Neuronal nitric oxide synthase inhibition sensitizes the tubuloglomerular feedback mechanism after volume expansion

Brown, Russell D.; Ollerstam, Anna; Erik, A.; Persson, Gunnar

doi:10.1111/j.1523-1755.2004.00509.x

Cited by 33 publications

(40 citation statements)

References 38 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, micropuncture experiments (41) showed that the tubuloglomerular feedback (TGF), which is an important mechanism in the control of GFR and blood pressure regulation, is reset during volume expansion in a paradoxical way to a much higher sensitivity and activity in the hydronephrotic kidney. The regulation of the sensitivity and reactivity of the TGF is intimately coupled to NO production in the macula densa (4) and the same kind of TGF resetting has been described in animal models for hypertension (11,49,59).…”

mentioning

confidence: 74%

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals

Carlström¹,

Brown²,

Edlund³

et al. 2008

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals. Am J Physiol Renal Physiol 294: F362-F370, 2008. First published November 21, 2007 doi:10.1152/ajprenal.00410.2007.-Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N G -nitro-L-arginine methyl ester (L-NAME) or L-arginine. Blood samples for ADMA, SDMA, and L-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. L-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.ADMA; tubuloglomerular feedback; L-arginine; L-NAME; telemetry; blood pressure HYPERTENSION IS THE MOST COMMON chronic disorders worldwide and secondary forms of hypertension are found in 5-10% of the hypertensive population, of which most can be linked to renal disease (24). In humans, as well as in experimental models of salt-sensitive hypertension, there is a growing body of evidence pointing at a close relationship between nitric oxide (NO) deficiency and development of hypertension (37).Hydronephrosis due to obstruction at the level of the pelvicureteric junction is a common condition in children, with an incidence in newborns of ϳ1%. The obstruction is mostly partial and congenital of origin. Unilateral hydronephrosis causes salt-sensitive hypertension in both rats (5) and mice (7).The renal function in hydronephrotic animals, measured as renal blood flow and glomerular filtration rate (GFR), is rather...

show abstract

mentioning

confidence: 74%

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals

Carlström¹,

Brown²,

Edlund³

et al. 2008

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…Interestingly, Brown et al (39) have shown that increased NO activity desensitizes the tubuloglomerular feedback mechanism, which could explain the increased GFR in the diabetic animals observed after L-arginine injection (40). The inverse mechanism could be responsible for the decreased GFR in the control animals observed after inhibition of NO production.…”

Section: Discussionmentioning

confidence: 99%

Reduced Nitric Oxide Concentration in the Renal Cortex of Streptozotocin-Induced Diabetic Rats

et al. 2005

View full text Add to dashboard Cite

Nitric oxide (NO) regulates vascular tone and mitochondrial respiration. We investigated the hypothesis that there is reduced NO concentration in the renal cortex of diabetic rats that mediates reduced renal cortical blood perfusion and oxygen tension (PO 2 ). Streptozotocin-induced diabetic and control rats were injected with L-arginine followed by N-nitro-L-arginine-metyl-ester (L-NAME). NO and PO 2 were measured using microsensors, and local blood flow was recorded by laser-Doppler flowmetry. Plasma arginine and asymmetric dimethylarginine (ADMA) were analyzed by high-performance liquid chromatography. L-Arginine increased cortical NO concentrations more in diabetic animals, whereas changes in blood flow were similar. Cortical PO 2 was unaffected by L-arginine in both groups. L-NAME decreased NO in control animals by 87 ؎ 15 nmol/l compared with 45 ؎ 7 nmol/l in diabetic animals. L-NAME decreased blood perfusion more in diabetic animals, but it only affected PO 2 in control animals. Plasma arginine was significantly lower in diabetic animals (79.7 ؎ 6.7 vs. 127.9 ؎ 3.9 mmol/l), whereas ADMA was unchanged. A larger increase in renal cortical NO concentration after L-arginine injection, a smaller decrease in NO after L-NAME, and reduced plasma arginine suggest substrate limitation for NO formation in the renal cortex of diabetic animals. This demonstrates a new mechanism for diabetesinduced alteration in renal oxygen metabolism and local blood flow regulation. Diabetes 54:3282-3287, 2005 N itric oxide (NO) regulates vascular tone in resistance vessels and thereby blood perfusion in most capillary beds. Systemic inhibition of NO synthase (NOS) decreases renal blood perfusion, both in the cortex and in the medulla (1-3), and increases mean arterial blood pressure (4). Previous investigations in vitro have also shown that NO is a potent competitive inhibitor of oxygen consumption (5) at the level of cytochrome oxidase, the terminal electron acceptor in mitochondria (6). Therefore, the magnitude of the inhibition of oxygen consumption by NO will increase at low PO 2 (7).Long-term hyperglycemia is associated with increased oxidative stress, i.e., increased production of reactive oxygen species (ROS) (8 -11). ROS can react with NO, forming peroxynitrite, and thus decrease the bioavailability of NO (11). The bioavailability of NO and formation of peroxynitrite are also highly dependent on superoxide dismutase, as modeled by Buerk et al. (12). Decreased influence of NO has therefore been suggested to be involved in the increased renal cortical cellular oxygen consumption closely associated with manifest diabetes (10,13,14). Furthermore, involvement of endogenous competitive NOS inhibitor asymmetric dimethylarginine (ADMA) in the development of vascular complications has gained increasing support over the last few decades (15).Because NO regulates the delivery of oxygen to tissue both by setting the level of vascular tone and blood pressure and by inhibiting cellular oxygen consumption, alterations in NO activity might ...

