Endothelial nitric oxide synthase plays an essential role in regulation of renal oxygen consumption by NO

Adler, Stephen; Huang, Harer; Loke, Kit E.; Xü, Xinsheng; Tada, Hideo; Laumas, Arupam; Hintze, Thomas H.

doi:10.1152/ajprenal.2001.280.5.f838

Cited by 48 publications

(43 citation statements)

References 29 publications

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“…We have previously shown that NO production by the eNOS isoenzyme in the kidney is responsible for regulation of renal oxygen consumption (25). Whole-body oxygen consumption is increased in SHR, an observation consistent with a decreased effect of NO (26).…”

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confidence: 56%

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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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confidence: 56%

“…*, P Ͻ 0.05 versus WKY rats in the presence of L-NAME and SHR rats in the absence of L-NAME. ously reported in normal mice and dogs (25,28). In SHR, there was a significant decrease in the response to all three of these stimulators of endogenous NO production, suggesting a defect in renal NO production.…”

Section: Discussionmentioning

confidence: 79%

Impaired Regulation of Renal Oxygen Consumption in Spontaneously Hypertensive Rats

Adler

Huang

2002

Journal of the American Society of Nephrology

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“…Indeed, the site of NO production seems to be of major importance. Stimulation of eNOS by bradykinin increases the inhibition of mitochondrial respiration, supporting the idea of a regulatory role for eNOS (168). Furthermore, Clementi et al (169) found that only cell-secreted NO competes with O 2 and to regulate mitochondrial respiration.…”

Section: Mitochondrial Activity and No-mediated O 2 Consumptionmentioning

confidence: 84%

Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

Legrand

Mik

Johannes³

et al. 2008

Mol Med

237

169

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Ischemia is the most common cause of acute renal failure. Ischemic-induced renal tissue hypoxia is thought to be a major component in the development of acute renal failure in promoting the initial tubular damage. Renal oxygenation originates from a balance between oxygen supply and consumption. Recent investigations have provided new insights into alterations in oxygenation pathways in the ischemic kidney. These findings have identified a central role of microvascular dysfunction related to an imbalance between vasoconstrictors and vasodilators, endothelial damage and endothelium-leukocyte interactions, leading to decreased renal oxygen supply. Reduced microcirculatory oxygen supply may be associated with altered cellular oxygen consumption (dysoxia), because of mitochondrial dysfunction and activity of alternative oxygen-consuming pathways. Alterations in oxygen utilization and/or supply might therefore contribute to the occurrence of organ dysfunction. This view places oxygen pathways' alterations as a potential central player in the pathogenesis of acute kidney injury. Both in regulation of oxygen supply and consumption, nitric oxide seems to play a pivotal role. Furthermore, recent studies suggest that, following acute ischemic renal injury, persistent tissue hypoxia contributes to the development of chronic renal dysfunction. Adaptative mechanisms to renal hypoxia may be ineffective in more severe cases and lead to the development of chronic renal failure following ischemia-reperfusion. This paper is aimed at reviewing the current insights into oxygen transport pathways, from oxygen supply to oxygen consumption in the kidney and from the adaptation mechanisms to renal hypoxia. Their role in the development of ischemia-induced renal damage and ischemic acute renal failure are discussed.

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“…NO has a number of beneficial effects in various systems and importantly functions as a physiological vasodilator in the coronary artery vascular bed, a regulator of mitochondrial respiration, a modulator of myocardial contractility, and a key metabolite in blood pressure regulation (1,30,32,59). Most of the functions for NO in the cardiovascular system are attributable to the enzyme eNOS, which is expressed in the endothelium as well as the cardiomyocyte.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced left ventricular dysfunction in myoglobin-deficient mice

Mammen¹,

Kanatous²,

Yuhanna³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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. Hypoxia-induced left ventricular dysfunction in myoglobin-deficient mice. Am J Physiol Heart Circ Physiol 285: H2132-H2141, 2003. First published July 24, 2003 10.1152/ajpheart.00147.2003.-Myoglobin-deficient mice are viable and have preserved cardiac function due to their ability to mount a complex compensatory response involving increased vascularization and the induction of the hypoxia gene program (hypoxia-inducible factor-1␣, endothelial PAS, heat shock protein27, etc.). To further define and explore functional roles for myoglobin, we challenged age-and gender-matched wild-type and myoglobin-null mice to chronic hypoxia (10% oxygen for 1 day to 3 wk). We observed a 30% reduction in cardiac systolic function in the myoglobin mutant mice exposed to chronic hypoxia with no changes observed in the wild-type control hearts. The cardiac dysfunction observed in the hypoxic myoglobin-null mice was reversible with reexposure to normoxic conditions and could be prevented with treatment of an inhibitor of nitric oxide (NO) synthases. These results support the conclusion that hypoxia-induced cardiac dysfunction in myoglobin-null mice occurs via a NO-mediated mechanism. Utilizing enzymatic assays for NO synthases and immunohistochemical analyses, we observed a marked induction of inducible NO synthase in the hypoxic myoglobin mutant ventricle compared with the wild-type hypoxic control ventricle. These new data establish that myoglobin is an important cytoplasmic cardiac hemoprotein that functions in regulating NO homeostasis within cardiomyocytes.

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Endothelial nitric oxide synthase plays an essential role in regulation of renal oxygen consumption by NO

Cited by 48 publications

References 29 publications

Impaired Regulation of Renal Oxygen Consumption in Spontaneously Hypertensive Rats

Impaired Regulation of Renal Oxygen Consumption in Spontaneously Hypertensive Rats

Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

Hypoxia-induced left ventricular dysfunction in myoglobin-deficient mice

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