Role of Nitric Oxide in the Control of Renal Oxygen Consumption and the Regulation of Chemical Work in the Kidney

Laycock, Sarra; Vogel, Traci; Forfia, Paul R.; Tuzman, Joshua; Xü, Xinsheng; Ochoa, Manuel; Thompson, Carl I.; Nasjletti, Alberto; Hintze, Thomas H.

doi:10.1161/01.res.82.12.1263

Cited by 112 publications

(102 citation statements)

References 31 publications

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“…; and (3) Can the vascular and/or tubular architecture influence the observations? All NOS isoforms are expressed in the kidney,38 and the synthesized NO itself is known to inhibit reabsorption of Na + along the nephron by reducing the respiratory rate of mitochondria8, 39, 40, 41 therefore, NO inhibits oxygen consumption. Three lines of evidence support our observations.…”

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%

“…The majority of renal NOS activity is located in the medulla 7. On the other hand, NOS inhibition also increases renal oxygen consumption 8. Oxygen consumption efficiency is decreased in diabetic rats because of disturbed NO metabolism 9.…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats

Emans

Janssen

Joles

et al. 2018

JAHA

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“…Another explana tion may be diminished renal nitric oxide (NO) genera tion because of endothelial damage and downregulation of endothelial NO synthase (eNOS/NOS-3). NO is a major regulator of microvascular oxygen supply and renal VO 2 [37]. Th rough vasodilation, NO increases renal blood fl ow and hence DO 2 .…”

Section: Renal Oxygenation In Clinical Ischemic Acute Kidney Injurymentioning

confidence: 99%

Renal Oxygenation in Clinical Acute Kidney Injury

Ricksten¹,

Bragadottir²,

Redfors³

2013

Annual Update in Intensive Care and Emergency Medicine 2013

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Renal oxygenation is defi ned as the relationship between renal oxygen delivery (DO 2 ) and renal oxygen consumption (VO 2 ) and it can easily be shown that the inverse of this relationship is equivalent to renal extraction of O 2 (O 2 Ex). An increase in renal O 2 Ex means that renal DO 2 has decreased in relation to renal VO 2 , i. e., renal oxygenation is impaired, and vice versa. When compared to other major organs, renal VO 2 is relatively high, second only to the heart. In sedated, mechanically ventilated patients, renal VO 2 is two-thirds (10 ml/min) that of myocardial oxygen consumption (15 ml/min) (Table 1) [1,2]. Renal blo od fl ow, w hich accounts for approximately 20 % of cardiac output, is three times higher than myocardial blood fl ow in this group of patients. Renal O 2 Ex in the non-failing kidney is therefore low, 10 %, compared with, e.g., the heart, in which O 2 E X is 55 % (Table 1). Determin a nts of renal oxygenationIt is well known from experimental studies that tubular sodium reabsorption is the major determinant of renal VO 2 [3] and tha t under normal physiological conditions, approximately 80 % is used to drive active tubular transport of particularly sodium, but also glucose, amino acids and other solutes. Tubular transport processes are highly load-dependent and it has been shown in experimental studies [4] and in p atients [2,[5][6][7] that the re i s a close linear correlation between glomerular fi ltration rate (GFR), renal sodium reabsorption and renal VO 2 (Fig. 1). Th e fi l tered load of sodium is, thus, an important determi nant of renal VO 2 and maneuvers that decrease GFR and the tubular sodium load act to decrease tubular sodium reabsorption and renal VO 2 , and vice versa [8]. It has b een shown that renal O 2 Ex remains stable over a wide range of renal blood fl ows, which means that changes in renal DO 2 , caused by changes in renal blood fl ow, are directly off set by changes in renal VO 2 [9], i. e., r enal VO 2 is fl ow-dependent. Th us, unlike other organs where increases in blood fl ow will improve oxygenation, increased renal blood fl ow augments GFR and the fi ltered load of sodium, which will increase renal VO 2 . Due to this fl ow-dependency of renal VO 2 , renal oxygenation will re main constant, as long as renal blood fl ow and GFR change in parallel. Regional intrarenal oxygenation and medullary hypoxiaTh e relatively high renal blood fl ow is directed preferentially to the cortex to optimize the fi ltration process and solute reabsorption. In contrast, blood fl ow in the outer medulla is less than 50 % of the cortical blood fl ow to preserve osmotic gradients and to enhance urinary concentration [10]. Th e combi nation of low me dullary perfusion, high oxygen consumption of the medullary thick ascending limbs (mTAL) and the countercurrent exchange of oxygen within the vasa recta, results in a poorly oxygenated outer medulla [11]. Oxygen av ailability is, therefore, low in the outer medulla, which has an oxygen tissue partial pressure (PO 2 ) of 10-20 mm Hg ...

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“…NO is inactivated by reaction with superoxide (O 2 Ϫ ) to produce peroxynitrite and increased production of superoxide has been demonstrated in SHR (13,19 -21). Manipulations that reduce superoxide production have also been shown to lower BP in these animals (19 -21).NO also modulates oxygen consumption in the whole animal and in isolated tissues, such as heart and kidney, with an inverse relationship between NO production and oxygen consumption (22)(23)(24). We have previously shown that NO production by the eNOS isoenzyme in the kidney is responsible for regulation of renal oxygen consumption (25).…”

mentioning

confidence: 99%

“…NO also modulates oxygen consumption in the whole animal and in isolated tissues, such as heart and kidney, with an inverse relationship between NO production and oxygen consumption (22)(23)(24). We have previously shown that NO production by the eNOS isoenzyme in the kidney is responsible for regulation of renal oxygen consumption (25).…”

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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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Role of Nitric Oxide in the Control of Renal Oxygen Consumption and the Regulation of Chemical Work in the Kidney

Cited by 112 publications

References 31 publications

Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats

Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats

Renal Oxygenation in Clinical Acute Kidney Injury

Impaired Regulation of Renal Oxygen Consumption in Spontaneously Hypertensive Rats

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