Decreased Renal Expression of Nitric Oxide Synthase Isoforms in Adrenocorticotropin-Induced and Corticosterone-Induced Hypertension

Lou, Yi-kun; Cheng, Wen; Li, Ming; Adams, David J.; Wang, Minxia; Yang, F.; Morris, Brian J.; Whitworth, Judith A.

doi:10.1161/01.hyp.37.4.1164

Cited by 63 publications

(45 citation statements)

References 33 publications

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“…Thus, AG was discernibly less efficacious in promoting hypertension, tachycardia, and increase in sympathetic vasomotor tone in SHR, and the cardiovascular-depressive actions of L-Arg, which is iNOS dependent, 11 was absent. An increase 25,29 or decrease 30 in nNOS mRNA expression in the RVLM was reported in hypertensive animals. Our results indicate that both nNOS mRNA and protein levels in the ventrolateral medulla remained unchanged under basal conditions or on microinjection of LPS into the RVLM in young normotensive SHR or captopril-treated adult SHR.…”

Section: Discussionmentioning

confidence: 91%

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Downregulation of Basal iNOS at the Rostral Ventrolateral Medulla Is Innate in SHR

2003

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Abstract-We demonstrated recently that a significant reduction in both the molecular synthesis and functional expression of inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic vasomotor outflow, underlies the augmented sympathetic vasomotor tone during hypertension. This study further evaluated the hypothesis that this downregulation of basal iNOS at the RVLM during hypertension is innate. In adult spontaneously hypertensive rats (SHR) treated for 4 weeks with the antihypertensive captopril to normalize elevated blood pressure or in young prehypertensive SHR, the significantly lower iNOS mRNA and protein levels at the ventrolateral medulla under basal conditions or on activation by microinjection bilaterally into the RVLM of lipopolysaccharide (10 ng) remained unaltered. The retarded efficacy of lipopolysaccharide (10 ng) to elicit cardiovascular depression (hypotension, bradycardia, and reduction in sympathetic vasomotor tone) also persevered in captopril-treated adult or young normotensive SHR. On the other hand, compared with Wistar-Kyoto normotensive rats, the magnitude of cardiovascular depression induced in adult SHR by local administration into the RVLM of the NO precursor L-arginine (40 nmol) was significantly smaller. In addition, microinjection bilaterally into the RVLM of a selective iNOS inhibitor, aminoguanidine (125 or 250 pmol), was discernibly less efficacious in unmasking hypertension, tachycardia, and the increase in sympathetic vasomotor tone in adult SHR. We conclude that a predisposed reduction in molecular synthesis and functional expression of basal iNOS in the RVLM is associated with the sympathetic vasomotor overactivity during hypertension. Key Words: nitric oxide synthase Ⅲ hypertension, essential Ⅲ nitric oxide Ⅲ blood pressure Ⅲ heart rate Ⅲ nervous system, autonomic W hereas the notion that hypertension in human patients 1,2 and animal models 3-5 is attributable to an augmented central sympathetic outflow to the heart or peripheral vasculature is well accepted, the mechanism that underlies sympathetic overactivity during hypertension requires further delineation. Recent studies 6 -8 implicate an abnormality of the nitric oxide (NO) system in the brain in hypertension. Originally identified as an endothelium-derived vascular relaxing factor, 9 NO is now known to play an active role in central cardiovascular regulation. 6,7 In the rostral ventrolateral medulla (RVLM), where premotor neurons that provide the tonic sympathetic vasomotor drive are located, 10 we demonstrated 11 recently that whereas small amounts of NO generated by neuronal NO synthase (nNOS) in the RVLM promote sympathoexcitation, large amounts of NO produced by inducible NOS (iNOS) elicit sympathoinhibition. Under physiological conditions, the prevalence of nNOS over iNOS activity and the associated dominance of sympathoexcitation over sympathoinhibition are responsible for the maintenance of neurogenic vasomotor tone and stable arterial pressure elici...

