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(Hypertension. 1999;33:232-237.)
© 1999 American Heart Association, Inc.

Scientific Contribution

Role of Aldosterone in Renal Vascular Injury in Stroke-Prone Hypertensive Rats

Ricardo Rocha; Praveen N. Chander; Andrea Zuckerman; Charles T. Stier, Jr.

Correspondence to Charles T. Stier, Jr., PhD, Department of Pharmacology, Basic Science Building, New York Medical College, Valhalla, NY 10595. E-mail Charles_Stier{at}NYMC.edu

	Abstract

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Abstract—Stroke-prone spontaneously hypertensive rats (SHRSP) on 1% NaCl drinking solution and Stroke-Prone Rodent Diet develop severe hypertension and glomerular and vascular lesions characteristic of thrombotic microangiopathy seen in malignant nephrosclerosis. We recently reported that spironolactone, a mineralocorticoid receptor antagonist, markedly reduced proteinuria and malignant nephrosclerotic lesions in these animals. This observation, together with our previous findings that angiotensin-converting enzyme inhibitors prevent the development of vascular damage, suggests that mineralocorticoids, as part of the renin-angiotensin-aldosterone system, play a pathophysiological role in this model. In the present study, we examined whether chronic (2-week) infusion of aldosterone can reverse the renal vascular protective effects of captopril in SHRSP. SHRSP received vehicle (n=8); captopril alone (50 mg · kg^-1 · d^-1, orally) (n=10); aldosterone infusion alone (40 µg · kg^-1 · d^-1, SC) (n=7); or captopril and aldosterone at 20 (n=6) or 40 (n=7) µg · kg^-1 · d^-1. Systolic blood pressure was markedly elevated in all groups. Vehicle- and aldosterone-infused SHRSP developed severe proteinuria and comparable degrees of renal injury (21±3% and 29±3%, respectively) manifested as thrombotic and proliferative lesions in the arterioles and glomeruli. Captopril treatment reduced plasma aldosterone levels concomitant with marked reductions in proteinuria and the absence of histologic lesions of malignant nephrosclerosis. Aldosterone substitution at 20 or 40 µg · kg^-1 · d^-1 in captopril-treated SHRSP resulted in the development of severe renal lesions (16±3% and 21±2%, respectively) and proteinuria comparable with that observed in SHRSP given either aldosterone or vehicle alone. These findings support a major role for aldosterone in the development of malignant nephrosclerosis in saline-drinking SHRSP, independent of the effects of blood pressure.

Key Words: hypertension • kidney • malignant nephrosclerosis • captopril • aldosterone

	Introduction

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The participation of the renin-angiotensin-aldosterone system (RAAS) in the development of hypertensive vascular injury has been widely demonstrated.¹ Numerous studies with angiotensin-converting enzyme (ACE) inhibitors and with angiotensin (Ang) II receptor antagonists have clearly identified Ang II as a major factor responsible for the development of end-organ damage in hypertensive vascular disease. However, mineralocorticoids may also play an important role, because animals with deoxycorticosterone acetate (DOCA)-salt hypertension typically develop severe vascular pathology, and resultant malignant nephrosclerosis, myocardial necrosis, and stroke,^{2 3 4 5} despite low levels of plasma renin activity.^{2 5 6} The renal lesions that develop in DOCA-salt hypertensive rats are characterized by fibrinoid necrosis of blood vessels and proliferative arteriopathy^{2 3 4} and are very similar to those seen in stroke-prone spontaneously hypertensive rats (SHRSP) receiving a high sodium chloride diet^{7 8 9 10 11} and in rats with Ang II-salt–induced hypertension.¹² We have shown that chronic administration of agents that interfere with the formation or actions of Ang II will prevent the development of malignant nephrosclerosis and stroke in saline-drinking SHRSP.^{7 8 9} Because Ang II stimulates the synthesis and release of aldosterone,¹³ we recently investigated whether endogenous mineralocorticoids contribute to the development of vascular injury in these rats. We found that, similar to our findings with ACE inhibitors and Ang II receptor antagonists, blockade of the mineralocorticoid receptor (MR) with spironolactone markedly attenuated the development of vascular injury and provided end-organ protection in the absence of reductions in arterial blood pressure.¹⁴ These observations are consistent with a major role for endogenous mineralocorticoids as hormonal, or local, mediators of vascular injury in SHRSP.

Although the beneficial effects of ACE inhibitors typically have been attributed to reductions in the vascular actions of Ang II, these agents can also inhibit aldosterone release.^{15 16 17} In the present study, we evaluated the hypothesis that the renal vascular protective effects observed with ACE inhibitor therapy in SHRSP are the consequence of interference with endogenous aldosterone formation. If the above-mentioned hypothesis is true, chronic exogenous infusion of aldosterone should reverse the renal protective effect of ACE inhibition. If not, the vascular protective effect provided by ACE inhibition should be maintained despite exogenous administration of aldosterone. To evaluate these possibilities, we performed experiments in saline-drinking SHRSP chronically treated with captopril under experimental conditions that afford complete protection against renal microvascular injury as reported previously by us.⁷

	Methods

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Animals
Studies were conducted in accordance with institutional guidelines with use of male SHRSP/A3N (generations F 75 to 78), n=38, from our local colony. All animals were housed in a room lighted 12 hours per day at an ambient temperature of 22±1°C in the Animal Care Facility at New York Medical College. Rats were weaned at 4 weeks of age and allowed free access to Purina Laboratory Chow 5001 (Ralston Purina Inc.) and tap water until the initiation of the experiment.

