Salt-Sensitive Hypertension Develops After Short-Term Exposure to Angiotensin II

Lombardi, Donna; Gordon, Katherine; Polinsky, Patti; Suga, Shin-ichi; Schwartz, Stephen M.; Johnson, Richard J.

doi:10.1161/01.hyp.33.4.1013

Cited by 147 publications

(149 citation statements)

References 20 publications

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“…11 All animals were preconditioned for BP measurements 1 week before each experiment. Serum uric acid was measured by a carbonate phosphotungstate method.…”

Section: Discussionmentioning

confidence: 99%

Elevated Uric Acid Increases Blood Pressure in the Rat by a Novel Crystal-Independent Mechanism

Mazzali¹,

Hughes²,

Kim³

et al. 2001

Hypertension

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1,126

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Abstract-An elevation in circulating serum uric acid is strongly associated with the development of hypertension and renal disease, but whether uric acid has a causal role or whether it simply indicates patients at risk for these complications remains controversial. We tested the hypothesis that uric acid may have a causal role in the development of hypertension and renal disease by examining the effects of mild hyperuricemia in rats. Mild hyperuricemia was induced in rats by providing a uricase inhibitor (oxonic acid) in the diet. Hyperuricemic rats developed elevated blood pressure after 3 weeks, whereas control rats remained normotensive. The development of hypertension was prevented by concurrent treatment with either a xanthine oxidase inhibitor (allopurinol) or a uricosuric agent (benziodarone), both of which lowered uric acid levels. Blood pressure could also be lowered by reducing uric acid levels with either allopurinol or oxonic acid withdrawal. A direct relationship was found between blood pressure and uric acid (rϭ0.75, nϭ69), with a 10 -mm Hg blood pressure increase for each 0.03-mmol/L (0.5-mg/dL) incremental rise in serum uric acid. The kidneys were devoid of urate crystals and were normal by light microscopy. However, immunohistochemical stains documented an ischemic type of injury with collagen deposition, macrophage infiltration, and an increase in tubular expression of osteopontin. Hyperuricemic rats also exhibited an increase in juxtaglomerular renin and a decrease in macula densa neuronal NO synthase. Both the renal injury and hypertension were reduced by treatment with enalapril or L-arginine. In conclusion, mild hyperuricemia causes hypertension and renal injury in the rat via a crystal-independent mechanism, with stimulation of the renin-angiotensin system and inhibition of neuronal NO synthase. Key Words: uric acid Ⅲ hypertension, renal Ⅲ renin-angiotensin system Ⅲ nitric oxide U ric acid is a purine metabolite that in most mammals is degraded by the hepatic enzyme uricase to allantoin. However, mutations in the uricase gene occurred during primate development, with the consequence that humans have relatively higher levels of serum uric acid. 1 An elevation in serum uric acid has been associated with an increased risk for the development of hypertension, 2-4 and 25% to 50% of hypertensive individuals are hyperuricemic. 4 Hyperuricemia also confers increased risk for cardiovascular mortality, especially in women. 5,6 Despite the clinical and epidemiological evidence, many authorities do not consider an elevated uric acid to be a true cardiovascular risk factor, because patients with hyperuricemia often have other wellestablished risk factors for cardiovascular disease, such as hypertension, renal disease, obesity, dyslipidemia, and insulin resistance. 6 Several studies have found that an elevated uric acid level is an independent risk factor for cardiovascular disease after controlling for the contribution of established risk factors by multivariate analyses 2,3,7 ; however, other studies...

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“…11 All animals were preconditioned for BP measurements 1 week before each experiment. Serum uric acid was measured by a carbonate phosphotungstate method.…”

Section: Discussionmentioning

confidence: 99%

Elevated Uric Acid Increases Blood Pressure in the Rat by a Novel Crystal-Independent Mechanism

Mazzali¹,

Hughes²,

Kim³

et al. 2001

Hypertension

Self Cite

1,126

960

View full text Add to dashboard Cite

show abstract

“…Therefore, infusion of this dose of ANG II provides a documented technique to produce progressive activation the SNS so the effects of increased dietary sodium could be quantified. Although plasma concentrations of ANG II probably exceed those observed under physiological conditions, similar or higher systemic doses of ANG II are routinely used to investigate the central actions of the systemic peptide (25,29,42,43).…”

