Changes in nitric oxide precursor, L-arginine, and metabolites, nitrate and nitrite, with aging

Reckelhoff, Jane F.; Kellum, Joseph A.; Blanchard, Elise; Bacon, Elsie E.; Wesley, Arma J.; Kruckeberg, Walter C.

doi:10.1016/0024-3205(94)00521-4

Cited by 121 publications

(88 citation statements)

References 19 publications

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“…Based on animal studies, [18][19][20] we had anticipated that baseline total NO production would decrease with advancing age, and in addition, the ability of a high salt intake to increase NO production would be attenuated with aging. However, there was clearly no decline in total NO production with advancing age in our subjects, and variations in dietary salt intake had no differential effects on NO-cGMP levels in individuals of differing ages.…”

Section: Discussionmentioning

confidence: 99%

“…In aging rats, vascular (indicated from in vitro vascular reactivity studies) 18 and total NO production (indicated from decreases in 24-hour excretion of the oxidation products of NO [NO X ]) 19,20 decline. These observations raise the possibility that age-dependent decrements in the NO system contribute to increased salt-dependent hypertension in older humans.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

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Effects of aging and alterations in dietary sodium intake on total nitric oxide production

Schmidt

Beierwaltes

Baylis

2001

American Journal of Kidney Diseases

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Animal studies suggest that nitric oxide (NO) deficiency is linked to salt-sensitive hypertension and that NO activity decreases during normal aging. This study investigates the impact of increasing age and manipulations in dietary salt intake on biochemical indices of the NO system in healthy humans. We measured NO 2 + NO 3 (NO X ; stable oxidation products of NO) and cyclic guanosine monophosphate (cGMP; major second messenger) in plasma and urine of 30 healthy subjects aged 22 to 77 years. Subjects were maintained on controlled low NO X and low-, normal-, or high-salt diets for 3 days. Salt sensitivity of blood pressure was seen only in the oldest subjects. Plasma renin activity was suppressed by a high salt intake in all age groups, and baseline values declined with advancing age. Neither age nor salt intake correlated with indices of NO activity over the third 24-hour period of controlled salt intake. In a subgroup of subjects aged 33 ± 4 years challenged with ultrahigh sodium intake (400 mEq/24 h), again there was no increase in NO 2 + NO 3 or cGMP measures. In contrast to animal studies, there is no correlation in humans between either salt intake or age and total NO production and activity, indicated by NO 2 + NO 3 and cGMP measures. This does not preclude undetected alterations occurring in NO production and/or activity in strategic locations in the kidney and cardiovascular system. Limitations of blood and urine measurements of NO 2 + NO 3 and cGMP as indices of NO activity are discussed. Index WordsSodium excretion; blood pressure (BP); salt-sensitive hypertension; cyclic guanosine monophosphate (cGMP); NO 2 + NO 3 (NO X ); nitric oxide (NO) With Advancing Age, the kidney is less able to either conserve sodium in response to dietary restriction or remove sodium after excess intake. 1,2 Both aging rats and humans have a blunted ability to excrete an acutely administered sodium load, 1,3,4 and pressure natriuresis is attenuated in the old rat. 5,6 According to Guyton et al, 7 impaired pressure natriuresis leads to salt-sensitive hypertension, and the incidence of salt-sensitive hypertension increases substantially in humans with increasing age, 8 reflected by an increased frequency of low-renin essential hypertension. 9 Increased nitric oxide (NO) production occurs in response to high dietary salt intake in normal rats, and chronic NO synthase (NOS) inhibition combined with high dietary salt intake can lead to volume-dependent hypertension. [10][11][12][13] In addition, the genetically salt-sensitive hypertension in the Dahl rat is associated with defective NO production in the face of high sodium intake. 14,15 NO directly inhibits sodium transport in several parts of the tubule. NO is NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript also a powerful renal vasodilator, and in NO deficiency experimentally induced by NOS inhibition, pressure natriuresis is attenuated. 16,17 It therefore is widely held that an appropriate increase in NO production in the kidney and perip...

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Section: Discussionmentioning

confidence: 99%

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Effects of aging and alterations in dietary sodium intake on total nitric oxide production

Schmidt

Beierwaltes

Baylis

2001

American Journal of Kidney Diseases

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“…Total body NO production can be estimated from the urinary excretion of NO x (NO x = NO 2 + NO 3 ; the stable oxidation products of NO), providing that the NO x intake is controlled. There is clear evidence that U NO x V falls in the aging (male) rat (Reckelhoff et al, 1994;Sonaka et al, 1990;Hill et al, 1997;Erdely et al, 2003), denoting a reduction in total NO production. In man, we were unable to document a fall in U NO x V with age (Schmidt et al, 2001) although Lyons et al (1997) did report reductions in U NO x V in healthy old age.…”

Section: Nitric Oxidementioning

confidence: 99%

“…We first investigated the substrate (arginine) availability in aging rats, since declines in arginine availability had been reported previously in the aging male Sprague-Dawley (Reckelhoff et al, 1994). Endogenous arginine synthesis involves a series of enzymatic reactions in the small intestine leading to formation of citrulline, which is then transported in the blood to the kidney for enzymatic conversion to L-arginine.…”

