Copyright © 2006, European Society of Cardiology
The role of peroxynitrite in chemical preconditioning with 3-nitropropionic acid in rat hearts
aDepartment of Pharmacology, Faculty of Pharmacy, Gazi University, Ankara, Turkey
bDepartment of Cardiology, Medical University of Vienna, Vienna, Austria
cCardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary
dPharmahungary 2000 Ltd, Szeged, Hungary
* Corresponding author. Cardiovascular Research Group, Department of Biochemistry University of Szeged, Faculty of Medicine Dóm tér 9, Szeged, H-6720, Hungary. Tel.: +36 62 545 755; fax: +36 62 545 097. Email address: peter{at}bioch.szote.u-szeged.huhttp://www.cardiovasc.com
Objectives 3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, has been shown to protect against ischemic injury in the brain and in the heart via a preconditioning-like effect; however, the cellular mechanism is not known. The aim of the present study was to investigate if 3-NP pretreatment reduces infarct size and if altered metabolism of nitric oxide and reactive oxygen species are involved.
Methods Hearts were assigned into 3 groups: 3 intermittent cycles of 5 min no-flow ischemia separated by 5 min aerobic perfusion protocol were used to induce ischemic preconditioning as a positive control; a time-matched non-preconditioning group served as control; and 3-NP (20 mg/kg, i.p.) was injected 3 h before the perfusion protocol to induce pharmacological preconditioning. Hearts from all groups were then subjected to 30 min global ischemia followed by 120 min reperfusion.
Results Infarct size and lactate dehydrogenase release were significantly reduced after ischemia/reperfusion. While cardiac nitric oxide (NO) was increased, superoxide formation, nitrotyrosine level, and cardiac NADH oxidase and xanthine oxidase (XO) activities were markedly reduced by 3-NP administration. Cardiac activities of NO synthase and superoxide dismutase were not changed by 3-NP.
Conclusion This is the first demonstration in the rat myocardium that 3-NP induces pharmacological preconditioning, thereby limiting infarct size, and that this effect is associated with increased NO bioavailability and reduced peroxynitrite formation due to inhibition of superoxide formation by XO and NADH oxidase.
KEYWORDS 3-nitropropionic acid; Chemical preconditioning; Peroxynitrite; Nitric oxide; Superoxide; Xanthine oxidoreductase; NADH oxidase; Heart; Rat
Time for primary review 23 days
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