Protocol
SHRSP were housed in individual metabolic cages beginning at 7 weeks of age. All animals were given Stroke-Prone Rodent Diet (Catalog No. 39-288, Zeigler Bros Inc, Gardners, PA) and 1% NaCl drinking solution ad libitum starting at 7.5 weeks of age. At 8.2 weeks of age, all SHRSP received 1 of 4 dosing protocols: (1) an infusion of the vehicle (0.5% ethanol) used to dissolve aldosterone with no captopril (n=8), (2) captopril alone (50 mg · kg^-1 · d^-1, orally; n=10), (3) aldosterone infusion alone (40 µg · kg^-1 · d^-1, SC) with no captopril (n=7), or (4) combined dosing with captopril and infusion of aldosterone at 20 (n=6) or 40 µg · kg^-1 · d^-1 (n=7). Aldosterone (d-aldosterone) and captopril were purchased from Sigma Chemical Co. Alzet osmotic minipumps (model 2002 Alza Co.) containing aldosterone or vehicle were implanted beneath the skin at the nape of the neck in SHRSP receiving inhalatory anesthesia with isofluorane (Ohmeda Caribe Inc.). The concentration of aldosterone used to fill the pumps was calculated based on the mean pump rate provided by the manufacturer, the body weight of the animals, and the dose intended. The doses of aldosterone were selected because they are similar to the minimal dose shown to significantly enhance plasma aldosterone levels in saline-drinking rats¹⁸ and are similar to or lower than those used by other investigators to induce the development of renal and cardiovascular injury in rats.^{17 19 20}

Animals were handled and weighed daily. Twenty-four-hour fluid and food intake, and urine output were measured before and after surgery and each week thereafter. Urine samples were collected at different time points for the assessment of proteinuria and electrolyte excretion. Systolic blood pressure was measured each week. After 2 weeks of treatment, animals were decapitated, trunk blood was collected into chilled tubes containing EDTA, and kidneys were removed, blotted dry, and weighed immediately. Kidney sections were stored in fixative and later processed for light microscopic evaluation.

Assays and Analyses
Systolic blood pressure of awake animals was measured by tail-cuff plethysmography with a Natsume KN-210 manometer and tachometer (Peninsula Laboratories Inc.). Rats were warmed at 37°C for 10 minutes and allowed to rest quietly in a Lucite chamber before measurement of blood pressure. Urinary protein concentration was determined by the sulfosalicylic acid turbidity method and urinary protein excretion was calculated as the product of the urinary concentration times the urine flow rate. Plasma aldosterone concentration was determined by radioimmunoassay (Diagnostic Products Co.).

Histology
Kidneys were preserved in 10% phosphate-buffered formalin. Coronal sections of kidney were cut at 3 to 4 mm, and at least 3 to 4 such blocks were sampled and embedded in paraffin. Histologic sections (2 to 3 µm) were stained with hematoxylin and eosin and examined by light microscopy at x20 and x40 in a blinded fashion for lesions, as previously described.^{7 8 9} Glomerular damage was categorized as ischemic or thrombotic. Ischemic lesions were defined as retraction of glomerular capillary tufts with or without appreciable mesangiolysis. Glomerular thrombotic lesions were defined as segmental to global fibrinoid necrosis, focal thrombosis of glomerular capillaries, often accompanied by swelling and occasionally by proliferation of intracapillary (endothelial and mesangial) and extracapillary cells (crescents), and edematous expansion of mesangium without significant hypercellularity. The number of glomeruli exhibiting lesions in either category was enumerated from each kidney and was expressed as a percentage of the total number of glomeruli present per midcoronal section (mean±SE=218±5 glomeruli per animal; range=167 to 274 glomeruli). Vascular damage was assessed by counting the total number of arterial and arteriolar profiles in the same midcoronal section showing thrombotic and/or proliferative arteriopathy. Vascular thrombotic lesions were defined as mural fibrinoid necrosis, extravasation of red blood cells, and luminal and mural thrombosis. Proliferative arteriopathy was characterized by proliferation of markedly swollen cells with large round to ovoid vesicular nuclei surrounded by mucinous extracellular matrix ("onion skinning") often resulting in nodular thickening. Vascular damage was expressed as the number of arteries and arterioles with lesions per 100 glomeruli and was calculated by dividing the total number of vascular profiles with lesions by the total number of glomeruli in the same midcoronal section, and multiplied by 100.

Statistical Analysis
Significant effects with respect to treatment and time were determined by two-way ANOVA. Data with only one grouping variable were analyzed statistically by unpaired Student's t tests or one-way ANOVA followed by post hoc analysis with use of the Newman-Keuls multiple comparison test. Data were analyzed with use of version 2.01 of the GraphPad Prism statistical software package obtained from GraphPad Software Inc. A value of P<0.05 was considered to be statistically significant. Data are reported as mean±SEM.

	Results

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All groups of SHRSP demonstrated a progressive increase in systolic blood pressure with age and were severely hypertensive 2 weeks after implantation of pumps (Figure 1). No significant differences in blood pressure were found up until 10.5 weeks of age. At that time, the blood pressure of the group infused with aldosterone alone was higher than that of the groups treated with captopril alone or captopril and aldosterone at 20 µg · kg^-1 · d^-1. No significant differences were found among the other groups.

View larger version (28K): [in this window] [in a new window]   Figure 1. Line graphs showing SBP in stroke-prone, spontaneously hypertensive rats receiving captopril or vehicle treatment since 8.2 weeks of age. At the same time, Alzet osmotic minipumps containing 0.5% ethanol or aldosterone solution prepared to administer aldosterone at 20 µg · kg-1 · d-1 (ALDO 20) or 40 µg · kg-1 · d-1 (ALDO 40) were implanted subcutaneously at the nape of the neck. All animals were maintained on a 1% NaCl drinking solution and Stroke-Prone Rodent Diet and euthanatized 2 weeks later. **P<0.01 compared with captopril; #P<0.05 compared with captopril+ALDO 20 at 10.5 weeks of age. Values are mean±SEM. SBP indicates systolic arterial blood pressure; ALDO, aldosterone.

