High salt intake and the brain renin–angiotensin system in Dahl salt-sensitive rats

Zhao, Xigeng; White, Roselyn; Huang, Bing; Huysse, James Van; Leenen, Frans H. H.

doi:10.1097/00004872-200101000-00012

Cited by 53 publications

(48 citation statements)

References 22 publications

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“…However, ACE concentration and activity is not only influenced by genotype but also by a myriad of mechanisms, including pharmacological therapy [36] and fluid management [37]. The current authors, therefore, made no attempt to measure concentration or activity of ACE in BAL fluid or serum.…”

Section: Discussionmentioning

confidence: 95%

ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS

Adamzik

Frey²,

Sixt³

et al. 2007

European Respiratory Journal

101

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The intrapulmonary renin-angiotensin system via tissue concentration of angiotensin II or bradykinin may have multiple effects on pulmonary pathophysiology. Therefore, it was investigated whether the presence of the D allele of the angiotensinconverting enzyme (ACE) insertion/deletion (I/D) polymorphism or the A allele of angiotensinogen (AGT) promoter polymorphism (-6)A/G are independent risk factors for 30-day survival in acute respiratory distress syndrome (ARDS) patients.In a prospective study, adults (Germans of Caucasian ethnicity) with ARDS (n584) were recruited from the current authors' intensive care unit and genotyped for the ACE I/D and the AGT (-6)A/G polymorphisms, as were 200 healthy Caucasian controls.Mortality was increased in the ACE DD genotype compared with the I allele, and the ACE I/D polymorphism was an independent prognostic factor for 30-day survival. Patients with a homozygous DD genotype were at highest risk for death (hazard ratio 5.7; 95% confidence interval 1.7-19.2) compared with the II genotype. In contrast, the AGT (-6)A/G polymorphism was neither associated with an increased risk for development of ARDS nor with outcome.In patients with acute respiratory distress syndrome, the angiotensin-converting enzyme insertion/deletion polymorphism but not the angiotensinogen (-6)A/G promoter polymorphism is an independent risk factor with a pronounced effect on 30-day survival.

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Section: Discussionmentioning

confidence: 95%

ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS

Adamzik

Frey²,

Sixt³

et al. 2007

European Respiratory Journal

101

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“…Ang II was applied at concentrations from 3 nmol/L, comparable to endogenous Ang II concentrations in brain tissues. 45 In vehicle-treated neurons, DCF fluorescence remained stable during the monitoring period ( Figure 1B and 1C). Ang II dosedependently increased DCF intensity, reflecting an increase in ROS.…”

Section: Currents In Dmnts Neuronsmentioning

confidence: 87%

Nox2, Ca ²⁺ , and Protein Kinase C Play a Role in Angiotensin II-Induced Free Radical Production in Nucleus Tractus Solitarius

et al. 2006

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Abstract-The dorsomedial portion of the nucleus tractus solitarius (dmNTS) is the site of termination of baroreceptor and cardiorespiratory vagal afferents and plays a critical role in cardiovascular regulation. Angiotensin II (Ang II) is a powerful signaling molecule in dmNTS neurons and exerts some of its biological effects by modulating Ca 2ϩ currents via reactive oxygen species (ROS) derived from reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase. We investigated whether a Nox2-containing NADPH oxidase is the source of the Ang II-induced ROS production and whether the signaling mechanisms of its activation require intracellular Ca 2ϩ or protein kinase C (PKC). Second-order dmNTS neurons were anterogradely labeled with 4-(4-[didecylamino]styryl)-N-methylpyridinium iodide transported from the vagus and isolated from the brain stem. ROS production was assessed in 4-(4-[didecylamino]styryl)-N-methylpyridinium iodide-positive dmNTS neurons using the fluorescent dye 6-carboxy-2Ј,7Ј-dichlorodihydro-fluorescein di(acetoxymethyl ester). Ang II (3 to 2000 nmol/L) increased ROS production in dmNTS neurons (EC 50 ϭ38.3 nmol/L). The effect was abolished by the ROS scavenger Mn (III) porphyrin 5,10,20-tetrakis (benzoic acid) porphyrin manganese (III), the Ang II type 1 receptor antagonist losartan, or the NADPH oxidase inhibitors apocynin or gp91ds-tat. Ang II failed to increase ROS production or to potentiate L-type Ca 2ϩ currents in dmNTS neurons of mice lacking Nox2. The PKC inhibitor GF109203X or depletion of intracellular Ca 2ϩ attenuated Ang II-elicited ROS production. We conclude that the powerful effects of Ang II on Ca 2ϩ currents in dmNTS neurons are mediated by PKC activation leading to ROS production via Nox2. Thus, a Nox2-containing NADPH oxidase is the critical link between Ang II and the enhancement of Key Words: arterial hypertension Ⅲ baroreflex Ⅲ calcium channels Ⅲ oxidative stress Ⅲ blood pressure Ⅲ autonomic nervous system A select group of brain stem nuclei regulates the systemic circulation by modulating cardiac output, vascular resistance, and fluid balance. 1,2 In particular, the dorsomedial region of the nucleus of the solitary tract (dmNTS), wherein vagal afferents from aortic baroreceptors and cardiorespiratory chemoreceptors terminate, plays a major role in cardiovascular regulation. [3][4][5] There is increasing evidence that angiotensin II (Ang II) is a critical neuromodulator in central autonomic nuclei, 6 -9 including the dmNTS. 10 -13 Within the dmNTS, activation of Ang II type 1 (AT 1 ) receptors alters cardiorespiratory reflexes including baroreceptor excitability and ion channel permeability. 10,14 These changes may contribute to Ang II-induced sympathoexcitation, 15-18 hypertension, 15,16 and heart failure. 17,18 Superoxide generated by the enzyme NADPH oxidase has emerged as a key intermediary in the central and peripheral effects of Ang II. 10,14 -16,18 -21 NADPH oxidase, initially described in neutrophils, 22,23 is now known to be present in diverse cell types, inc...

