Nitrate tolerance aggravates postischemic myocardial apoptosis and impairs cardiac functional recovery after ischemia.
OBJECTIVE
This study examined the effects of nitrate tolerance (NT) on myocardial ischemia reperfusion (MI/R) injury and elucidated the potential mechanisms involved. Furthermore, the effects of GSH on postischemic myocardial apoptosis in NT rats were investigated.


RESULTS
Male Sprague-Dawley rats were randomized to receive nitroglycerin (60 microg/kg/h) or saline for 12 h followed by 40 min of MI and 4 h of reperfusion. Myocardial apoptosis, infarct size, nitrotyrosine formation, plasma CK and LDH activity, and cardiac function were determined. MI/R resulted in significant apoptotic cell death, which was further increased in animals with NT. In addition, NT further increased plasma CK and LDH activity, enlarged infarct size, and impaired cardiac functional recovery after ischemia. Myocardial nitrotyrosine, a footprint for cytotoxic reactive nitrogen species formation, was further enhanced in the NT heart after MI/R. Treatment of NT animals with exogenous GSH inhibited nitrotyrosine formation, reduced apoptosis, decreased infarct size, and improved cardiac functional recovery.


CONCLUSIONS
Our results demonstrate that nitrate tolerance markedly enhances MI/R injury and that increased peroxynitrite formation likely plays a role in this pathologic process. In addition, our results suggest that GSH could decrease peroxynitrite formation and reduce MI/R injury in nitrate tolerant hearts.
Fan
Q
Q
Department of Physiology, Fourth Military Medical University, Xi-An, PR China.
Gao
F
F
Zhang
L
L
Christopher
T A
TA
Lopez
B L
BL
Ma
X L
XL
D000222:Adaptation, Physiological / Q000187:drug effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood; D019587:Dietary Supplements; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009566:Nitrates / Q000494:pharmacology*; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D014664:Vasodilation / Q000187:drug effects
D009566:Nitrates; C002744:3-nitrotyrosine; D014443:Tyrosine; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D053148:Caspase 3; D005996:Nitroglycerin; D005978:Glutathione