Figure 2 shows data obtained at the end of the 2-week treatment period. Captopril reduced endogenous aldosterone levels (Figure 2A) and prevented the development of proteinuria (Figure 2B) compared with vehicle-control SHRSP. Histopathological analysis of kidneys from captopril-treated SHRSP showed neither glomerular (Figure 2C) nor renal vascular lesions (Figure 2D). Plasma aldosterone levels in aldosterone-infused animals were elevated relative to the vehicle controls, but were not significantly different from those observed in captopril-treated SHRSP receiving aldosterone infusion at 20 or 40 µg · kg^-1 · d^-1 (Figure 2A). SHRSP infused with vehicle or aldosterone alone developed severe proteinuria (Figure 2B) and similar degrees of glomerular and renal vascular damage (Figure 2C, D). Despite concurrent ACE inhibitor therapy, captopril-treated SHRSP infused with aldosterone at either 20 or 40 µg · kg^-1 · d^-1 developed levels of proteinuria and renal injury similar to SHRSP receiving vehicle or aldosterone alone. Histopathological analysis of the kidneys revealed prominent glomerular and vascular lesions of thrombotic microangiopathy characteristic of malignant nephrosclerosis in captopril plus low- or high-dose aldosterone-infused SHRSP that were similar to those in vehicle- or aldosterone-infused SHRSP (Figure 3 top, bottom). Vascular lesions were confined primarily to the renal cortex and affected medium-sized to small interlobular arteries as well as arterioles. Glomeruli revealed predominantly ischemic retraction of capillary tufts with or without mesangiolysis. These were probably secondary to preglomerular vascular occlusions. In contrast to these changes, captopril-treated SHRSP exhibited absence of both vascular and glomerular lesions (Figure 3 middle). Commensurate with the development of malignant nephrosclerosis, animals in all groups, with the exception of captopril alone, showed progressive decreases in food intake and body weight, and the development of polyuria and polydipsia (data not shown) at the end of the experiment.

View larger version (43K): [in this window] [in a new window]   Figure 2. Bar graphs showing plasma aldosterone (A), urinary protein excretion (B), glomerular lesions (C), and renal vascular lesions (D), in captopril-treated, saline-drinking stroke-prone spontaneously hypertensive rats at the end of 2 weeks of treatment with aldosterone or vehicle. Captopril or vehicle treatment was started at 8.2 weeks of age. At the same time, Alzet osmotic minipumps containing 0.5% ethanol or aldosterone solution prepared to administer aldosterone at 20 µg · kg-1 · d-1 (ALDO 20) or 40 µg · kg-1 · d-1 (ALDO 40) were implanted subcutaneously at the nape of the neck. Animals were euthanatized after 2 weeks of treatment. **P<0.01, ***P<0.001 compared with captopril; ##P<0.01, ###P<0.001 compared with vehicle. Values are mean±SEM. capt indicates captopril; ALDO, aldosterone.

View larger version (100K): [in this window] [in a new window]   Figure 3. Representative photomicrographs (hematoxylin and eosin, x130) of renal cortex from saline-drinking SHRSP after 2 weeks of treatment with (top) vehicle, (middle) captopril plus vehicle, and (bottom) captopril plus aldosterone at 40 µg · kg-1 · d-1. (top) Typical lesions of malignant nephrosclerosis consisting of ischemic or thrombotic glomeruli (large arrows), extensive mural fibrinoid deposits in microvessels (large arrowheads) focally associated with fragmented extravasated erythrocytes (small arrowhead) are present in vehicle-treated animals. (middle) After captopril treatment glomerular or vascular pathology virtually disappeared. (bottom) Captopril plus aldosterone leads to reversal of protection by captopril and malignant nephrosclerotic lesions comparable with vehicle-treated animals (top) can be seen again. Thrombotic glomeruli (large arrows) and ischemic glomeruli (small arrows) proliferative arteriopathy with fragmented extravasated erythrocytes (arrowheads).

	Discussion

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We previously reported that agents that interfere with the formation or actions of Ang II will prevent the development of vascular injury in saline-drinking SHRSP.^{7 8 9} More recently we demonstrated that substantial vascular protection can also be achieved when these animals are chronically treated with the MR antagonist spironolactone.¹⁴ Because Ang II stimulates the synthesis and release of aldosterone, the above-mentioned observations suggest that aldosterone could play a pathophysiological role in saline-drinking SHRSP subsequent to activation of the RAAS. The present studies were performed to further evaluate this possibility. We found that aldosterone infusion could completely reverse the ability of ACE inhibitor therapy with captopril to protect against the development of proteinuria and renal vascular and glomerular lesions in these animals. This observation is consistent with a central role for aldosterone in the evolution of malignant nephrosclerotic injury in SHRSP and implicates activation of the RAAS as the initiating event.

