Brain angiotensin II contributes to the development of hypertension in Dahl-Iwai salt-sensitive rats

Teruya, Hiroshi; Muratani, Hiromi; Takishita, Shuichi; Sesoko, Shogo; Matayoshi, Rijiko; Fukiyama, Koshiro

doi:10.1097/00004872-199508000-00009

Cited by 46 publications

(24 citation statements)

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“…Chronic ICV infusion of the AT 1 receptor blocker CV-11974 prevented the development of hypertension in Dahl-Iwai salt-sensitive rats on high salt. 11 The present study shows that similar to SHR on high salt, 6 in Dahl S chronic ICV infusion of losartan not only prevents the hypertension but also prevents an increase in sympathoexcitation and decrease in sympathoinhibition by high salt intake. Thus, the brain RAS appears also to be involved in the salt-induced sympathetic hyperactivity and hypertension in Dahl S rats.…”

Section: Brain Ang II Sympathetic Hyperactivity and Hypertensionsupporting

confidence: 56%

“…In Dahl S on high salt diet, acute intracerebroventricular (ICV) injection of the angiotensin type 1 (AT 1 ) receptor blocker losartan did not decrease BP, 10 but chronic ICV administration of the AT 1 blocker CV-11974 prevented the development of hypertension. 11 Whether in Dahl S rats brain Ang II is involved in the sympathoexcitation and impairment of baroreflex function by high salt intake has not yet been evaluated. In the present study, we examined in Dahl S rats whether both brain Ang II and "ouabain" contribute to the impairment of arterial and cardiopulmonary baroreflex function, as well as the sympathetic hyperactivity and hypertension caused by high dietary salt intake.…”

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confidence: 99%

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Both Brain Angiotensin II and “Ouabain” Contribute to Sympathoexcitation and Hypertension in Dahl S Rats on High Salt Intake

1998

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Abstract-Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats from 5 to 9 weeks of age received a regular or high salt diet and concomitantly an intracerebroventricular infusion of the angiotensin type 1 blocker losartan (1 mg ⅐ kg Ϫ1 ⅐ d Ϫ1) or antibody Fab fragments, which bind ouabain and related steroids with high affinity, or ␥-globulins as control (200 g/d for both). At 9 weeks of age, blood pressure (BP), heart rate (HR), central venous pressure, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air stress and to intracerebroventricular ␣ 2 -agonist guanabenz (50 g) and ouabain (0.5 g). Baroreflex function was assessed by acute volume expansion with intravenous 5% dextrose and ramp changes of BP by Ϯ50 mm Hg induced by intravenous phenylephrine and sodium nitroprusside. In Dahl S but not R rats, high salt significantly increased BP and HR; enhanced BP, HR, and renal sympathetic nerve activity responses to air stress and guanabenz; and attenuated cardiopulmonary and arterial baroreflex control of renal sympathetic nerve activity and HR. Both losartan and Fab fragments prevented these responses to high salt to a similar extent in Dahl S rats but had no effect in Dahl R rats on high salt. Sympathoexcitatory responses to ouabain were attenuated in Dahl S on high versus regular salt and were abolished in Dahl R or S treated with losartan or Fab fragments. Consistent with previous studies in SHR, the present data indicate that in Dahl S on high salt, both brain "ouabain" and angiotensin II contribute to decreased sympathoinhibition and increased sympathoexcitation, impairment of baroreflex, and therefore hypertension. (Hypertension. 1998;32:1028-1033.) Key Words: sympathetic nervous system Ⅲ baroreflex Ⅲ losartan Ⅲ stress Ⅲ guanabenz Ⅲ antibody Fab fragments N eural mechanisms leading to sympathetic hyperactivity play a major role in the pathogenesis of salt-dependent hypertension in Dahl salt-sensitive (Dahl S) rats.1 In Dahl S rats, high salt intake enhances sympathoexcitatory responses and attenuates sympathoinhibitory responses.2 Arterial 3,4 and cardiopulmonary 5 baroreflex control of efferent sympathetic nerve activity and/or heart rate (HR) are impaired in Dahl S rats, even before the commencement of high salt intake. 3,5 High salt intake also causes sympathetic hyperactivity 6 and impairment of baroreflex function 7 in spontaneously hypertensive rats (SHR), another model of salt-sensitive hypertension. In a series of studies we have shown that high salt intake increases ouabain-like activity ("ouabain") 8,9 in several brain areas and that in both SHR and Dahl S rats, blockade of brain "ouabain" prevents sympathoexcitation, baroreflex impairment, and exaggeration of hypertension. 2,4,6,9 In SHR, it appears that high dietary salt increases brain "ouabain" and the latter exerts its sympathoexcitatory and pressor effects via the brain renin-angiotensin system (RAS).6 Whether brain angiotensin II (Ang II) is also involved in the impairment of baroreflex ...

