Abstract
Objectives: 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.
Methods and results: Male Sprague–Dawley rats were randomized to receive nitroglycerin (60 μg/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.
Conclusion: 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.
Similar content being viewed by others
References
Abrams J. Beneficial actions of nitrates in cardiovascular disease. Am J Cardiol 1996; 77: 31C–37C.
Kleschyov AL, Oelze M, Daiber A, et al. Does nitric oxide mediate the vasodilator activity of nitroglycerin? Circ Res 2003; 93: e104–e112.
Lefer AM, Siegfried MR, Ma XL. Protection of ischemia-reperfusion injury by sydnonimine NO donors via inhibition of neutrophil-endothelium interaction. J Cardiovasc Pharmacol 1993; 22(Suppl 7): S27–S33.
GISSI-3. Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994; 343: 1115–1122.
Nakamura Y, Moss AJ, Brown MW, Kinoshita M, Kawai C. Long-term nitrate use may be deleterious in ischemic heart disease: A study using the databases from two large-scale postinfarction studies. Multicenter Myocardial Ischemia Research Group. Am Heart J 1999; 138: 577–585.
Parker JD, Parker JO. Nitrate therapy for stable angina pectoris. N Engl J Med 1998; 338: 520–531.
Parker JD. Nitrate tolerance, oxidative stress, and mitochondrial function: Another worrisome chapter on the effects of organic nitrates. J Clin Invest 2004; 113: 352–354.
Munzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG. Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Invest 1995; 95: 187–194.
Mihm MJ, Coyle CM, Jing L, Bauer JA. Vascular peroxynitrite formation during organic nitrate tolerance. J Pharmacol Exp Ther 1999; 291: 194–198.
Csont T, Csonka C, Onody A, et al. Nitrate tolerance does not increase production of peroxynitrite in the heart. Am J Physiol: Heart Circ Physiol 2002; 283: H69–H76.
Bolli R. Oyygen-derived free radicals and myocardial reperfusion injury: An overview. Cardiovasc Drug Ther 1991; 5: 249–268.
Tao L, Gao E, Bryan NS, et al. Cardioprotective effects of thioredoxin in myocardial ischemia and reperfusion: Role of S-nitrosation. Pro Nat Acad Sci 2004; 101: 11471–11476.
Gao F, Tao L, Yan W, et al. Early anti-apoptosis treatment reduces myocardial infarct size after a prolonged reperfusion. Apoptosis 2004; 9: 553–559.
Zhang HF, Fan Q, Qian XX, et al. Role of insulin in the anti-apoptotic effect of glucose-insulin-potassium in rabbits with acute myocardial ischemia and reperfusion. Apoptosis 2004; 9: 777–783.
Wang EQ, Balthasar JP, Fung HL. Pharmacodynamics of in vivo nitroglycerin tolerance in normal conscious rats: Effects of dose and dosing protocol. Pharm Res 2004; 21: 114–120.
Gao F, Yao CL, Gao E, et al. Enhancement of glutathione cardioprotection by ascorbic acid in myocardial reperfusion injury. J Pharmacol Exp Ther 2002; 301: 543–550.
Nakamura M, Thourani VH, Ronson RS, et al. Glutathione reverses endothelial damage from peroxynitrite, the byproduct of nitric oxide degradation, in crystalloid cardioplegia. Circulation 2000; 102: III332–III338.
Moro MA, Darley-Usmar VM, Lizasoain I, et al. The formation of nitric oxide donors from peroxynitrite. Br J Pharmacol 1995; 116: 1999–2004.
Wu M, Pritchard KA, Jr., Kaminski PM, Fayngersh RP, Hintze TH, Wolin MS. Involvement of nitric oxide and nitrosothiols in relaxation of pulmonary arteries to peroxynitrite. Am J Physiol: Heart Circ Physiol 1994; 266: H2108–H2113.
Beckman JS. Parsing the effects of nitric oxide, S-nitrosothiols, and peroxynitrite on inducible nitric oxide synthase-dependent cardiac myocyte apoptosis. Circ Res 1999; 85: 870–871.
Liang F, Gao E, Tao L, et al. Critical timing of L-arginine treatment in post-ischemic myocardial apoptosis-role of NOS isoforms. Cardiovasc Res 2004; 62: 568–577.
Boesgaard S, Petersen JS, Aldershvile J, Poulsen HE, Flachs H. Nitrate tolerance: Effect of thiol supplementation during prolonged nitroglycerin infusion in an in vivo rat model. J Pharmacol Exp Ther 1991; 258: 851–856.
Briviba K, Kissner R, Koppenol WH, Sies H. Kinetic study of the reaction of glutathione peroxidase with peroxynitrite. Che Res Toxicol 1998; 11: 1398–1401.
Sies H, Sharov VS, Klotz LO, Briviba K. Glutathione peroxidase protects against peroxynitrite-mediated oxidations - A new function for selenoproteins as peroxynitrite reductase. J Biol Chem 1997; 272: 27812–27817.
Balazy M, Kaminski PM, Mao KY, Tan JZ, Wolin MS. S-nitroglutathione, a product of the reaction between peroxynitrite and glutathione that generates nitric oxide. J Biol Chem 1998; 273: 32009–32015.
Barker JE, Bolaños JP, Land JM, Clark JB, Heales SJR. Glutathione protects astrocytes from peroxynitrite-mediated mitochondrial damage: Implications for neuronal astrocytic trafficking and neurodegeneration. Dev Neurosci 1996; 18: 391–396.
Jones CM, Lawrence A, Wardman P, Burkitt MJ. Kinetics of superoxide scavenging by glutathione: An evaluation of its role in the removal of mitochondrial superoxide. Biochem Soc Trans 2003; 31: 1337–1339.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fan, Q., Gao, F., Zhang, L. et al. Nitrate tolerance aggravates postischemic myocardial apoptosis and impairs cardiac functional recovery after ischemia. Apoptosis 10, 1235–1242 (2005). https://doi.org/10.1007/s10495-005-1455-5
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10495-005-1455-5