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Section: Discussionmentioning

confidence: 91%

“…[23][24][25] Aerosol iNOS gene transfer increases pulmonary NO production and reduces hypoxic pulmonary hypertension. 26 The augmented iNOS protein expression reported in the aorta and heart of SHR is, however, consequential to the hypertensive state.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Basal iNOS at the Rostral Ventrolateral Medulla Is Innate in SHR

2003

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“…5,6 Exogenous cortisol inhibits forearm vascular responses to acetylcholine but not to sodium nitroprusside 6 and decreases nitric oxide metabolites in humans, 5 and both adrenocorticotropic hormone and corticosterone downregulate expression of endothelial nitric oxide synthases in the rat. 9,10 Furthermore, L-arginine, but not D-arginine, prevents corticotropin-induced increases in blood pressure in the rat, 4 suggesting a relative insufficiency of substrate availability. This beneficial effect of L-arginine was, however, not observed in humans.…”

Section: Discussionmentioning

confidence: 98%

l -Arginine Transport in Humans With Cortisol-Induced Hypertension

et al. 2003

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Abstract-A deficient L-arginine-nitric oxide system is implicated in cortisol-induced hypertension. We investigate whether abnormalities in L-arginine uptake contribute to this deficiency. Eight healthy men were recruited. Hydrocortisone acetate (50 mg) was given orally every 6 hours for 24 hours after a 5-day fixed-salt diet (150 mmol/d).Crossover studies were performed 2 weeks apart. Thirty milliliters of blood was obtained for isolation of peripheral blood mononuclear cells after each treatment period. L-Arginine uptake was assessed in mononuclear cells incubated with L-arginine (1 to 300 mol/L), incorporating 100 nmol/L [ 3 H]-L-arginine for a period of 5 minutes at 37°C. Forearm Key Words: cortisol Ⅲ hypertension, mineralocorticoid Ⅲ nitric oxide Ⅲ arginine Ⅲ human C ortisol, the major naturally occurring human glucocorticoid, is implicated in the pathogenesis of some forms of essential hypertension, 1 but the mechanisms by which cortisol raises blood pressure are not fully defined. Cardiac output is increased but is not essential for the increase, 2 and sympathetic activity is, if anything, decreased. 3 A role for the nitric oxide system in cortisol-induced hypertension has been implicated in animal models of cortisol-induced hypertension; L-arginine, the substrate precursor to nitric oxide, prevents and reverses the development of adrenocorticotropin-induced hypertension in rats. 4 In humans, cortisol-increases in blood pressure occur in association with reductions in plasma nitrate/nitrite concentrations, but no change in plasma arginine or symmetric or asymmetric dimethyl arginine has been observed, indicating that the reductions in nitrate could not be explained by changes in substrate availability or endogenous nitric oxide synthase inhibitors. 5 More recently, using bilateral forearm plethysmography, we have found impaired cholinergic vasodilatation after cortisol administration. Cortisol did not affect the response to sodium nitroprusside, and although N G -monomethyl-L-arginine inhibited cholinergic vasodilation in placebo-treated subjects, it had no additional effect in the presence of cortisol. 6 Taken together, these results are consistent with a role for abnormalities of the nitric oxide system in cortisol-induced hypertension in humans.In the current study, we explored whether cortisol reduces the cellular uptake of L-arginine and whether this mechanism might provide an explanation for the decreased synthesis or secretion of nitric oxide. The study was performed in healthy adult men against a background of a restricted-nitrate diet. L-Arginine transport was assessed in peripheral blood mononuclear cells isolated from these subjects as well as in vivo in the forearm vascular bed. Methods SubjectsHealthy (or disease-free) men were recruited by advertisement. All underwent a physical medical examination and had their medical history recorded. Persons with a history of major illness, including diabetes, cardiovascular disease, respiratory illness, and any contraindication to corticosteroid therapy...

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“…In addition, NO generated by iNOS has been shown to play an important role in the maintenance of renal hemodynamics and in the long-term control of arterial pressure under both normal physiological conditions and in response to pathophysiological conditions. 6,7,8,9,10 Therefore, as iNOS may be both constitutively and inducibly expressed within the kidney, this data suggests that the renal hemodynamic changes that occur during pregnancy may be mediated in part by the iNOS isoform. As NO may play an important role in normal pregnancy, NO deficiency may play an important role in preeclampsia.…”

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confidence: 86%

“…6 In addition, iNOS has been suggested to play an important role in mediating salt-induced hypertension in normotensive Sprague-Dawley rats 7 and the Dahl saltresistance rat 8 and in mediating corticosterone-induced hypertension. 9 In rats with liver cirrhosis, maintenance of GFR in the early stage of this disease is mediated by NO produced by iNOS. 10 Thus, as the functional role of the inducible NOS isoform in mediating increases in renal hemodynamics during pregnancy is not clear, the purpose of this study was to examine the effect of iNOS selective inhibitors on renal hemodynamics in pregnant rats.…”