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Section: Brain Ang II Sympathetic Hyperactivity and Hypertensionsupporting

confidence: 56%

mentioning

confidence: 99%

Both Brain Angiotensin II and “Ouabain” Contribute to Sympathoexcitation and Hypertension in Dahl S Rats on High Salt Intake

1998

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“…Functional studies (8,23) have clearly established that the brain RAS, through AT 1 receptor activation, plays an essential role in the sympathoexcitation and development of hypertension in Dahl S rats on highsalt diet. The larger blood pressure response to intracerebroventricular captopril in the Dahl S rats on high salt intake is consistent with these previous studies.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 93%

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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“…Chronic blockade of brain AT1 receptors by icv losartan prevents both the sympathetic hyperactivity and exacerbation of hypertension in SHR on high sodium (15). Chronic icv infusion of the AT1 receptor blocker CV-11974 (active metabolite of candesartan) or losartan prevents the development of hypertension in DahlIwai salt-sensitive rats (16) and Dahl S rats (17). Therefore, activation of brain AT1 receptors seems to be essential for development of salt-sensitive hypertension in SHR and Dahl S rats.…”

Section: Discussionmentioning

confidence: 99%

Effects of Centrally Administered Losartan on Deoxycorticosterone-salt Hypertension Rats

Park

Leenen

2001

J Korean Med Sci

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INTRODUCTIONIn deoxycorticosterone acetate (DOCA)-salt hypertensive rats the development and maintenance of hypertension is considered to be independent of the renin-angiotensin system, because plasma renin in this model is low (1), and peripheral administration of angiotensin converting enzyme (ACE) inhibitors (2) or angiotensin (Ang) II receptor antagonists (3) has no effect on blood pressure (BP). However, there is some evidence for a role of the brain renin-angiotensin system in the pathogenesis of DOCA-salt hypertension in rats.DOCA-salt-treated rats show higher Ang II receptor density in brain areas involved in cardiovascular regulation, such as the nucleus of solitary tract, area postrema, median preoptic nucleus, subfornical organ, and solitary vagal area (4-6), and have elevated levels of renin and Ang II in hypothalamus and brain stem nuclei (7,8). Acute intracerebroventricular (icv) administration of captopril decreases the blood pressure of DOCA-salt hypertensive rats (9). Chronic icv administration of captopril attenuates the development of hypertension in DOCA-salt hypertensive rats (10). However, the interpretation of these findings is complicated because ACE is involved in the metabolism of various peptides that may participate in regulating BP, including bradykinin, enkephalin and substance P (11).Three studies assessed the effects of icv Ang II receptor antagonists on BP in DOCA-salt hypertensive rats. Acute icv administration of salarasin did not lower BP during 30 min of follow-up (12). In contrast, injection of losartan icv or into the rostral part of the third ventricle did lower BP for more than 1 hr in 4 weeks DOCA-salt hypertensive rats (13). Moreover, continuous icv infusion of CV-11974 (active metabolite of candesartan) for 7 days lowered BP from the fourth day after infusion (14). However, because hemodynamic measurements in these studies were done under anesthesia in 4 weeks and 6 weeks DOCA-salt hypertensive rats, the role of brain Ang II in the development of the hypertension in the DOCA-salt hypertensive rat model is not known yet.The aim of the present study was to determine the acute central effects of the type 1 Ang II (AT1) receptor antagonist losartan in conscious DOCA-salt hypertensive rats, at either 2 weeks during the development of the hypertension or at 4 weeks in the maintenance phase of the hypertension. MATERIALS AND METHODS AnimalsMale Wistar rats aged 5 weeks, weighing 140-170 g, were J Korean Med Sci 2001; 16: 553-7 ISSN 1011-8934 Copyright � The Korean Academy of Medical Sciences 553 Effects of Centrally Administered Losartan on Deoxycorticosteronesalt Hypertension RatsTo investigate whether brain AT1 receptor stimulation contributes as a hypertensive mechanism to deoxycorticosterone acetate (DOCA)-salt hypertension, losartan (1 mg/4 L) or artificial cerebrospinal fluid (aCSF) was injected into the lateral cerebral ventricle in conscious control uninephrectomized Wistar rats or rats with DOCA-salt for 2 or 4 weeks, and mean arterial pressure (MAP) and heart r...

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Brain angiotensin II contributes to the development of hypertension in Dahl-Iwai salt-sensitive rats

Cited by 46 publications

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Both Brain Angiotensin II and “Ouabain” Contribute to Sympathoexcitation and Hypertension in Dahl S Rats on High Salt Intake

Both Brain Angiotensin II and “Ouabain” Contribute to Sympathoexcitation and Hypertension in Dahl S Rats on High Salt Intake

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

Effects of Centrally Administered Losartan on Deoxycorticosterone-salt Hypertension Rats

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Brain angiotensin II contributes to the development of hypertension in Dahl-Iwai salt-sensitive rats

Cited by 46 publications

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Both Brain Angiotensin II and “Ouabain” Contribute to Sympathoexcitation and Hypertension in Dahl S Rats on High Salt Intake

Both Brain Angiotensin II and “Ouabain” Contribute to Sympathoexcitation and Hypertension in Dahl S Rats on High Salt Intake

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

Effects of Centrally Administered Losartan on Deoxycorticosterone-salt Hypertension Rats

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