© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Attenuation of myocardial ischemia/reperfusion injury in mice with myocyte-specific overexpression of endothelial nitric oxide synthase
aInstitut für Pharmakologie und Toxikologie, Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria
bMedizinische Universitätsklinik, Auenbruggerplatz 15, A-8036 Graz, Austria
cInstitut für Molekularbiologie, Karl-Franzens-Universität Graz, Heinrichstraße 31a, A-8010 Graz, Austria
* Corresponding author. Tel.: +43-316-380-5559; fax: +43-316-380-9890 friedrich.brunner{at}kfunigraz.ac.at
Objective: The role of nitric oxide (NO) in myocardial ischemia/reperfusion injury remains controversial as both NO donors and NO synthase (NOS) inhibitors have shown to be protective. We generated transgenic (TG) mice that overexpress endothelial NOS (eNOS) exclusively in cardiac myocytes to determine the effects of high cardiac NO levels on ischemia/reperfusion injury and cellular Ca2+ homeostasis. Wild-type (WT) mice served as controls. Methods: Hearts were perfused in vitro and subjected to 20 min of total no-flow ischemia and 30 min of reperfusion (n=5 per group). Left ventricular function, cGMP levels and intracellular Ca2+ transients (Ca2+i) were determined. Results: Left ventricular pressure was reduced (maximum, –33%) and basal cardiac cGMP was increased (twofold) in TG hearts, and the changes were reversed by NOS blockade with NG-nitro-L-arginine methyl ester (L-NAME). Relative to baseline, recovery of reperfusion contractile function was significantly better in hearts from TG (98%) than WT (51%) mice, and L-NAME abolished this effect. Heart rate and coronary perfusion pressure were not different between groups. Systolic and diastolic Ca2+i concentrations were similar in WT and TG hearts, but Ca2+i overload during early reperfusion tended to be less in TG hearts. Kinetic analysis of pressure curves and Ca2+i transients revealed a faster left ventricular diastolic relaxation and abbreviated aequorin light signals in TG hearts at baseline and during reperfusion. Conclusions: High levels of NO/cGMP strongly protect against ischemia/reperfusion injury, the protection is largely independent of changes in Ca2+i modulation, but relates to reduced preischemic performance. Myocyte-specific NO augmentation may aid in studies of the (patho)physiological roles of cardiac-derived NO.
KEYWORDS Calcium (cellular); Contractile function; Ischemia; Nitric oxide; Reperfusion; Ventricular function
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