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confidence: 99%

Inducible Nitric Oxide Synthase Inhibition Attenuates Renal Hemodynamics During Pregnancy

et al. 2002

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Abstract-Acute, nonselective nitric oxide synthase inhibition in the pregnant rat decreases glomerular filtration rate and renal plasma flow, suggesting a role for nitric oxide in mediating renal vasodilation during pregnancy. As mid-gestation in the rat is associated with a significant increase in renal protein expression of inducible nitric oxide synthase, the aim of this study was to examine the role of inducible nitric oxide synthase in mediating renal hemodynamics changes at mid-gestation in the rat. At day 16 of pregnancy, glomerular filtration rate was significantly higher in pregnant rats compared with virgin rats (3.1Ϯ0.4 versus 2.7Ϯ0.3 mL/min, respectively; PϽ0.05), as was effective renal plasma flow (13.4Ϯ2.5 versus 10.9Ϯ2.2 mL/min, respectively; PϽ0.05). Acute administration of the inducible nitric oxide synthase selective inhibitor, AMT hydrochloride (750 nmol/h), markedly attenuated the increase in glomerular filtration rate observed in pregnant rats (2.3Ϯ0.2 mL/min, PϽ0.01 versus pregnant) without significantly altering glomerular filtration rate in virgin rats (2.1Ϯ0.2 mL/min). Acute AMT administration significantly decreased effective renal plasma flow in pregnant (8.9Ϯ1.8 mL/min, PϽ0.01 versus pregnant) and virgin rats (7.1Ϯ0.9 mL/min, PϽ0.05 versus virgin). Acute administration of EIT (380 nmol/h), another inducible nitric oxide synthase selective inhibitor, also attenuated pregnancy-induced increases in glomerular filtration rate (2.1Ϯ0.2, 2.8Ϯ0.3, and 2.3Ϯ0.3 mL/min; virgin, pregnant, and EIT, respectively) and effective renal plasma flow (8.5Ϯ1.1, 13.8Ϯ2.1, and 9.0Ϯ1.1 mL/min; virgin, pregnant, and EIT, respectively). Therefore, these findings suggest that inducible nitric oxide synthase may play an important role in mediating the renal hemodynamic changes that occur during normal pregnancy. Key Words: pregnancy Ⅲ nitric oxide synthase Ⅲ kidney Ⅲ hemodynamics Ⅲ rats N ormal pregnancy is associated with significant increases in renal hemodynamics as increases in glomerular filtration rate (GFR) and renal plasma flow (RPF) of Ͼ40% are observed in pregnant women. 1 In the rat, GFR and RPF are increased by Ͼ20% at mid-gestation with a return to prepregnant values by late pregnancy. 2,3 These increases in renal hemodynamics at mid-gestation in the rat are associated with significant increases in whole-body nitric oxide (NO) production 3,4 and renal protein expression of both inducible and neuronal nitric oxide synthase (iNOS and nNOS, respectively). 3 A role for NO in mediating renal vasodilation during pregnancy is suggested in a study by Danielson and Conrad in which acute nonselective NOS inhibition equalized GFR and effective RPF (ERPF) in virgin rats and pregnant rats at mid-gestation. 5 However, nonselective inhibition of all three NOS isoforms, endothelial (eNOS), neuronal (nNOS), and inducible (iNOS), does not elucidate which specific isoform is an important source of NO during pregnancy.Several lines of evidence suggest that NO generated by the iNOS isoform may play an important role in...

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Decreased Renal Expression of Nitric Oxide Synthase Isoforms in Adrenocorticotropin-Induced and Corticosterone-Induced Hypertension

Cited by 63 publications

References 33 publications

Downregulation of Basal iNOS at the Rostral Ventrolateral Medulla Is Innate in SHR

Downregulation of Basal iNOS at the Rostral Ventrolateral Medulla Is Innate in SHR

l -Arginine Transport in Humans With Cortisol-Induced Hypertension

Inducible Nitric Oxide Synthase Inhibition Attenuates Renal Hemodynamics During Pregnancy

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