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“…In Dahl S rats, AT 1 receptor mRNA increased threefold in brain homogenates following 6 wk of a high-salt diet (21). A high-salt diet for 2-5 wk caused a marked increase in angiotensin-converting enzyme (ACE) mRNA and activity measured in hypothalamic and pons homogenates in Dahl S rats compared with Dahl salt-resistant (Dahl R) rats (27). These studies (22,27) do not provide information on where the increases in expression occur in the brain, and AT 1 receptor mRNA increases may not accurately reflect changes in the functional receptor.…”

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confidence: 99%

Effects of high salt intake on brain AT₁ receptor densities in Dahl rats

Wang

Veerasingham

Tan

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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To assess effects of dietary salt on brain AT 1 receptor densities, 4-wk-old Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats were fed a regular (101 mol Na/g) or high (1,370 mol Na/g)-salt diet for 1, 2, or 4 wk. AT 1 receptors were assessed by quantitative in vitro autoradiography. AT 1 receptor densities did not differ significantly between strains on the regular salt diet. The high-salt diet for 1 or 2 wk increased AT 1 receptor binding by 21-64% in the Dahl S rats in the subfornical organ, median preoptic nucleus, paraventricular nucleus, and suprachiasmatic nucleus. No changes were noted in the Dahl R rats. After 4 wk on a high-salt diet, increases in AT1 receptor binding persisted in Dahl S rats but were now also noted in the paraventricular nucleus, median preoptic nucleus, and suprachiasmatic nucleus of Dahl R rats. At 4 wk on the diet, intracerebroventricular captopril caused clear decreases in blood pressure only in the Dahl S on the highsalt diet but caused largely similar relative increases in brain AT1 receptor densities in Dahl S and R on the high-salt diet versus regular salt diet. These data demonstrate that high salt intake rapidly (within 1 wk) increases AT1 receptor densities in specific brain nuclei in Dahl S and later (by 4 wk) also in Dahl R rats. Because the brain renin-angiotensin system only contributes to salt-induced hypertension in Dahl S rats, further studies are needed to determine which of the salt-induced increases in brain AT1 receptor densities contribute to the hypertension and which to other aspects of body homeostasis. brain renin-angiotensin system; salt-induced hypertension; angiotensin II; autoradiography THE BRAIN RENIN-ANGIOTENSIN SYSTEM (RAS) plays an important role in sodium homeostasis and central cardiovascular regulation. Components of the brain RAS are distributed in central regions that mediate these functions, including circumventricular organs, such as the organum vasculosum laminae terminalis (OVLT) and the subfornical organ (SFO), which are exposed to blood-borne angiotensins, and many regions within the blood-brain barrier (BBB), such as the paraventricular nucleus (PVN), median preoptic nucleus (MnPO), and suprachiasmatic nucleus (SCh) (1, 3). These areas express a predominance of AT 1 receptors that bind ANG II and ANG III with high affinity. Central AT 1 receptor stimulation appears to play a critical role in the development of salt-induced hypertension in the Dahl saltsensitive (Dahl S) rat, a genetic model of salt-sensitive hypertension. Chronic central infusion of CV-11974, a nonpeptide AT 1 receptor antagonist, prevents the development of hypertension in Dahl-Iwai salt-sensitive rats on a high-salt diet (23). Our group (8, 9) demonstrated that chronic blockade of central AT 1 receptors, by intracerebroventricular infusion of losartan, prevents sympathoexcitation and exacerbation of hypertension in Dahl S rats as well as spontaneously hypertensive rats (SHR) on a high-salt diet.The activity of the RAS may be enhanced by the increased relea...

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High salt intake and the brain renin–angiotensin system in Dahl salt-sensitive rats

Cited by 53 publications

References 22 publications

ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS

ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS

Nox2, Ca ²⁺ , and Protein Kinase C Play a Role in Angiotensin II-Induced Free Radical Production in Nucleus Tractus Solitarius

Effects of high salt intake on brain AT₁ receptor densities in Dahl rats

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High salt intake and the brain renin–angiotensin system in Dahl salt-sensitive rats

Cited by 53 publications

References 22 publications

ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS

ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS

Nox2, Ca 2+ , and Protein Kinase C Play a Role in Angiotensin II-Induced Free Radical Production in Nucleus Tractus Solitarius

Effects of high salt intake on brain AT1 receptor densities in Dahl rats

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Nox2, Ca ²⁺ , and Protein Kinase C Play a Role in Angiotensin II-Induced Free Radical Production in Nucleus Tractus Solitarius

Effects of high salt intake on brain AT₁ receptor densities in Dahl rats