Greene and coworkers¹⁷ have also evaluated the ability of aldosterone to reverse the renal protective effects of blockade of the RAAS in the 5/6 nephrectomy model of hypertension and glomerulosclerosis. In those studies, interruption of the RAAS was associated with substantial reductions in plasma aldosterone levels, systolic blood pressure, proteinuria, and renal lesions which were reversed when aldosterone was infused concurrently. In a second set of studies, animals with remnant kidneys were treated with spironolactone. Whereas proteinuria diminished at 2 weeks, no differences were noted in urinary protein excretion and the number of sclerotic glomeruli at 4 weeks. Blood pressure showed a slight but significant lowering at this time. Unlike these observations, we have found that chronic treatment with spironolactone markedly protects SHRSP against the development of renal injury in the absence of blood pressure reduction.¹⁴ The explanation for the discrepancy in the degree of renal protection seen with mineralocorticoid receptor antagonism between these models is not clear but may relate to differences in the types of lesions that develop. Rats with remnant kidneys develop glomerular lesions of focal glomerulosclerosis, whereas SHRSP primarily develop vascular lesions of thrombotic microangiopathy. In TGR(mREN)27 rats, a model of severe hypertension that closely resembles the SHRSP, a recent preliminary study also found that spironolactone greatly prolongs survival without lowering blood pressure.²¹

In our model of malignant hypertension, aldosterone completely restores renal lesion development in captopril-treated SHRSP in the absence of major changes in blood pressure. Systolic blood pressure in captopril-treated SHRSP receiving aldosterone at either 20 or 40 µg · kg^-1 · d^-1 was not significantly different from the group treated with captopril alone, yet they developed extensive renal damage. This observation suggests that the vasculotoxic mechanism for aldosterone is independent of alterations in blood pressure. These results are consistent with our previous observations, and they support the hypothesis that severe elevation of blood pressure alone is not sufficient for development of vascular injury but also requires the concurrent participation of hormonal or local factors, with aldosterone as a major participant. Whether aldosterone can induce vascular injury in the absence of hypertension in SHRSP remains to be determined. However, intracerebroventricular infusion of a mineralocorticoid receptor antagonist in aldosterone-salt hypertensive rats blocked arterial blood pressure elevation, but not cardiac hypertrophy or fibrosis.²² This observation suggests that concurrent hypertension may not be an absolute requirement for aldosterone and high salt to induce vascular damage. Whether a similar result can be observed in the microvasculature of the kidney remains to be established. Consonant with renal damage, many of the SHRSP receiving aldosterone, captopril plus aldosterone, or vehicle alone also exhibited clinical signs of stroke during the 2-week period of study, whereas none of the SHRSP receiving captopril treatment alone showed signs of stroke. These findings confirm the observation of MacLeod and collaborators¹⁶ that aldosterone can reverse the beneficial effects of captopril treatment against development of stroke in SHRSP. In addition to these findings in the brain, and our present observations on the kidney, several reports have implicated aldosterone in the development of pathophysiological changes in the aorta^{20 23} and the heart.^{19 23 24 25 26} Together, these observations suggest that the pathophysiological role of aldosterone can be elicited in several different target organs in hypertensive vascular disease.

The beneficial effects of ACE inhibitor therapy have been related to reductions in the vascular actions of Ang II. However, in the present study we observed complete restoration of renal injury in saline-drinking SHRSP receiving an exogenous infusion of aldosterone, despite continued ACE inhibitor therapy. This effect was observed with doses of either 20 or 40 µg · kg^-1 · d^-1, and was associated with the reestablishment of elevated plasma aldosterone levels. The protection obtained with captopril treatment, in turn, was associated with reduced plasma aldosterone levels. Previous experiments have also demonstrated a marked lowering of plasma aldosterone levels by captopril in SHRSP.¹⁶ These observations suggest that the beneficial effect of ACE inhibitors in saline-drinking SHRSP is related to the inhibitory effect of these agents on aldosterone release. However, in patients with cardiac failure, this inhibitory effect on aldosterone is not long-lasting because restoration of hyperaldosteronism occurs with time.²⁷ This phenomenon has been referred to as aldosterone "escape" and has provided the basis for the current Randomized Aldactone Evaluation Study (RALES) to examine the effect of combining an aldosterone receptor antagonist with ACE inhibitor therapy.²⁸ Whether aldosterone plays a pathophysiological role in other clinical settings remains to be established.

We previously found that spironolactone offers marked protection against renal and cerebral vascular injury in SHRSP independent of changes in SBR or water and electrolyte excretion.¹⁴ Enhanced expression of mRNA for the MR and/or aldosterone synthase has been demonstrated in blood vessels from SHRSP.²⁹ These observations, taken together with our present findings, support a direct pathological effect of aldosterone at nonepithelial sites which is unrelated to alterations in blood pressure. However, further investigations are necessary to elucidate the actual mechanisms by which aldosterone induces vascular pathology in saline-drinking SHRSP.

In summary, captopril treatment reduces plasma aldosterone levels, preventing the development of proteinuria and renal vascular and glomerular injury in saline-drinking SHRSP. These effects can be fully reversed by chronic exogenous administration of aldosterone and are independent of major changes in arterial blood pressure. The results of the present study strongly support a toxic effect of aldosterone at the level of the renal microvasculature, which seems to be independent of other components of the RAAS.

	Acknowledgments

 
This work was supported by US Public Health Service Grant HL-35522. The authors thank Jessica Burstein, Kavita Khanna, and James Cho for technical assistance and Saramma George-Mathew for expert processing of tissue for histology.

	Footnotes

 
Departments of Pharmacology (R.R., C.T.S.), Pathology (P.N.C.), and Pediatrics (A.Z.) New York Medical College, Valhalla, NY 10595.

Received September 17, 1998; first decision October 19, 1998; accepted October 29, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Laragh JH, Sealey JE. The renin-angiotensin-aldosterone system in hypertensive disorders: A key to two forms of arteriolar contriction and a possible clue to risk of vascular injury (heart attack and stroke) and prognosis. In Laragh JH, Brenner BM (eds). Hypertension: Pathophysiology, Diagnosis, and Management. New York, Raven Press Publishers, 1990, pp 1329–1348.

