}kfunigraz.ac.at

Abstract

We investigated the role of nitric oxide (NO) in myocardial ischemia-reperfusion injury of diabetic mice with myocyte-specific overexpression of endothelial NO synthase (eNOS). 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 non-diabetic and diabetic animals generated less left-ventricular developed pressure (LVDevP) compared to 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 non-diabetic hearts, whereas the transgene had no effect in the diabetic group. Similarly, the transgene also improved reperfusion systolic and diastolic function in non-diabetic but not in diabetic hearts. NOS inhibition worsened reperfusion function in diabetic hearts. Post-ischemic nitrite and cGMP formation were higher in non-diabetic 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 non-diabetic WT and TG hearts, but significantly higher in diabetic TG hearts. Stimulating endogenous NO production with bradykinin (10 µM) 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 non-diabetic hearts against ischemia-induced injury, but for a similar protection in diabetic hearts, effective scavenging of ROS is also important.


Key words: NOS transgenic, cardiomyopathy, diabetes, ischemia-reperfusion, nitric oxide, reactive oxygen species




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