Increased angiotensin II receptors in brain nuclei of DOCA-salt hypertensive rats

Gutkind, J. Silvio; Kurihara, Masaki; Saavedra, Juan M.

doi:10.1152/ajpheart.1988.255.3.h646

Cited by 48 publications

(44 citation statements)

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“…The systemic RAS activity was lower in DOCA-salt rats than in sham-operated rats as indicated by the significantly lower plasma renin activity [0.6 Ϯ 0.1 ng of AngI produced per ml per h, n ϭ 6, vs. 1.7 Ϯ 0.3, n ϭ 6 (P Ͻ 0.05)]. In contrast, the brain RAS was hyperactive in DOCA-salt rats as previously shown by the increased density of AT 1 receptor binding sites observed in the brain of these animals as compared to normotensive WKY rats (33). This hyperactivity could account for the higher pressor response to i.c.v.…”

Section: Effects Of Icv Injections Of Ec33 and Rb150 On Arterial Bmentioning

confidence: 55%

Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension

Fournié‐Zaluski

Fassot

Valentin

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

122

131

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The hyperactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. We previously reported that in the murine brain, aminopeptidase A (APA) is involved in the conversion of angiotensin II (AngII) to AngIII and that AngIII is one of the main effector peptides of the brain RAS in the control of vasopressin release. Here we report that brain AngIII exerts a tonic stimulatory effect on blood pressure in a model of salt-dependent hypertension, the DOCA-salt rat, characterized by a depressed systemic but a hyperactive brain RAS. Similar high blood pressure accompanied by a low systemic renin state was described in some patients, especially in hypertensive African Americans who are resistant to treatment by blockers of the systemic RAS. We developed RB150, a prodrug of the specific and selective APA inhibitor, EC33. RB150 given i.v. is able to cross the blood-brain barrier, to inhibit brain APA, and to block the formation of central AngIII. A single dose of systemic RB150 (15 mg͞kg, i.v.) in conscious DOCA-salt rats inhibited brain APA activity and markedly reduced blood pressure for up to 24 h. These results demonstrate the crucial role of brain APA as a candidate target for the treatment of hypertension and suggest that RB150, a potent systemically active APA inhibitor, could be the prototype of a new class of antihypertensive agents for the treatment of certain forms of hypertension.

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Section: Effects Of Icv Injections Of Ec33 and Rb150 On Arterial Bmentioning

confidence: 55%

Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension

Fournié‐Zaluski

Fassot

Valentin

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

122

131

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“…After DOCA-salt treatment for 1 month, renin-like activity and Ang II in hypothalamus and brain stem nuclei were elevated, but plasma renin activity was very low (7,8). In rats with DOCA-salt hypertension for 4-8 weeks, angiotensin II receptor binding on autoradiography was also elevated in selected brain areas involved in cardiovascular regulation, such as nucleus of solitary tract, area postrema, median preoptic nucleus, subfornical organ, and solitary vagal area (4)(5)(6). Moreover, BP responses to centrally administered Ang II were significant- (4,25).…”

Section: Discussionmentioning

confidence: 98%

“…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)(5)(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).…”

Section: Introductionmentioning

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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“…Additionally, drinking stimulated by central injection of angiotensin II was increased after DOC administration, demonstrating the behavioral consequences of mineralcorticoid-mediated increases in angiotensin II binding sites (Wilson et al, 1986). Subsequent studies identified increased angiotensin II receptor binding in specific brain regions following DOC administration (De Nicola et al, 1993;Gutkind et al, 1988) as well as within cultured neurons (Sumners & Fregly, 1989). Whether the up-regulation of angiotensin II receptors was due to the actions of mineralcorticoids, glucocorticoids, or a combination of both remained to be determined.…”

Section: Central Interactions Of Aldosterone and Angiotensin IImentioning

confidence: 99%

Richter and sodium appetite: From adrenalectomy to molecular biology

Krause

Sakai

2007

Appetite

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Nearly three-quarters of a century ago, Curt Richter removed the adrenal glands from rats and noted that the animal's vitality was dependent on its increased consumption of sodium chloride. In doing so, Richter revealed an innate behavioral mechanism that serves to maintain the hydromineral balance of an animal faced with sodium deficit. This experiment and others like it, led to the development of a field of research devoted to the investigation of salt appetite. The following is a discussion of how Richter's initial observations gave birth to an evolving field that incorporates multiple approaches to examine the drive to consume sodium. KeywordsSalt appetite; Angiotensin; Aldosterone; Corticosterone; Richter The Discovery of Salt AppetiteAt the time that Richter began his career at Johns Hopkins University much of the research examining ingestive behavior focused on the responses of individual organs or closely coordinated systems. Richter's pioneering work initiated a fundamental paradigm shift that moved the focus to adaptations of the organism as a whole. Specifically, he was interested in changes in behavior that compensated for perturbations in the internal environment. His approach toward investigation of such behaviors was as thorough as it was fundamental. Richter manipulated diet, interfered with the nervous system, and removed or replaced glandular secretions in attempt to understand the nutritional, neural, and endocrine signals that contribute to behavior.Richter created disturbances in the nutritional or mineral content of the internal environment with dietary deficiency. Subsequently, "self selection" experiments were performed where choices of different minerals and nutrients were presented for consumption. More often than not, animals would consume minerals and nutrients in amounts that would alleviate their experimentally-induced deficiencies. One of the most striking behaviors that Richter observed was that of rats voluntarily ingesting salt when faced with sodium deficit. Sodium chloride was removed from the rats' food and they were given access to water and 3 % NaCl solution. The intake of the NaCl solution was approximately 1% of the total diet, which remarkably, is the

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Increased angiotensin II receptors in brain nuclei of DOCA-salt hypertensive rats

Cited by 48 publications

References 0 publications

Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension

Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension

Effects of Centrally Administered Losartan on Deoxycorticosterone-salt Hypertension Rats

Richter and sodium appetite: From adrenalectomy to molecular biology

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