Increases in CSF [Na<sup>+</sup>] precede the increases in blood pressure in Dahl S rats and SHR on a high-salt diet

Huang, Bing; Vliet, Bruce N. Van; Leenen, Frans H. H.

doi:10.1152/ajpheart.00126.2004

Cited by 131 publications

(156 citation statements)

References 38 publications

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“…An increase in OLC in the CNS may have two functions. First, OLC released into the CSF may inhibit the Na ϩ -K ϩ -ATPase on the CSF side in the choroid plexus and prevent further increase in CSF [Na ϩ ], as we previously reported in Dahl S rats on high salt intake (20). Such a negative feedback mechanism may explain why in the present study a 9% increase in CSF Na ϩ loading by intracerebroventricular Na ϩ -rich aCSF caused only a 3% increase in CSF [Na ϩ ].…”

Section: Discussionsupporting

confidence: 63%

“…This increase appears as large, but is within the range, seen in Dahl S rats on a high-sodium diet (20,30), in sheep after water deprivation (34), or in patients with hypertension on high salt intake (26).…”

Section: Possible Limitations Of Present Studymentioning

confidence: 50%

“…After the BP and HR measurements, 1.5 ml blood was withdrawn from the arterial line in conscious rats into an ice-chilled tube containing EDTA and centrifuged at 3,000 g for 10 min for separation of plasma. Subsequently, with the rats under halothane anesthesia, each rat was placed in a stereotaxic frame, and 100 -200 l CSF sample was collected at Ͻ5 l/s from a cannula that was inserted into the cisterna magna, as described previously (20). Electrolytes in plasma and CSF were determined using an ion-selective electrode (model 917, Hitachi electrode).…”

Section: Protocol 1: Role Of Brain Mr In Effects Of Namentioning

confidence: 99%

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Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats

Huang

Cheung²,

Wang³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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tional studies indicate that the sympathoexcitatory and pressor responses to an increase in cerebrospinal fluid (CSF) [Na ϩ ] by central infusion of Na ϩ -rich artificial cerebrospinal fluid (aCSF) in Wistar rats are mediated in the brain by mineralocorticoid receptor (MR) activation, ouabain-like compounds (OLC), and AT1-receptor stimulation. In the present study, we examined whether increasing CSF [Na ϩ ] by intracerebroventricular infusion of Na ϩ -rich aCSF activates MR and thereby increases OLC and components of the renin-angiotensin system in the brain. Male Wistar rats received via osmotic minipump an intracerebroventricular infusion of aCSF or Na ϩ -rich aCSF, in some groups combined with intracerebroventricular infusion of spironolactone (100 ng/h), antibody Fab fragments (to bind OLC), or as control ␥-globulins. After 2 wk of infusion, resting blood pressure and heart rate were recorded, OLC and aldosterone content in the hypothalamus were assessed by a specific ELISA or radioimmunoassay, and angiotensin-converting enzyme (ACE) and AT1-receptor binding densities in various brain nuclei were measured by autoradiography using 125 I-labeled 351 A and 125 I-labeled ANG II. When compared with intracerebroventricular aCSF, intracerebroventricular Na ϩ -rich aCSF increased CSF [Na ϩ ] by ϳ5 mmol/l, mean arterial pressure by ϳ20 mmHg, heart rate by ϳ65 beats/min, and hypothalamic content of OLC by 50% and of aldosterone by 33%. Intracerebroventricular spironolactone did not affect CSF [Na ϩ ] but blocked the Na ϩ -rich aCSF-induced increases in blood pressure and heart rate and OLC content. Intracerebroventricular Na ϩ -rich aCSF increased ACE and AT 1-receptor-binding densities in several brain nuclei, and Fab fragments blocked these increases. These data indicate that in Wistar rats, a chronic increase in CSF [Na ϩ ] may increase hypothalamic aldosterone and activate CNS pathways involving MR, and OLC, leading to increases in AT 1-receptor and ACE densities in brain areas involved in cardiovascular regulation and hypertension. brain mineralocorticoid receptor; ouabain; angiotensin-converting enzyme; AT 1-receptor NEURAL MECHANISMS play a major role in the development of salt-induced hypertension in Dahl salt-sensitive (S) rats (3). In Dahl S rats but not salt-resistant (R) rats, high salt intake increases cerebrospinal fluid (CSF) [Na ϩ ] (20), associated with increases in hypothalamic ouabain-like compounds (OLC) (41) and in angiotensin-converting enzyme (ACE) activity (46) and AT 1 -receptors (44). Functional studies indicate that high saltinduced sympathetic hyperactivity and hypertension can be prevented by CNS blockade of aldosterone synthesis (15), mineralocorticoid receptors (MR) (14, 32), epithelial sodium channels (ENaC) (42), OLC, or of AT 1 -receptors (19). We proposed (23) that in Dahl S rats on high salt, genetically determined enhancement in the activity of MR-ENaC activates central pathways involving OLC and AT 1 -receptors resulting in sympathetic hyperactivity and hypertension.Recent studies...

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Section: Discussionsupporting

confidence: 63%

Section: Possible Limitations Of Present Studymentioning

confidence: 50%

Section: Protocol 1: Role Of Brain Mr In Effects Of Namentioning

confidence: 99%

See 1 more Smart Citation

Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats

Huang

Cheung²,

Wang³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…There are reports that EO also may be produced in the brain (38) and that elevated cerebrospinal fluid levels (39) are associated with hypertension without an elevation in the circulating EO level (48).…”

Section: Endogenous Ouabain and Other Endogenous Cardiotonic Steroidsmentioning

confidence: 99%

How does salt retention raise blood pressure?

