Increased blood pressure in rats after long-term inhibition of the neuronal isoform of nitric oxide synthase.

Ollerstam, Anna; Pittner, J.; Persson, A. Erik G.; Thorup, C.

doi:10.1172/jci119394

Cited by 119 publications

(119 citation statements)

References 37 publications

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“…The same kind of TGF resetting is seen in both Milan hypertensive strain rats before they develop hypertension (49) and spontaneous hypertensive rats (SHR) (11). Furthermore, chronic blockade of nNOS, located in the macula densa cells, increases TGF sensitivity and leads to the development of hypertension (43).…”

Section: Discussionmentioning

confidence: 88%

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

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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...

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Section: Discussionmentioning

confidence: 88%

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

“…[3][4][5][6][7] The latency of the onset of the sympathectomy-sensitive component of intravenous infusion of L-NAME-induced hypertension, however, was 1 to 2 hours. 24 The latency of onset of neural component after oral administration of L-NAME might be longer than intravenous infusion; 24 hours is when the neural component of L-NAME-induced blood pressure elevation becomes apparent.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Although this hypertension was initially attributed to the inhibition of endothelial NO synthesis, numerous studies suggest that inhibition of neuronal NO also plays an important role in blood pressure regulation. [3][4][5][6][7] A previous study demonstrated that increased sympathetic nerve activity plays a role in hypertension caused by chronic NO synthesis inhibition, and activation of the renin-angiotensin system in the nucleus tractus solitarii (NTS) of the brainstem via angiotensin II type 1 receptors is involved. 8 Chronic inhibition of NO synthesis might activate the Rho/ Rho-kinase pathway in the cardiac tissues or vasculature.…”

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confidence: 99%

Rho/Rho-Kinase Pathway in the Brainstem Contributes to Hypertension Caused by Chronic Nitric Oxide Synthase Inhibition

et al. 2004

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Abstract-Central nervous system mechanisms are involved in hypertension caused by chronic inhibition of nitric oxide (NO) synthesis. Chronic inhibition of NO synthesis might also activate the Rho/Rho-kinase pathway in the vasculature.We recently demonstrated that activation of the Rho/Rho-kinase pathway in the nucleus tractus solitarii (NTS) contributes to hypertensive mechanisms in spontaneously hypertensive rats. The aim of the present study was to determine whether activation of this pathway also contributes to neurogenic hypertensive mechanisms caused by chronic NO synthesis inhibition. The NO synthase inhibitor N -nitro-L-arginine methyl ester (L-NAME) was administered to Wistar-Kyoto rats in their drinking water (1 mg/mL) for 2 weeks. Bilateral microinjection of Y-27632, a specific Rho-kinase inhibitor, into the NTS elicited decreases in arterial pressure, heart rate, and renal sympathetic nerve activity in control rats and L-NAME-treated rats. The magnitude of the decrease, however, was significantly greater in L-NAME-treated than in control rats. In another group of rats, the specific Rho-kinase inhibitor, Y-27632, was administered intracisternally for 2 weeks with a mini-osmotic pump from the beginning of treatment with L-NAME. Y-27632 co-treatment significantly attenuated the increase in arterial pressure. Furthermore, the expression level of membranous RhoA and phosphorylation of the target proteins of Rho-kinase, the ERM (ezrin, radixin, moesin) family members, was significantly greater in L-NAME-treated rats than in control rats. These results indicate that activation of the Rho/Rho-kinase pathway in the NTS contributes to neurogenic hypertension caused by chronic NO synthase inhibition. Key Words: nitric oxide Ⅲ blood pressure Ⅲ sympathetic nervous system Ⅲ hypertension Ⅲ brain I nhibition of nitric oxide (NO) synthesis produces hypertension in many species. 1,2 Although this hypertension was initially attributed to the inhibition of endothelial NO synthesis, numerous studies suggest that inhibition of neuronal NO also plays an important role in blood pressure regulation. [3][4][5][6][7] A previous study demonstrated that increased sympathetic nerve activity plays a role in hypertension caused by chronic NO synthesis inhibition, and activation of the renin-angiotensin system in the nucleus tractus solitarii (NTS) of the brainstem via angiotensin II type 1 receptors is involved. 8 Chronic inhibition of NO synthesis might activate the Rho/ Rho-kinase pathway in the cardiac tissues or vasculature. 9,10 The Rho/Rho-kinase pathway regulates the phosphorylation state of myosin light chains and contributes to smooth muscle contraction. 11 Y-27632, a specific Rho-kinase inhibitor, dramatically reduces blood pressure in rat models of hypertension. 12 In addition, Rho-kinase activity is augmented in hypertensive blood vessels 13 and inhibition of Rho-kinase induces preferential forearm vasodilatation in hypertensive patients, but not in normal subjects. 14 Thus, the Rho/Rhokinase pathway plays an important r...

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“…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 hypertension, and in animals subjected to neuronal NO synthase (NOS) inhibition. 9 These studies suggest an important role for changes of the TGF function in the pathophysiology of hypertension. Afferent arterioles (AAs) are effectors in the feedback loop and, therefore, contribute to the responsiveness of TGF.…”

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confidence: 93%

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

et al. 2008

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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...

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Increased blood pressure in rats after long-term inhibition of the neuronal isoform of nitric oxide synthase.

Cited by 119 publications

References 37 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

Rho/Rho-Kinase Pathway in the Brainstem Contributes to Hypertension Caused by Chronic Nitric Oxide Synthase Inhibition

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

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