2. Gavras H, Brunner HR, Laragh JH, Vaughan ED Jr, Koss M, Cote LJ, Gavras I. Malignant hypertension resulting from deoxycorticosterone acetate and salt excess. Role of renin and sodium in vascular changes. Circ Res. 1975;36:300–309.[Abstract/Free Full Text]

3. Dworkin LD, Hostetter TH, Rennke HG, Brenner BM. Hemodynamic basis for glomerular injury in rats with desoxycorticosterone-salt hypertension. J Clin Invest. 1984;73:1448–1461.

4. Hill GS, Heptinstall RH. Steroid-induced hypertension in the rat. Am J Pathol. 1968;52:1–39.[Medline] [Order article via Infotrieve]

5. Xu Y, Arnal J-F, Hinglais N, Appay M-D, Laboulandine I, Bariety J, Michel J-B. Renal hypertensive angiopathy: comparison between chronic NO suppression and DOCA-salt intoxication. Am J Hypertens. 1995;8:167–176.[Medline] [Order article via Infotrieve]

6. Schiffrin EL, Thome FS, Genest J. Vascular angiotensin II receptors in renal and DOCA-salt hypertensive rats. Hypertension. 1983;5(supp V):V16–V21.

7. Stier CT Jr, Chander PN, Gutstein WH, Levine S, Itskovitz HD. Therapeutic benefit of captopril in salt-loaded stroke-prone spontaneously hypertensive rats is independent of hypotensive effect. Am J Hypertens.. 1991;4:680–687.[Medline] [Order article via Infotrieve]

8. Stier CT Jr, Benter IF, Ahmad S, Zuo H, Selig N, Roethel S, Levine S, Itskovitz HD. Enalapril prevents stroke and kidney dysfunction in salt-loaded stroke-prone spontaneously hypertensive rats. Hypertension.. 1989;13:115–121.[Abstract/Free Full Text]

9. Stier CT Jr, Adler LA, Levine S, Chander PN. Stroke prevention by losartan in stroke-prone spontaneously hypertensive rats. J Hypertens. 1993;11(supp 3):S37–S42.

10. Vacher E, Fornes P, Domergue V, Richer C, Bruneval P, Giudicelli J-F. Quinapril prevents stroke both during and after the treatment period in stroke-prone spontaneously hypertensive rats. Am J Hypertens.. 1993;6:951–959.[Medline] [Order article via Infotrieve]

11. Camargo MJF, von Lutterotti N, Campbell WG Jr, Pecker MS, James GD, Timmermans PB, Laragh JH. Control of blood pressure and end-organ damage in maturing salt-loaded stroke-prone spontaneously hypertensive rats by oral angiotensin II receptor blockade. J Hypertens. 1993;11:31–40.[Medline] [Order article via Infotrieve]

12. Mistry M, Muirhead EE, Yamaguchi Y, Nasjletti A. Renal function in rats with angiotensin II-salt-induced hypertension: effect of thromboxane synthesis inhibition and receptor blockade. J Hypertens. 1990;8:75–83.[Medline] [Order article via Infotrieve]

13. Quinn SJ, Williams GH. Regulation of aldosterone secretion. Annu Rev Physiol. 1988;50:409–426.[Medline] [Order article via Infotrieve]

14. Rocha R, Chander PN, Khanna K, Zuckerman A, Stier CT Jr. Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension.. 1998;31:451–458.[Abstract/Free Full Text]

15. Reams GP, Bauer JH. Effect of enalapril in subjects with hypertension associated with moderate to severe renal dysfunction. Arch Intern Med. 1986;146:2145–2148.[Abstract/Free Full Text]

16. MacLeod AB, Vasdev S, Smeda JS. The role of blood pressure and aldosterone in the production of hemorrhagic stroke in captopril-treated hypertensive rats. Stroke. 1997;28:1821–1829.[Abstract/Free Full Text]

17. Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Invest. 1996;98:1063–1068.[Medline] [Order article via Infotrieve]

18. Garwitz ET, Jones AW. Aldosterone infusion into the rat and dose-dependent changes in blood pressure and arterial ionic transport. Hypertension. 1982;4:374–381.[Abstract/Free Full Text]

19. Brilla CG, Weber KT. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med. 1992;120:893–901.[Medline] [Order article via Infotrieve]

20. Benetos A, Lacolley P, Safar ME. Prevention of aortic fibrosis by spironolactone in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol. 1997;17:1152–1156.[Abstract/Free Full Text]

21. Diz DI,, Chappell MC, Bosch SM, Westwood B, Ganten D, Ferrario CM, Dean RH. Spironolactone increases survival in mREN2(27) transgenic rats with malignant hypertension. Am J Hypertens. 1998;11(4, part 2):34A.

22. Young M, Head G, Funder J. Determinants of cardiac fibrosis in experimental hypermineralocorticoid states. Am J Physiol. 1995;32:E657–E662.

