Low dose nitrite improves reoxygenation following renal ischemia in rats

Abstract

In hypoxic and acidic tissue environments, nitrite is metabolised to nitric oxide, thus, bringing about novel therapeutic options in myocardial infarction, peripheral artery disease, stroke, and hypertension. Following renal ischemia, reperfusion of the kidney remains incomplete and tissue oxygenation is reduced for several minutes to hours. Thus, in renal ischemia-reperfusion injury, providing nitrite may have outstanding therapeutic value. Here we demonstrate nitrite's distinct potential to rapidly restore tissue oxygenation in the renal cortex and medulla after 45 minutes of complete unilateral kidney ischemia in the rat. Notably, tissue oxygenation was completely restored, while tissue perfusion did not fully reach pre-ischemia levels within 60 minutes of reperfusion. Nitrite was infused intravenously in a dose, which can be translated to the human. Specifically, methaemoglobin did not exceed 3%, which is biologically negligible. Hypotension was not observed. Providing nitrite well before ischemia and maintaining nitrite infusion throughout the reperfusion period prevented the increase in serum creatinine by ischemia reperfusion injury. In conclusion, low-dose nitrite restores renal tissue oxygenation in renal ischemia reperfusion injury and enhances regional kidney post-ischemic perfusion. As nitrite provides nitric oxide predominantly in hypoxic tissues, it may prove a specific measure to reduce renal ischemia reperfusion injury.

Figure 1

Methaemoglobin at baseline, after 20 min, and after 140 min of continuous nitrite or saline infusion. Data are mean ± SEM, n = 9 for the saline group (control), n = 11 for the nitrite group, *denotes p < 0.05 control vs. nitrite group, + denotes p < 0.05 vs. baseline in the nitrite group. Both groups were exposed to a brief hypoxic challenge and to unilateral ischemia-reperfusion between the blood sampling at 20 min and that at 140 min.

Figure 2

Response of arterial pressure (panel A), hindquarter blood flow (B), hindquarter vascular conductance (C), total renal blood flow (D), and renal vascular conductance (E) to a brief hypoxic challenge (inspiratory fraction of oxygen 10%). Data are percentage changes at the end of 100 s of hypoxia as related to the values recorded immediately before commencement of the hypoxia intervention (mean ± SEM, n = 9 for the saline group [control], n = 11 for the nitrite group); *denotes p < 0.05 control vs. nitrite group, x denotes p < 0.05 normoxia vs. hypoxia in the control group, +denotes p < 0.05 normoxia vs. hypoxia in the nitrite group.

Figure 3

Response of arterial blood pressure (panel A), total renal blood flow (B), cortical laser flux (C), medullary laser flux (D), cortical tissue pO₂ (E), and medullary tissue pO₂ (F) to 45 min of unilateral warm renal ischemia (from time −45 min to time 0 min) followed by 60 min of reperfusion. Data are relative changes as related to the values recorded immediately before commencement of the renal ischemia (mean ± SEM; n = 9 for the saline group [control], n = 11 for the nitrite group); *denotes p < 0.05 control vs. nitrite group, significance bars indicate data that significantly differ from their pre-ischemia values, with x denoting p < 0.05 in the control group and +denoting p < 0.05 in the nitrite group.