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EDITORIAL FOCUS

Nitrite therapy for protection against ischemia-reperfusion injury

Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York

RECENT EXPERIMENTAL EVIDENCE suggests that the anion nitrite represents an important storage form of nitric oxide (NO) that subsequently regulates a number of very important physiological activities (2–5, 10). This is a radical concept because nitrite was largely considered to be a biologically inert breakdown product of NO that served no physiological purpose. In fact, circulating nitrite levels were used as an indirect method to assess alterations in circulating NO levels in various animal models for many years. The nitrite anion forms as a consequence of oxidation of NO and then accumulates in the blood compartment as well as in tissues (5, 10) (Fig. 1). Under conditions of acidosis, hypoxia, and tissue ischemia-reperfusion, nitrite is reduced to form NO as a result of reduction by deoxyhemoglobin, myoglobin, tissue heme proteins, and nonenzymatic disproportionation (4, 5). In this manner, it seems highly logical that nitrite could very tightly regulate blood flow and tissue perfusion to maintain organs within the normal physiological ranges. This exciting series of discoveries has created an entirely new field of research that entails the investigation of the molecular, biochemical, and physiological activities of nitrite under a variety of physiological and pathophysiological states.

View larger version (85K): [in this window] [in a new window]   Fig. 1. Proposed model for the bioconversion of nitrite (NO2–) to nitiric oxide (NO) in the circulating red blood cell (RBC). NO is generated by the action of endothelial nitric oxide synthase (eNOS) during the conversion of L-arginine to L-citrulline in the vascular endothelium. NO combines with oxygen to form NO2–, which in turn is taken up into the RBC and stored. Under conditions of acidosis, hypoxia, and/or ischemia, NO2– is converted back to NO via the action of a putative nitrite reductase. NO is then transported out of the RBC and exerts a number of biological actions including vasodilation. In this manner, tissue perfusion can be appropriately regulated to ensure adequate oxygen delivery and maintain cell viability. SMC, smooth muscle cell; EC, endothelial cell; L-Arg, L-arginine; L-Cit, L-citruline.

In the present issue of the American Journal of Physiology-Renal Physiology, Basireddy and colleagues (1) have investigated the effects of intravenous sodium nitrite administration on renal ischemia-reperfusion injury. Rats were subjected to a right nephrectomy followed by left renal ischemia, and sodium nitrite therapy was initiated at various times during the experimental protocol. In initial studies, nitrite therapy (0.12–12 nmol/g body wt) was initiated during renal ischemia, and in subsequent studies nitrite was injected before the onset of renal ischemia. In all experimental studies, the authors failed to demonstrate any protective effects of sodium nitrite therapy compared with saline or sodium nitrate. Renal injury was assessed using a number of methods including serum creatinine, histology, and renal function. The authors have very carefully performed the experimental studies, and the data are unequivocal. The present study by Basireddy et al. (1) does serve to raise a number of questions that need to be resolved. It is possible that the bioactivation of nitrite to NO did not occur under these experimental conditions, and therefore the authors failed to observe significant protection. It is very difficult to measure NO levels in the circulation or in tissues in vivo under conditions of ischemia-reperfusion, and these studies may not be possible at present. Similarly, larger doses of sodium nitrite may be required for renal protection compared with other organs such as the heart and liver. Additional studies might involve an expanded dose range to determine the effects of higher nitrite doses in this model system. Studies investigating NO donors or inhaled NO would also add to our understanding of the results of the present study because NO therapy may not prove beneficial in this model of renal ischemia-reperfusion injury. Nonetheless, the study of Basireddy et al. does significantly extend our current knowledge regarding nitrite therapy in ischemic disorders and lays the foundation for additional studies to clarify the clinical potential of nitrite therapy for ischemia-reperfusion injury. It is important to determine which pathological states are amenable to nitrite therapy and to have additional confirmation of the protective effects mediated by nitrite in the heart, brain, liver, and lungs.

Without question, the field of nitrite chemistry and biology is a truly exciting area of research that is certain to expand in the near future and lead to a dramatically improved understanding of the physiology of NO synthases and NO in terms of cytoprotection.

	ACKNOWLEDGMENTS

 
Research studies performed in the author's laboratory that are discussed above were supported by research grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (2RO1-HL-60849) and the American Diabetes Association (7–04-RA-59).

	FOOTNOTES

 

Address for reprint requests and other correspondence: D. J. Lefer, Dept. of Medicine, Div. of Cardiology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461 (e-mail: dlefer{at}aecom.yu.edu)

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TOP REFERENCES

 

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