23. Sun Y, Ramires FJA, Weber KT. Fibrosis of atria and great vessels in response to angiotensin II or aldosterone infusion. Cardiovasc Res. 1997;35:138–147.[Abstract/Free Full Text]

24. Robert V, Silvestre JS, Charlemagne D, Sabri A, Trouve P, Wassef M, Swynghedauw B, Delcayre C. Biological determinants of aldosterone-induced cardiac fibrosis in rats. Hypertension. 1995;26:971–978.[Abstract/Free Full Text]

25. Young MJ, Funder JW. The renin-angiotensin-aldosterone system in experimental mineralocorticoid-salt-induced cardiac fibrosis. Am J Physiol. 1996;271:E883–E888.[Free Full Text]

26. Nicoletti A, Heudes D, Hinglais N, Appay MD, Philippe M, Sassy-Prigent C, Bariety J, Michel JB. Left ventricular fibrosis in renovascular hypertensive rats. Effect of losartan and spironolactone. Hypertension. 1995;26:101–111.[Abstract/Free Full Text]

27. Staessen J, Lijnen P, Fagard R, Verschueren LJ, Amery A. Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol. 1981;91:457–465.[Abstract/Free Full Text]

28. Pitt B. ACE inhibitor co-therapy in patients with heart failure: rationale for the Randomized Aldactone Evaluation Study (RALES). Eur Heart J. 1995;16(suppl N):107–110.

29. Takeda Y, Miyamori I, Inaba S, Furukawa K, Hatakeyama H, Yoneda T, Mabuchi H, Takeda R. Vascular aldosterone in genetically hypertensive rats. Hypertension. 1997;29:45–48.[Abstract/Free Full Text]

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				J. M. C. Connell, S. M. MacKenzie, E. M. Freel, R. Fraser, and E. Davies A Lifetime of Aldosterone Excess: Long-Term Consequences of Altered Regulation of Aldosterone Production for Cardiovascular Function Endocr. Rev., April 1, 2008; 29(2): 133 - 154. [Abstract] [Full Text] [PDF]

				D. G. Romero, M. W. Plonczynski, B. L. Welsh, C. E. Gomez-Sanchez, M. Y. Zhou, and E. P. Gomez-Sanchez Gene expression profile in rat adrenal zona glomerulosa cells stimulated with aldosterone secretagogues Physiol Genomics, December 19, 2007; 32(1): 117 - 127. [Abstract] [Full Text] [PDF]

				J. C. Sullivan, L. Semprun-Prieto, E. I. Boesen, D. M. Pollock, and J. S. Pollock Sex and sex hormones influence the development of albuminuria and renal macrophage infiltration in spontaneously hypertensive rats Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1573 - R1579. [Abstract] [Full Text] [PDF]

				A. Zhang, Z. Jia, X. Guo, and T. Yang Aldosterone induces epithelial-mesenchymal transition via ROS of mitochondrial origin Am J Physiol Renal Physiol, September 1, 2007; 293(3): F723 - F731. [Abstract] [Full Text] [PDF]

				N. A. Bobadilla and G. Gamba New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone Am J Physiol Renal Physiol, July 1, 2007; 293(1): F2 - F9. [Abstract] [Full Text] [PDF]

				J. M. Mejia-Vilet, V. Ramirez, C. Cruz, N. Uribe, G. Gamba, and N. A. Bobadilla Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone Am J Physiol Renal Physiol, July 1, 2007; 293(1): F78 - F86. [Abstract] [Full Text] [PDF]

				A. S. Bomback and P. J. Klemmer Association of low-grade urinary albumin excretion with left ventricular hypertrophy in the general population: a reply Nephrol. Dial. Transplant., June 1, 2007; 22(6): 1787 - 1788. [Full Text] [PDF]

				K. Hayashi, S. Wakino, N. Sugano, Y. Ozawa, K. Homma, and T. Saruta Ca2+ Channel Subtypes and Pharmacology in the Kidney Circ. Res., February 16, 2007; 100(3): 342 - 353. [Abstract] [Full Text] [PDF]

				J. Perez-Rojas, J. A. Blanco, C. Cruz, J. Trujillo, V. S. Vaidya, N. Uribe, J. V. Bonventre, G. Gamba, and N. A. Bobadilla Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity Am J Physiol Renal Physiol, January 1, 2007; 292(1): F131 - F139. [Abstract] [Full Text] [PDF]

				J. Lepenies and M. Quinkler MR blockade in patients with chronic renal disease--not the more the merrier, but the earlier the better Nephrol. Dial. Transplant., November 1, 2006; 21(11): 3343 - 3344. [Full Text] [PDF]

				E. Pimenta and D. A. Calhoun Aldosterone, Dietary Salt, and Renal Disease Hypertension, August 1, 2006; 48(2): 209 - 210. [Full Text] [PDF]

				E. Y. M. Lam, J. W. Funder, D. J. Nikolic-Paterson, P. J. Fuller, and M. J. Young Mineralocorticoid Receptor Blockade But Not Steroid Withdrawal Reverses Renal Fibrosis in Deoxycorticosterone/Salt Rats Endocrinology, July 1, 2006; 147(7): 3623 - 3629. [Abstract] [Full Text] [PDF]

				M. P. Ponda and T. H. Hostetter Aldosterone Antagonism in Chronic Kidney Disease Clin. J. Am. Soc. Nephrol., July 1, 2006; 1(4): 668 - 677. [Full Text] [PDF]

				S.-Y. Han, C.-H. Kim, H.-S. Kim, Y.-H. Jee, H.-K. Song, M.-H. Lee, K.-H. Han, H.-K. Kim, Y.-S. Kang, J.-Y. Han, et al. Spironolactone Prevents Diabetic Nephropathy through an Anti-Inflammatory Mechanism in Type 2 Diabetic Rats J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1362 - 1372. [Abstract] [Full Text] [PDF]

				E. L. Schiffrin Effects of Aldosterone on the Vasculature Hypertension, March 1, 2006; 47(3): 312 - 318. [Full Text] [PDF]

				S. Sethi, S. Iida, C. D. Sigmund, and D. D. Heistad Renal Thrombotic Microangiopathy in a Genetic Model of Hypertension in Mice Experimental Biology and Medicine, February 1, 2006; 231(2): 196 - 203. [Abstract] [Full Text] [PDF]

