Abstract
BackgroundRenal ischemia-reperfusion injury is a common cause of acute kidney injury in intensive care and surgery. Recently, novel organic mononitrites of 1,2-propanediol (PDNO) were synthesized and shown to rapidly and controllably deploy nitric oxide in the circulation when administered intravenously. We hypothesized that intravenous infusion of PDNO during renal ischemia reperfusion would improve post-ischemic renal function and microcirculation.MethodsSixteen sheep were anesthetized, mechanically ventilated, and surgically instrumented. The left renal artery was clamped for 90 min, and the effects of ischemia were studied for a total of 8 h. Fifteen minutes prior to the release of the clamp, intravenous infusions of PDNO (n = 8) or vehicle (1,2 propanediol + inorganic nitrite, n = 8) were initiated (180 nmol/kg/min for 30 min, thereafter 60 nmol/kg/min for the remainder of the experiment).ResultsRenal artery blood flow, cortical and medullary perfusion, and diuresis and creatinine clearance decreased in the left kidney post ischemia. However, in the sheep treated with PDNO, diuresis and creatinine clearance in the left kidney were significantly higher post ischemia compared to vehicle-treated animals (1.7 ± 0.5 vs 0.7 ± 0.3 ml/kg/h, p = 0.04 and 7.5 ± 2.1 vs 1.7 ± 0.6 ml/min, p = 0.02, respectively). Left renal medullary perfusion and oxygen uptake were higher in the PDNO group (73 ± 9 vs 37 ± 5% of baseline, p = 0.004 and 2.6 ± 0.4 vs 1.6 ± 0.3 ml/min, p = 0.02, respectively). PDNO significantly increased renal oxygen consumption and reduced the oxygen utilization for sodium reabsorption (p = 0.03 for both). Mean arterial blood pressure was significantly reduced by PDNO (83 ± 3 vs 94 ± 3 mmHg, p = 0.02) but was still within normal limits. Total renal blood flow was not affected, and there were no signs of increased blood methemoglobin concentrations or tachyphylaxis.ConclusionsThe novel nitric oxide donor PDNO improved renal function after ischemia. PDNO also prevented the persistent reduction in medullary perfusion during reperfusion and improved renal oxygen utilization without severe side effects.
Highlights
Renal ischemia-reperfusion injury is a common cause of acute kidney injury in intensive care and surgery
The most important finding in the current study was that the novel Nitric oxide (NO) donor PDNO improved renal function, as estimated by urine output and creatinine clearance (Fig. 2), compared to a vehicle containing comparable amounts of inorganic nitrite
The fact that PDNO was able to improve both these variables (Fig. 2) in a clinically relevant large animal model is important as it, for the first time, indicates that this new NO donor could be a future tool in the treatment of Acute kidney injury (AKI) induced by ischemia reperfusion
Summary
Renal ischemia-reperfusion injury is a common cause of acute kidney injury in intensive care and surgery. We hypothesized that intravenous infusion of PDNO during renal ischemia reperfusion would improve post-ischemic renal function and microcirculation. Still warm ischemia is most likely a central component in the pathogenesis of AKI during prolonged hypotension, hypovolemia, and when blood flow is disrupted during cardiovascular events or vascular surgery [4]. Ischemia causes lingering vascular effects, including endothelial dysfunction, increased vascular tone, and a dysfunctional microcirculation, which further diminish renal function even if blood flow returns [6–8]. Several of these effects have been related to the release of free oxygen radicals [9]
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