show abstract

“…The responsiveness of the TGF mechanism involves the action of different vasoactive substances, of which NO is an important determinant. 20,26 Hydronephrotic kidneys display reduced renal NO availability, which is associated with a sensitized TGF response. 5 In the present study, unspecific NOS inhibition with L-NAME did not cause any significant constriction of AAs from the hydronephrotic kidneys of wild-type mice, but the controls constricted Ϫ12% and the AAs of the contralateral kidney constricted as much as Ϫ43% after 15 minutes of treatment.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Deficiency and Increased Adenosine Response of Afferent Arterioles in Hydronephrotic Mice With Hypertension

et al. 2008

View full text Add to dashboard Cite

Abstract-Afferent arterioles were used to investigate the role of adenosine, angiotensin II, NO, and reactive oxygen species in the pathogenesis of increased tubuloglomerular feedback response in hydronephrosis. Hydronephrosis was induced in wild-type mice, superoxide dismutase-1 overexpressed mice (superoxide-dismutase-1 transgenic), and deficient mice (superoxide dismutase-1 knockout). Isotonic contractions in isolated perfused arterioles and mRNA expression of NO synthase isoforms, adenosine, and angiotensin II receptors were measured. In wild-type mice, N G -nitro-L-arginine methyl ester (L-NAME) did not change the basal arteriolar diameter of hydronephrotic kidneys (Ϫ6%) but reduced it in control (Ϫ12%) and contralateral arterioles (Ϫ43%). Angiotensin II mediated a weaker maximum contraction of hydronephrotic arterioles (Ϫ18%) than in control (Ϫ42%) and contralateral arterioles (Ϫ49%). The maximum adenosine-induced constriction was stronger in hydronephrotic (Ϫ19%) compared with control (Ϫ8%) and contralateral kidneys (Ϯ0%). The response to angiotensin II became stronger in the presence of adenosine in hydronephrotic kidneys and attenuated in contralateral arterioles. L-NAME increased angiotensin II responses of all of the groups but less in hydronephrotic kidneys. The mRNA expression of endothelial NO synthase and inducible NO synthase was upregulated in the hydronephrotic arterioles. No differences were found for adenosine or angiotensin II receptors. In superoxide dismutase-1 transgenic mice, strong but similar L-NAME response (Ϫ40%) was observed for all of the groups. This response was totally abolished in arterioles of hydronephrotic superoxide dismutase-1 knockout mice. In conclusion, hydronephrosis is associated with changes in the arteriolar reactivity of both hydronephrotic and contralateral kidneys. Increased oxidative stress, reduced NO availability, and stronger reactivity to adenosine of the hydronephrotic kidney may contribute to the enhanced tubuloglomerular feedback responsiveness in hydronephrosis and be involved in the development of hypertension. Key Words: angiotensin II Ⅲ L-NAME Ⅲ oxidative stress Ⅲ NO synthase Ⅲ superoxide dismutase Ⅲ tubuloglomerular feedback H ydronephrosis because of uretero-pelvic junction obstruction is a common condition in newborns, with an incidence of Ϸ1%. Both rats and mice with hydronephrosis, because of chronic partial ureteral obstruction, develop renal injury 1 and salt-sensitive hypertension 2,3 that can be attenuated by relief of the obstruction. 4 The mechanisms are thought to be associated with increased activity of the renin-angiotensin system, 2 increased oxidative stress, and reduced NO availability in the diseased kidney. 5 In micropuncture studies of hydronephrotic animals, the tubuloglomerular feedback (TGF) has a higher responsiveness in the hydronephrotic kidney. 5,6 An increased TGF response, as seen in hydronephrotic kidneys, has also been described in spontaneously hypertensive rats, 7 Milan hypertensive rats 8 during development of hyperte...

show abstract

Neuronal nitric oxide synthase inhibition sensitizes the tubuloglomerular feedback mechanism after volume expansion

Cited by 33 publications

References 38 publications

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals

Reduced Nitric Oxide Concentration in the Renal Cortex of Streptozotocin-Induced Diabetic Rats

Nitric Oxide Deficiency and Increased Adenosine Response of Afferent Arterioles in Hydronephrotic Mice With Hypertension

Contact Info

Product

Resources

About