				J. C. Aldigier, T. Kanjanbuch, L.-J. Ma, N. J. Brown, and A. B. Fogo Regression of Existing Glomerulosclerosis by Inhibition of Aldosterone J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3306 - 3314. [Abstract] [Full Text] [PDF]

				J. M. Perez-Rojas, S. Derive, J. A. Blanco, C. Cruz, L. M. de la Maza, G. Gamba, and N. A. Bobadilla Renocortical mRNA expression of vasoactive factors during spironolactone protective effect in chronic cyclosporine nephrotoxicity Am J Physiol Renal Physiol, November 1, 2005; 289(5): F1020 - F1030. [Abstract] [Full Text] [PDF]

				K. Miyata, M. Rahman, T. Shokoji, Y. Nagai, G.-X. Zhang, G.-P. Sun, S. Kimura, T. Yukimura, H. Kiyomoto, M. Kohno, et al. Aldosterone Stimulates Reactive Oxygen Species Production through Activation of NADPH Oxidase in Rat Mesangial Cells J. Am. Soc. Nephrol., October 1, 2005; 16(10): 2906 - 2912. [Abstract] [Full Text] [PDF]

				M. Quinkler, D. Zehnder, K. S. Eardley, J. Lepenies, A. J. Howie, S. V. Hughes, P. Cockwell, M. Hewison, and P. M. Stewart Increased Expression of Mineralocorticoid Effector Mechanisms in Kidney Biopsies of Patients With Heavy Proteinuria Circulation, September 6, 2005; 112(10): 1435 - 1443. [Abstract] [Full Text] [PDF]

				L. Sironi, E. Gianazza, P. Gelosa, U. Guerrini, E. Nobili, A. Gianella, B. Cremonesi, R. Paoletti, and E. Tremoli Rosuvastatin, but not Simvastatin, Provides End-Organ Protection in Stroke-Prone Rats by Antiinflammatory Effects Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 598 - 603. [Abstract] [Full Text] [PDF]

				B. J Barnes and P. A Howard Eplerenone: A Selective Aldosterone Receptor Antagonist for Patients with Heart Failure Ann. Pharmacother., January 1, 2005; 39(1): 68 - 76. [Abstract] [Full Text] [PDF]

				L. Sironi, P. Gelosa, U. Guerrini, C. Banfi, V. Crippa, M. Brioschi, E. Gianazza, E. Nobili, A. Gianella, M. de Gasparo, et al. Anti-Inflammatory Effects of AT1 Receptor Blockade Provide End-Organ Protection in Stroke-Prone Rats Independently from Blood Pressure Fall J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 989 - 995. [Abstract] [Full Text] [PDF]

				E. L. Schiffrin The Many Targets of Aldosterone Hypertension, May 1, 2004; 43(5): 938 - 940. [Full Text] [PDF]

				A. Nishiyama, L. Yao, Y. Nagai, K. Miyata, M. Yoshizumi, S. Kagami, S. Kondo, H. Kiyomoto, T. Shokoji, S. Kimura, et al. Possible Contributions of Reactive Oxygen Species and Mitogen-Activated Protein Kinase to Renal Injury in Aldosterone/Salt-Induced Hypertensive Rats Hypertension, April 1, 2004; 43(4): 841 - 848. [Abstract] [Full Text] [PDF]

				A. D Struthers and T. M MacDonald Review of aldosterone- and angiotensin II-induced target organ damage and prevention Cardiovasc Res, March 1, 2004; 61(4): 663 - 670. [Abstract] [Full Text] [PDF]

				S. Arima, K. Kohagura, H.-L. Xu, A. Sugawara, A. Uruno, F. Satoh, K. Takeuchi, and S. Ito Endothelium-Derived Nitric Oxide Modulates Vascular Action of Aldosterone in Renal Arteriole Hypertension, February 1, 2004; 43(2): 352 - 357. [Abstract] [Full Text] [PDF]

				T.R. Uhrenholt, J. Schjerning, P.B. Hansen, R. Norregaard, B.L. Jensen, G.L. Sorensen, and O. Skott Rapid Inhibition of Vasoconstriction in Renal Afferent Arterioles by Aldosterone Circ. Res., December 12, 2003; 93(12): 1258 - 1266. [Abstract] [Full Text] [PDF]

				R. A. Ahokas, K. J. Warrington, I. C. Gerling, Y. Sun, L. A. Wodi, P. A. Herring, L. Lu, S. K. Bhattacharya, A. E. Postlethwaite, and K. T. Weber Aldosteronism and Peripheral Blood Mononuclear Cell Activation: A Neuroendocrine-Immune Interface Circ. Res., November 14, 2003; 93 (10): e124 - e135. [Abstract] [Full Text] [PDF]

				M. Epstein Aldosterone receptor blockade and the role of eplerenone: evolving perspectives Nephrol. Dial. Transplant., October 1, 2003; 18(10): 1984 - 1992. [Full Text] [PDF]

				B. Pitt, C. T Stier Jr, and S. Rajagopalan Mineralocorticoid receptor blockade: new insights into the mechanism of action in patients with cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 164 - 168. [Abstract] [PDF]

				S. Arima, K. Kohagura, H.-L. Xu, A. Sugawara, T. Abe, F. Satoh, K. Takeuchi, and S. Ito Nongenomic Vascular Action of Aldosterone in the Glomerular Microcirculation J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2255 - 2263. [Abstract] [Full Text] [PDF]

				T. H. Hostetter and H. N. Ibrahim Aldosterone in Chronic Kidney and Cardiac Disease J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2395 - 2401. [Abstract] [Full Text] [PDF]

