The Role of Aldosterone in the Development of Hypertension in Spontaneously Hypertensive Rats*

Kenyon, Christopher J.; Deconti, Giulio A.; Cupolo, Nora A.; Morris, David J.

doi:10.1210/endo-109-6-1841

Cited by 30 publications

(11 citation statements)

References 20 publications

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confidence: 99%

“…8,13,[17][18][19] Finally, in SHR, adrenocortical steroids are required for the development of hypertension, probably via the permissive action of both mineralocorticoid and glucocorticoid activities. 20,21 In the present study, we examined the contribution of brain MRs in the maintenance of high blood pressure in SHR. For this purpose, we assessed the effect of single ICV administration of the selective MR antagonist RU28318 on cardiovascular and renal functions of normotensive Wistar-Kyoto rats (WKY) and adult SHR that were fed a standard-or high-sodium diet.…”

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Involvement of Brain Mineralocorticoid Receptor in Salt-Enhanced Hypertension in Spontaneously Hypertensive Rats

et al. 2001

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Abstract-We recently showed that brain mineralocorticoid receptors (MRs) are involved in blood pressure and kidney function control in normotensive Wistar rats. We now assessed the involvement of brain MRs in spontaneously hypertensive rats (SHR), in which the presence of adrenocorticoids has been shown to be required for the development of hypertension. The effect of a single intracerebroventricular (ICV) injection of an MR antagonist (RU28318) on systolic blood pressure (SBP) and renal function was examined in conscious adult SHR and Wistar-Kyoto rats (WKY) maintained on a standard-sodium diet (0.4% Na ϩ ). In WKY, a long-lasting decrease in SBP was caused by the ICV injection of 10 ng RU28318 as previously reported in Wistar rats, associated with increased urinary excretion of water and electrolytes. In SHR maintained on the standard diet, the ICV injection of RU28318 (10 or 100 ng) had no effect on cardiovascular and renal functions. However, the ICV injection of 10 ng RU28318 in SHR after 3 weeks of high sodium intake (8% Na ϩ ) caused a long-lasting decrease in SBP. The effect was present at 8 hours (⌬SBP 34Ϯ2 mm Hg), persisted at 24 hours (⌬SBP 29Ϯ1 mm Hg), and disappeared at 48 hours after the injection. The hypotension was not associated with changes in heart rate, urinary excretion of water and electrolytes, and plasma renin activity, whereas renal denervation did not affect the decrease in SBP. A more pronounced decrease in SBP (49Ϯ3 mm Hg at 8 hours) was observed with 100 ng RU28318. This dose of the antagonist was without effect after subcutaneous administration. Key Words: brain Ⅲ mineralocorticoids Ⅲ rats, inbred SHR Ⅲ sodium Ⅲ rats, inbred WKY S everal lines of evidence suggest that brain mineralocorticoid receptors (MRs) are involved in blood pressure control in hypertension induced by mineralocorticoids but also appear to play a role in cardiovascular control in normotensive animals. [1][2][3][4] In normotensive Wistar rats, we recently showed that selective blockade of brain MRs induced a long-lasting decrease in blood pressure associated with increased diuresis and augmented urinary excretion of electrolytes. 4 The involvement of brain MRs in hypertension was demonstrated in deoxycorticosterone (DOCA)-salt rats as well as in genetic hypertension in Dahl salt-sensitive rats. Intracerebroventricular (ICV) infusion of an MR antagonist inhibited the rise in blood pressure induced by DOCA-salt as well as the development of salt-dependent hypertension in Dahl salt-sensitive rats. 2,5 For spontaneously hypertensive rats (SHR), data are lacking regarding a role of brain MRs in the development or maintenance of hypertension, except for a brief report suggesting refractoriness to high doses of an MR antagonist administered ICV in adult SHR. 6 The pathophysiology of the development of hypertension in SHR so far has not been resolved. However, evidence is substantial for a role of brain mechanisms that cause an early increase in sympathetic nervous activity. 7-9 SHR show enhanced pressor responses to a v...

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Involvement of Brain Mineralocorticoid Receptor in Salt-Enhanced Hypertension in Spontaneously Hypertensive Rats

et al. 2001

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“…The narrow and lipid-depleted zonae glomerulosae of the fish protein + 1 % salinefed rats suggests that these animals have been secreting extra quantities of aldosterone, specifically. In this connection, the author 26 and others [27][28][29] have shown that plasma renin levels are low in SHR while circulating aldosterone levels are elevated and treatment of adrenalectomized SHR with aldosterone will restore their high blood pressure.…”

Section: Pathologymentioning

confidence: 96%

Low protein fish vs low protein animal diet enhances the propensity for stroke in stroke-prone/SHR.

