Oxygen-dependent inhibition of respiration in isolated renal tubules by nitric oxide

Koivisto, Ari; Pittner, J.; Froelich, Matteus; Persson, A. Erik G.

doi:10.1046/j.1523-1755.1999.00474.x

Cited by 66 publications

(61 citation statements)

References 39 publications

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“…First, isolated renal tubules derived from cortex or medulla do not show differences in sensitivity toward NO inhibition 42. However, NO‐mediated inhibition of respiration in renal tubular cells is particularly marked when oxygen levels are low 42.…”

Section: Discussionmentioning

confidence: 99%

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Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats

Emans

Janssen

Joles

et al. 2018

JAHA

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BackgroundRenal hypoxia, implicated as crucial factor in onset and progression of chronic kidney disease, may be attributed to reduced nitric oxide because nitric oxide dilates vasculature and inhibits mitochondrial oxygen consumption. We hypothesized that chronic nitric oxide synthase inhibition would induce renal hypoxia.Methods and ResultsOxygen‐sensitive electrodes, attached to telemeters, were implanted in either renal cortex (n=6) or medulla (n=7) in rats. After recovery and stabilization, baseline oxygenation (pO 2) was recorded for 1 week. To inhibit nitric oxide synthase, N‐ω‐nitro‐l‐arginine (L‐NNA; 40 mg/kg/day) was administered via drinking water for 2 weeks. A separate group (n=8), instrumented with blood pressure telemeters, followed the same protocol. L‐NNA rapidly induced hypertension (165±6 versus 108±3 mm Hg; P<0.001) and proteinuria (79±12 versus 17±2 mg/day; P<0.001). Cortical pO 2, after initially dipping, returned to baseline and then increased. Medullary pO 2 decreased progressively (up to −19±6% versus baseline; P<0.05). After 14 days of L‐NNA, amplitude of diurnal medullary pO 2 was decreased (3.7 [2.2–5.3] versus 7.9 [7.5–8.4]; P<0.01), whereas amplitudes of blood pressure and cortical pO 2 were unaltered. Terminal glomerular filtration rate (1374±74 versus 2098±122 μL/min), renal blood flow (5014±336 versus 9966±905 μL/min), and sodium reabsorption efficiency (13.0±0.8 versus 22.8±1.7 μmol/μmol) decreased (all P<0.001).ConclusionsFor the first time, we show temporal development of renal cortical and medullary oxygenation during chronic nitric oxide synthase inhibition in unrestrained conscious rats. Whereas cortical pO 2 shows transient changes, medullary pO 2 decreased progressively. Chronic L‐NNA leads to decreased renal perfusion and sodium reabsorption efficiency, resulting in progressive medullary hypoxia, suggesting that juxtamedullary nephrons are potentially vulnerable to prolonged nitric oxide depletion.

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Section: Discussionmentioning

confidence: 99%

“…However, NO‐mediated inhibition of respiration in renal tubular cells is particularly marked when oxygen levels are low 42. This implies that the effect of NO inhibition on tubular Na + reabsorption is more effective in the relatively hypoxic medulla than in the well‐oxygenated cortex.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats

Emans

Janssen

Joles

et al. 2018

JAHA

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“…Studies by Brezis et al (34,35) found intrarenal pO 2 of approximately 46 mmHg in the cortex and 21 to 23 mmHg in the medulla. Studies that used isolated renal tubules have demonstrated a markedly enhanced effect of NO on inhibition of oxygen consumption as pO 2 drops to these levels (36). Under the hypoxic conditions present in the cortex, and even more so in the medulla, the effect of NO, or the lack thereof, on oxygen consumption will be magnified.…”

Section: Discussionmentioning

confidence: 99%

Impaired Regulation of Renal Oxygen Consumption in Spontaneously Hypertensive Rats