Section: Nitric Oxidementioning

confidence: 99%

Changes in renal hemodynamics and structure in the aging kidney; sexual dimorphism and the nitric oxide system

Baylis

2005

Experimental Gerontology

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With advancing age the kidney shows both functional declines (falls in GFR) and development of structural damage. In most individuals this occurs slowly and does not lead to severe renal impairment unless additional insults are superimposed. There is a pronounced sexual dimorphism with females protected, due both to beneficial effects of the estrogens and damaging effects of androgens, some of which act directly on the glomerular mesangial cell to regulate growth and extracellular matrix production. Nitric oxide is a major factor in regulation of vascular tone and growth and becomes deficient with advancing age, as endothelial dysfunction develops. Although the abundance of the substrate, L-arginine, is well maintained during aging, there are increases in the concentration of circulating endogenous nitric oxide synthase (nNOS) inhibitors, which will contribute, to the endothelial dysfunction. There is a clear sexual dimorphism in the NO system, with pre-menopausal females producing more NO than men. Within the kidney, declines in the abundance and activity of the neuronal form of the nitric oxide synthase (nNOS) correlate with development of disease. In the male rat where injury and dysfunction occurs, nNOS abundance declines markedly, whereas in the protected female, renal nNOS abundance is maintained. Taken together, it is likely that agedependent declines in NO generation contribute to age-dependent kidney damage.

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“…Plasma and urinary sodium concentrations were measured by flame photometry (Corning 435). NOx was measured using the Escherichia coli assay (29) and proteinuria by Bradford method (7). PRA was determined by radioimmunoassay (New England Nuclear) (17).…”

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confidence: 99%

Effect of losartan on renal microvasculature during chronic inhibition of nitric oxide visualized by micro-CT

Fortepiani

Ruiz

Passardi

et al. 2003

American Journal of Physiology-Renal Physiology

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G -nitro-Larginine methyl ester (L-NAME) leads to an elevated systemic blood pressure and reduction in renal blood flow without significant changes in urinary sodium and water excretion. Simultaneous administration of ANG II AT 1 receptor antagonist losartan and L-NAME prevents the alterations in blood pressure and renal hemodynamics. Microcomputed tomography (micro-CT) was used to investigate the role of ANG II in the changes of renal microvasculature during chronic NO inhibition. Sprague-Dawley rats were given L-NAME with or without AT 1 receptor antagonist losartan (40 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 each) in their drinking water for 19 days. Kidneys from each group (control, L-NAME-, and L-NAME ϩ losartan-treated rats) were perfusion-fixed in situ, infused with a silicon-based polymer containing lead chromate, and scanned by micro-CT. The microvasculature in the reconstructed three-dimensional renal images was studied using computerized analytic techniques. Kidneys of L-NAMEtreated rats had significantly fewer normal glomeruli (28,824 Ϯ 838) than those of control rats (36,266 Ϯ 3,572). Losartan normalized the number to control values (34,094 Ϯ 1,536). The amount of vasculature in the cortex, outer medulla, and inner medulla of L-NAME-treated rats was about two-thirds that of control rats; losartan normalized the values to control levels. These data indicate that chronic treatment with the NO synthase inhibitor L-NAME produces a generalized rarefaction of renal capillaries. Because simultaneous AT1 receptor blockade abolished those changes, the data suggest that the reduction in vasculature is mediated by ANG II through AT 1 receptors. NG -nitro-L-arginine methyl ester; angiotensin II NITRIC OXIDE (NO) is a physiologically important vasodilator, which plays a major role in the regulation of systemic and renal hemodynamics (16). Chronic inhibition of NO synthesis produces a general vasoconstriction that leads to an increased blood pressure and impairment of renal function including decreased renal blood flow (RBF) and glomerular filtration rate (GFR) without significant changes in urinary sodium and water excretion (3,11,30). Besides the functional changes, the inhibition of NO synthesis produces renal vascular damage including glomerulosclerosis, ischemia, necrosis, and increased interstitium (12, 24). The mechanism underlying the effect of NO synthesis inhibition is not completely understood, but it is likely that the renin-angiotensin system is responsible for the renal and systemic alterations induced by the chronically reduced NO bioavailability. For instance, the simultaneous blockade of NO synthesis and ANG II AT 1 receptor prevents the hypertension, renal functional and morphological consequences of the inhibition of NO synthesis alone (35). Ohishi et al. (20) found that the blockade of ANG II AT 1 receptors attenuated the vasoconstriction elicited by the inhibition of NO synthesis in juxtamedullary afferent and efferent arterioles perfused in vitro. In vivo experiments (23) showed that NO modulated the ANG II re...

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Changes in nitric oxide precursor, L-arginine, and metabolites, nitrate and nitrite, with aging

Cited by 121 publications

References 19 publications

Effects of aging and alterations in dietary sodium intake on total nitric oxide production

Effects of aging and alterations in dietary sodium intake on total nitric oxide production

Changes in renal hemodynamics and structure in the aging kidney; sexual dimorphism and the nitric oxide system

Effect of losartan on renal microvasculature during chronic inhibition of nitric oxide visualized by micro-CT

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