Blaustein¹,

Zhang²,

Ling³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

129

121

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A critical question in hypertension research is: How is long-term blood pressure controlled? Excessive NaCl ingestion or NaCl retention by the kidneys and the consequent tendency toward plasma volume expansion lead to hypertension. Nevertheless, the precise mechanisms linking salt to high blood pressure are unresolved. The discovery of endogenous ouabain, an adrenocortical hormone, provided an important clue. Ouabain, a selective Na ϩ pump inhibitor, has cardiotonic and vasotonic effects. Plasma endogenous ouabain levels are significantly elevated in Ϸ40% of patients with essential hypertension and in animals with several forms of salt-dependent hypertension. Also, prolonged ouabain administration induces hypertension in rodents. Mice with mutant Na ϩ pumps or Na/Ca exchangers (NCX) and studies with a ouabain antagonist and an NCX blocker are revealing the missing molecular mechanisms. These data demonstrate that ␣ 2 Na ϩ pumps and NCX1 participate in long-term regulation of vascular tone and blood pressure. Pharmacological agents or mutations in the ␣ 2 Na ϩ pump that interfere with the action of ouabain on the pump, and reduced NCX1 expression or agents that block NCX all impede the development of salt-dependent or ouabain-induced hypertension. Conversely, nanomolar ouabain, reduced ␣ 2 Na ϩ pump expression, and smooth muscle-specific overexpression of NCX1 all induce hypertension. Furthermore, ouabain and reduced ␣ 2 Na ϩ pump expression increase myogenic tone in isolated mesenteric small arteries in vitro, thereby tying these effects directly to the elevation of blood pressure. Thus, endogenous ouabain, and vascular ␣ 2 Na ϩ pumps and NCX1, are critical links between salt and hypertension. New pharmacological agents that act on these molecular links have potential in the clinical management of hypertension.ouabain; Na ϩ pump; Na/Ca exchanger; Ca 2ϩ ; myogenic tone HYPERTENSION, DEFINED AS A diastolic blood pressure (BP) Ն 90 mmHg and/or systolic BP Ն 140 mmHg, is endemic in Westernized societies. This is a very important public health issue because hypertension is a major risk factor for premature death and disability from heart attack, heart failure, stroke, and many other afflictions (16,59). In the United States, alone, Ϸ20% of the population (i.e., Ϸ50 million individuals) are hypertensive; moreover, more than half of all individuals over the age of 60 years have hypertension. In a small fraction of cases, the hypertension is due to specific causes, such as renal vascular disease or excessive secretion of aldosterone (primary aldosteronism) or catecholamines (pheochromocytoma). The vast majority (Ϸ90%) of patients, however, have elevated BP of unknown cause; hence the terms, primary or essential hypertension. The immediate cause for the elevated BP in nearly all chronic hypertensive persons is excessive narrowing of the small (resistance) arteries. Nevertheless, a key question in any discussion of hypertension is: What specific mechanisms actually lead to the abnormal arterial constriction and elevation ...

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“…Herein, we refer to salt-induced changes of this time course as 'acute' to distinguish them from much slower salt-induced effects discussed in subsequent sections. Acute salt sensitivity of blood pressure has been demonstrated in experiments involving a number of species including chickens, 19,20 dogs, [21][22][23][24] green monkeys, 25 mice, 26 pigs, 27 rabbits, 28,29 rats [30][31][32][33][34] and spider monkeys. 25,35 An example of the time course of the blood pressure response to a high-salt diet in regular Sprague-Dawley rats is shown in Figure 2.…”

Section: Acute Salt Sensitivity Of Blood Pressurementioning

confidence: 99%

The time course of salt-induced hypertension, and why it matters

Vliet

Montani

2008

Int J Obes

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The epidemiology of salt-induced hypertension has been explored in detail in animal studies, in some cases involving exposures to excess dietary salt for much of the animal's lifespan. The results of these studies demonstrate the presence of two distinct time courses of the blood pressure response to a high salt intake: an acute (rapid) blood pressure response occurring over days to weeks, and a slow and progressive blood pressure response that develops over extremely long periods of time, amounting to a significant fraction of the lifespan in normal individuals. The acute form of salt sensitivity is well known in humans, having often been demonstrated as a fall in blood pressure during the period of salt restriction. The slow and progressive form of salt sensitivity has been demonstrated directly in rats and chimpanzees and is also evident in analyses of human cross-population data as a salt dependency of age-associated changes of blood pressure. This slow and progressive component of salt-induced hypertension may be attributable, at least in part, to a progressive rise in the acute salt sensitivity of blood pressure during sustained exposure to high salt. However, a progressively irreversible or 'self sustaining' component of salt-induced hypertension has also been demonstrated in rat studies. This irreversible component has not been completely characterized, but its presence raises the possibility that blood pressure responses to salt restriction may not fully reveal the contribution of salt to blood pressure or the epidemiology of hypertension. These various components of salt sensitivity (acute vs slow, reversible vs irreversible) should be considered in any comprehensive explanation of the effects of salt on blood pressure and especially in experimental studies of the genetic and physiological mechanisms underlying salt-induced hypertension.

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Increases in CSF [Na⁺] precede the increases in blood pressure in Dahl S rats and SHR on a high-salt diet

Cited by 131 publications

References 38 publications

Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats

Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats

How does salt retention raise blood pressure?

The time course of salt-induced hypertension, and why it matters

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Increases in CSF [Na+] precede the increases in blood pressure in Dahl S rats and SHR on a high-salt diet

Cited by 131 publications

References 38 publications

Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats

Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats

How does salt retention raise blood pressure?

The time course of salt-induced hypertension, and why it matters

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Product

Resources

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Increases in CSF [Na⁺] precede the increases in blood pressure in Dahl S rats and SHR on a high-salt diet