Adler

Huang

2002

Journal of the American Society of Nephrology

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Abstract. Abnormalities of nitric oxide (NO) and oxygen radical synthesis and of oxygen consumption have been described in the spontaneously hypertensive rat (SHR) and may contribute to the pathogenesis of hypertension. NO plays a role in the regulation of renal oxygen consumption in normal kidney, so the response of renal cortical oxygen consumption to stimulators of NO production before and after the addition of the superoxide scavenging agent tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl) was studied. Baseline cortical oxygen consumption was similar in SHR and Wistar-Kyoto (WKY) rats (SHR: 600 Ϯ 55 nmol O 2 /min per g, WKY: 611 Ϯ 51 nmol O 2 /min per g, P Ͼ 0.05). Addition of bradykinin, enalaprilat, and amlodipine decreased oxygen consumption significantly less in SHR than WKY (SHR: bradykinin Ϫ13.9 Ϯ 1.9%, enalaprilat Ϫ15.3 Ϯ 1.6%, amlodipine Ϫ11.9 Ϯ 0.7%; WKY: bradykinin Ϫ22.8 Ϯ 1.0%, enalaprilat Ϫ24.1 Ϯ 2.0%, amlodipine Ϫ20.7 Ϯ 2.3%; P Ͻ 0.05), consistent with less NO effect in SHR. Addition of tempol reversed the defects in responsiveness to enalaprilat and amlodipine, suggesting that inactivation of NO by superoxide contributes to decreased NO availability. The response to an NO donor was similar in both groups and was unaffected by the addition of tempol. These results demonstrate that NO availability in the kidney is decreased in SHR, resulting in increased oxygen consumption. This effect is due to enhanced production of superoxide in SHR. By lowering intrarenal oxygen levels, reduced NO may contribute to susceptibility to injury and renal fibrosis. Increasing NO production, decreasing oxidant stress, or both might prevent these changes by improving renal oxygenation.Nitric oxide (NO) plays an important role in regulation of vascular tone. Absence of the NO generating enzyme endothelial nitric oxide synthase (eNOS) or impairment of NO production leads to hypertension in animal models and can increase vascular tone in humans (1-4). In a model of genetic hypertension in the rat, the spontaneously hypertensive rat (SHR), abnormalities in synthesis of NO, expression of the NO-synthesizing enzymes, or both have been described both in vitro and in vivo, but with conflicting results. Thus, several studies have been performed to provide evidence of impaired vasodilation in response to acetylcholine, an effect mediated by endothelium-derived relaxing factor or NO, decreased eNOS expression, or decreased NO synthesis in SHR (5-11). These abnormalities are present as early as 5 wk of age, a period before the development of hypertension (7). However, several of these studies have shown a decreased effect of NO rather than direct evidence of decreased production.On the other hand, evidence of increased expression of NO synthesizing enzymes (eNOS and inducible NO synthase), increased NO production, or both have also been noted (12-18), both before and after the onset of hypertension. One possible explanation for this discrepancy is inactivation of NO, explaining increased production but less effect in SHR...

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“…For non-diabetic rats, the buffer contained 5.8 mmol/l glucose, and for diabetic animals the buffer contained 23.2 mmol/l glucose (similar to the blood glucose concentrations in the latter animals). The renal cells were isolated as previously described [8,17,18]. In brief, the rats were anaesthetised with thiobutabarbital, the kidneys were excised and the renal capsule was removed.…”

Section: Isolation Of Renal Cells and Measurement Of In Vitro Oxygen mentioning

confidence: 99%

“…Oxygen consumption was measured as previously described [8,18]. In brief, a custom-made thermostatically controlled (37°C) gas-tight plexi-glass chamber with a total volume of 1.100 ml was used.…”

Section: Isolation Of Renal Cells and Measurement Of In Vitro Oxygen mentioning

confidence: 99%

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

et al. 2004

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Aims/hypothesis. The renal medullary region is particularly vulnerable to reduced oxygen concentration because of its low blood perfusion and high basal oxygen consumption. This study investigated renal metabolic changes in relation to the previously observed decreased oxygen tension in streptozotocin-induced diabetic rats. Methods. Blood perfusion, oxygen tension and consumption, interstitial pH, and glycolytic and purinebased metabolites were determined in the renal cortex and the medulla of non-diabetic and diabetic animals by, respectively, laser Doppler flowmetry, oxygen and pH microelectrodes, and microdialysis. The importance of increased polyol pathway activity for the observed alterations was investigated by daily treatment with the aldose reductase inhibitor AL-1576 throughout the course of diabetes.Results. The diabetes-induced decrease in renal oxygen tension, due to augmented oxygen consumption, did not result in manifest hypoxia in either the cortical or the medullary region, as evaluated by microdialysis measurements of purine-based metabolites. The profound alterations in medullary oxygen metabolism were, however, associated with an increased lactate : pyruvate ratio and a concomitantly decreased pH. Notably, the renal medullary changes in oxygen tension, oxygen consumption, lactate : pyruvate ratio and pH were preventable by inhibition of aldose reductase. Conclusions/interpretation. Substantial metabolic changes were observed in the renal medulla in diabetic animals. These disturbances seemed to be mediated by increased polyol pathway activity and could be prevented by inhibition of aldose reductase.

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Oxygen-dependent inhibition of respiration in isolated renal tubules by nitric oxide

Abstract: We suggest that because of its low PO2, the renal outer medulla is more sensitive to hypoxia, not because of the low PO2 as such, but probably because of the competition between NO and oxygen to control respiration.

Cited by 66 publications

References 39 publications

Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats

Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats

Impaired Regulation of Renal Oxygen Consumption in Spontaneously Hypertensive Rats

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

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