Section: Discussionmentioning

confidence: 99%

Increased dietary sodium alters neural control of blood pressure during intravenous ANG II infusion

Bealer

2003

American Journal of Physiology-Heart and Circulatory Physiology

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Bealer, Steven L. Increased dietary sodium alters neural control of blood pressure during intravenous ANG II infusion. Am J Physiol Heart Circ Physiol 284: H559-H565, 2003. First published October 24, 2002 10.1152/ajpheart.00628.2002Increased dietary sodium enhances both excitatory and inhibitory blood pressure responses to stimulation of the central sympathetic nervous system (SNS) centers. In addition, long-term (hours to days) administration of ANG II increases blood pressure by activation of the SNS. These studies investigated the effects of increased dietary sodium on SNS control of blood pressure during 0-to 24-h infusion of ANG II in conscious, male rats consuming either tap water or isotonic saline (Iso) for 2 to 3 wk. The SNS component (evaluated by ganglionic blockade with trimetaphan) of both control blood pressure and the pressor response to intravenous ANG II was reduced in Iso animals. Furthermore, although the pressor response to intravenous ANG II infusion was similar between groups, the baroreflexinduced bradycardia during the initial 6 h of ANG II infusion was significantly greater, whereas the tachycardia accompanying longer infusion periods was significantly attenuated in Iso animals. These data suggest that in normal rats increased dietary sodium enhances sympathoinhibitory responses during intravenous ANG II. baroreflex; heart rate; sympathoexcitation; sympathoinhibition; hypertension INCREASED DIETARY SODIUM has been associated with the enhanced risk of high blood pressure (4, 12) because increased salt intake induces and/or increases hypertension in several experimental animal models (1,15,34,40). However, the mechanisms of the hypertensinogenic effects of increased dietary sodium have not been completely defined. Several studies (37,38,47) have suggested that elevated sodium ingestion is associated with activation of the sympathetic nervous system (SNS), and it has been proposed that increasing dietary salt alters the SNS circuits that regulate SNS control of cardiovascular function (37,41).In support of this proposal, recent studies (19, 39) show that animals on a high-salt diet demonstrate enhanced pressor responses to microinjection of several excitatory neurotransmitters into the rostral ventrolateral medulla. These authors suggest that although dietary sodium does not increase blood pressure alone, it may contribute to development of hypertension by potentiating the actions of other hypertensive stimuli on SNS centers. However, in addition to enhancing sympathoexcitatory responses to stimulation of medullary pressor sites, increased dietary sodium also potentiates the depressor responses to both glutamate injections in the nucleus tractus solitarius (19) and aortic nerve stimulation (39) and enhances baroreflex-induced bradycardia (39). Therefore, it appears that both sympathoexcitatory and sympathoinhibitory responses are sensitized by increased dietary sodium. However, the physiological significance of these observations has not been completely defined.Systemic ANG II has been im...

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“…H 2 O 2 has biphasic actions on renal afferent arterioles, an initial vasoconstricting action followed later by a vasodilatory action (292). High-dose Ang II treatment of rats for 2 weeks leads to salt sensitivity and an increase in blood pressure in the succeeding weeks via a persistent inflammatory cell infiltrate in the renal cortex that leads to oxidative stress (194).…”

Section: Nephron Handling Of Ros and Hypertension: Redox Control Omentioning

confidence: 99%

Redox Control of Renal Function and Hypertension

Nistala

Whaley‐Connell

Sowers

2008

Antioxidants & Redox Signaling

134

122

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Salt-Sensitive Hypertension Develops After Short-Term Exposure to Angiotensin II

Cited by 147 publications

References 20 publications

Elevated Uric Acid Increases Blood Pressure in the Rat by a Novel Crystal-Independent Mechanism

Elevated Uric Acid Increases Blood Pressure in the Rat by a Novel Crystal-Independent Mechanism

Increased dietary sodium alters neural control of blood pressure during intravenous ANG II infusion

Redox Control of Renal Function and Hypertension

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