Wexler¹

1983

Stroke

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SUMMARY Weanling male and female, stroke-prone, spontaneously hypertensive rats (SHR/SP) were fed: 1) regular commercial rat chow, 2) low protein fish diet, 3) low protein fish diet +1% saline, 4) low protein animal diet, and 5) low protein animal diet + 1 % saline. The blood pressure of all of the SHR/SP rose rapidly reaching 240 mmHg at 90 days of age; blood pressure of low protein fish diet +1% saline-fed SHR/SP rose most rapidly, reaching levels ranging from 258 to 300 mmHg. All of these animals developed acute strokes by 90 days of age; none of the other diet-fed SHR/SP manifested cerebral damage. The protein poor diets prevented normal growth, caused hypogonadism, and severely reduced pituitary and adrenal gland weights. The low protein diets were stressful causing significantly increased secretion of adrenocorticotrophic hormone and marked increases in triglyceride, free fatty acid, cholesterol, glucose, and B.U.N, levels. The mixed hemorrhagic-thrombogenic cerebral lesions occurred ipsilaterally in the parietal lobe, involved basal ganglia, and appeared in areas of brain tissue nourished by the middle cerebral artery. It is concluded that the inclusion of 1% saline drinking water with a low protein diet offish tissue origin specifically, was synergistic in enhancing the propensity of SHR/SP rats to develop their geneticallyprogrammed hypertension and stroke.

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“…Similarly, animal models that either lack aldosterone (adrenalectomized Sprague-Dawley rats) or are resistant to aldosterone actions (Wistar-Furth rats) are characterized by resistance to remnant nephropathy [36,[38][39][40][41]. If aldosterone is reinstituted via an infusion, it markedly increases the blood pressure in adrenalectomized spontaneously hypertensive rats [42], induces lesions of malignant nephrosclerosis in the deoxycorticosterone acetate-salt hypertensive rat model [43], and restores proteinuria and glomerulosclerosis in remnant rats treated with losartan and enalapril to an extent similar to that seen in untreated remnant rats [44]. Rocha et al [45•] concluded that spontaneously hypertensive strokeprone rats (SHR-SPs) receiving the aldosterone antagonist, spironolactone, for 3 to 4 weeks had similar blood pressure profiles but fewer nephrosclerotic histologic lesions and less proteinuria than the placebo group.…”

Section: Aldosterone Synthesis and Receptorsmentioning

confidence: 99%

RAAS escape: A real clinical entity that may be important in the progression of cardiovascular and renal disease

Lakkis¹,

Lü²,

Weir

2003

Current Science Inc

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Interruption of the renin-angiotensin-aldosterone system (RAAS) at different levels is target-organ protective in several disease states; however, complete blockade is unlikely to be achieved due to escape mechanisms whenever blockade is attempted, incomplete knowledge of the role of all elements of the RAAS, and lack of pharmacotherapy against some elements that have been shown to contribute to disease states. Aldosterone has been overlooked as a mediator of RAAS escape and a key factor in target-organ injury despite the use of available RAAS blockers. Aldosterone is thought to play a role in the development of hypertension, alteration in vascular structure, vascular smooth muscle hypertrophy, endothelial dysfunction, structural renal injury, proteinuria, left ventricular remodeling, collagen synthesis, and myocardial fibrosis. Aldosterone receptor antagonists have been shown to antagonize all these effects in experimental models. Clinical trials with aldosterone antagonists showed an improvement in survival and left ventricular mass index in patients with congestive heart failure, and a reduction in urinary protein excretion and left ventricular mass index in patients with type 2 diabetes and early nephropathy who developed aldosterone synthesis escape. Consequently, aldosterone receptor antagonists may have specific benefits for reducing target-organ injury, particularly if there is evidence of RAAS escape.

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The Role of Aldosterone in the Development of Hypertension in Spontaneously Hypertensive Rats*

Cited by 30 publications

References 20 publications

Involvement of Brain Mineralocorticoid Receptor in Salt-Enhanced Hypertension in Spontaneously Hypertensive Rats

Involvement of Brain Mineralocorticoid Receptor in Salt-Enhanced Hypertension in Spontaneously Hypertensive Rats

Low protein fish vs low protein animal diet enhances the propensity for stroke in stroke-prone/SHR.

RAAS escape: A real clinical entity that may be important in the progression of cardiovascular and renal disease

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