				P. N. Chander, R. Rocha, J. Ranaudo, G. Singh, A. Zuckerman, and C. T. Stier Jr. Aldosterone Plays a Pivotal Role in the Pathogenesis of Thrombotic Microangiopathy in SHRSP J. Am. Soc. Nephrol., August 1, 2003; 14(8): 1990 - 1997. [Abstract] [Full Text] [PDF]

				Q. Pu, M. F. Neves, A. Virdis, R. M. Touyz, and E. L. Schiffrin Endothelin Antagonism on Aldosterone-Induced Oxidative Stress and Vascular Remodeling Hypertension, July 1, 2003; 42(1): 49 - 55. [Abstract] [Full Text] [PDF]

				H. T. Yu Progression of Chronic Renal Failure Arch Intern Med, June 23, 2003; 163(12): 1417 - 1429. [Abstract] [Full Text] [PDF]

				M. J. Young, L. Moussa, R. Dilley, and J. W. Funder Early Inflammatory Responses in Experimental Cardiac Hypertrophy and Fibrosis: Effects of 11{beta}-Hydroxysteroid Dehydrogenase Inactivation Endocrinology, March 1, 2003; 144(3): 1121 - 1125. [Abstract] [Full Text] [PDF]

				K. A. Griffin, I. Abu-Amarah, M. Picken, and A. K. Bidani Renoprotection by ACE Inhibition or Aldosterone Blockade Is Blood Pressure-Dependent Hypertension, February 1, 2003; 41(2): 201 - 206. [Abstract] [Full Text] [PDF]

				R. Rocha, A. E. Rudolph, G. E. Frierdich, D. A. Nachowiak, B. K. Kekec, E. A. G. Blomme, E. G. McMahon, and J. A. Delyani Aldosterone induces a vascular inflammatory phenotype in the rat heart Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1802 - H1810. [Abstract] [Full Text] [PDF]

				R. C. Campbell, P. Ruggenenti, and G. Remuzzi Halting the Progression of Chronic Nephropathy J. Am. Soc. Nephrol., November 1, 2002; 13(90003): S190 - 195. [Abstract] [Full Text]

				P. Sawathiparnich, S. Kumar, D. E. Vaughan, and N. J. Brown Spironolactone Abolishes the Relationship between Aldosterone and Plasminogen Activator Inhibitor-1 in Humans J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 448 - 452. [Abstract] [Full Text] [PDF]

				D. V. Martinez, R. Rocha, M. Matsumura, E. Oestreicher, M. Ochoa-Maya, W. Roubsanthisuk, G. H. Williams, and G. K. Adler Cardiac Damage Prevention by Eplerenone: Comparison With Low Sodium Diet or Potassium Loading Hypertension, February 1, 2002; 39(2): 614 - 618. [Abstract] [Full Text] [PDF]

				J. H. Pratt, G. J. Eckert, S. Newman, and W. T. Ambrosius Blood Pressure Responses to Small Doses of Amiloride and Spironolactone in Normotensive Subjects Hypertension, November 1, 2001; 38(5): 1124 - 1129. [Abstract] [Full Text] [PDF]

				L. Sironi, E. Tremoli, I. Miller, U. Guerrini, A. M. Calvio, I. Eberini, M. Gemeiner, M. Asdente, R. Paoletti, and E. Gianazza Acute-Phase Proteins Before Cerebral Ischemia in Stroke-Prone Rats : Identification by Proteomics Stroke, March 1, 2001; 32(3): 753 - 760. [Abstract] [Full Text] [PDF]

				A. Fiebeler, F. Schmidt, D. N. Muller, J.-K. Park, R. Dechend, M. Bieringer, E. Shagdarsuren, V. Breu, H. Haller, and F. C. Luft Mineralocorticoid Receptor Affects AP-1 and Nuclear Factor-{{kappa}}B Activation in Angiotensin II-Induced Cardiac Injury Hypertension, February 1, 2001; 37(2): 787 - 793. [Abstract] [Full Text] [PDF]

				M. Epstein Aldosterone as a determinant of cardiovascular and renal dysfunction J R Soc Med, January 8, 2001; 94(8): 378 - 383. [Full Text] [PDF]

				R. Rocha, C. T. Stier Jr., I. Kifor, M. R. Ochoa-Maya, H. G. Rennke, G. H. Williams, and G. K. Adler Aldosterone: A Mediator of Myocardial Necrosis and Renal Arteriopathy Endocrinology, October 1, 2000; 141(10): 3871 - 3878. [Abstract] [Full Text] [PDF]

				S. Kantachuvesiri, S. Fleming, J. Peters, B. Peters, G. Brooker, A. G. Lammie, I. McGrath, Y. Kotelevtsev, and J. J. Mullins Controlled Hypertension, a Transgenic Toggle Switch Reveals Differential Mechanisms Underlying Vascular Disease J. Biol. Chem., September 21, 2001; 276(39): 36727 - 36733. [Abstract] [Full Text] [PDF]

				P. N. Hopkins, S. C. Hunt, X. Jeunemaitre, B. Smith, D. Solorio, N. D.L. Fisher, N. K. Hollenberg, and G. H. Williams Angiotensinogen Genotype Affects Renal and Adrenal Responses to Angiotensin II in Essential Hypertension Circulation, April 23, 2002; 105(16): 1921 - 1927. [Abstract] [Full Text] [PDF]

				S. Rajagopalan, D. Duquaine, S. King, B. Pitt, and P. Patel Mineralocorticoid Receptor Antagonism in Experimental Atherosclerosis Circulation, May 7, 2002; 105(18): 2212 - 2216. [Abstract] [Full Text] [PDF]

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