(Hypertension. 1998;31:451.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Mineralocorticoid Blockade Reduces Vascular Injury in Stroke-Prone Hypertensive Rats
From the Departments of Pharmacology (R.R., K.K., C.T.S.), Pathology (P.N.C.) and Pediatrics (A.Z.) at New York Medical College, Valhalla, NY
Correspondence to Charles T. Stier, Jr., PhD, Department of Pharmacology, Basic Science Building, New York Medical College, Valhalla, New York 10595. E mail: Charles_Stier{at}NYMC.edu
Chronic treatment of saline-drinking stroke-prone spontaneously hypertensive rats (SHRSP) with agents that interfere with the formation or actions of angiotensin II (Ang II) prevents the development of stroke and renal vascular damage. Ang II, in addition to its direct vascular effects, stimulates the synthesis and release of aldosterone. To assess the role of aldosterone in the development of pathologic changes in these rats, we implanted time-release pellets containing 200 mg of the mineralocorticoid receptor antagonist, spironolactone, into 14 SHRSP at 7.5 weeks of age. Eight SHRSP littermates received placebo pellets. Over the period of study (3 to 4 weeks), systolic blood pressure (SBP) was not different between the groups. Spironolactone did not enhance water and electrolyte excretion. All placebo-treated SHRSP developed marked proteinuria (150±6 mg/d) whereas in spironolactone-treated SHRSP, urinary protein excretion (UPE) averaged 39±9 mg/d (P<.0001). In a second study to assess effects on survival, 6 SHRSP received spironolactone (10 mg/kg/d) and 6 received vehicle. All but one of the control rats displayed signs of stroke and died by 16 weeks of age, while the spironolactone-treated SHRSP remained asymptomatic through 19 weeks of age (P<.03). At 16 weeks of age, spironolactone-treated SHRSP were severely hypertensive (247±3 mm Hg), yet UPE remained at baseline levels. In contrast, preterminal UPE averaged 136±13 mg/d in control rats (P<.0001). In both studies, histopathologic examination revealed a marked protective effect of spironolactone against the development of malignant nephrosclerotic and cerebrovascular lesions. These observations indicate a vascular and end organ protective effect of spironolactone in the absence of lowered blood pressure in saline-drinking SHRSP and are consistent with a major role for mineralocorticoids as hormonal mediators of vascular injury.
Key Words: hypertension • kidney • malignant nephrosclerosis • spironolactone • stroke
Abbreviations: SHRSP = stroke-prone spontaneously hypertensive rats • PRA = plasma renin activity • RAAS = renin angiotensin aldosterone system • ACE = angiotensin converting enzyme • Ang II = angiotensin II • DOCA = deoxycorticosterone acetate • H & E = hematoxylin and eosin • SBP = systolic blood pressure • UPE = urinary protein excretion • UNa+V = urinary sodium excretion • UK+V = urinary potassium excretion
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C. Sierra and L. M Ruilope Review: Role of the selective aldosterone receptor blockers in arterial hypertension Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1): 23 - 25. [Abstract] [PDF]
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 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]
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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]
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W. A. Wilmer, B. H. Rovin, C. J. Hebert, S. V. Rao, K. Kumor, and L. A. Hebert Management of Glomerular Proteinuria: A Commentary J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3217 - 3232. [Abstract] [Full Text] [PDF]
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E. M. Oestreicher, D. Martinez-Vasquez, J. R. Stone, L. Jonasson, W. Roubsanthisuk, K. Mukasa, and G. K. Adler Aldosterone and Not Plasminogen Activator Inhibitor-1 Is a Critical Mediator of Early Angiotensin II/NG-Nitro-l-Arginine Methyl Ester-Induced Myocardial Injury Circulation, November 18, 2003; 108(20): 2517 - 2523. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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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]
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C. T. Stier Jr., P. N. Chander, L. Rosenfeld, and C. A. Powers Estrogen promotes microvascular pathology in female stroke-prone spontaneously hypertensive rats Am J Physiol Endocrinol Metab, July 1, 2003; 285(1): E232 - E239. [Abstract] [Full Text] [PDF]
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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]
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 H. T. Yu Progression of Chronic Renal Failure Arch Intern Med, June 23, 2003; 163(12): 1417 - 1429. [Abstract] [Full Text] [PDF]
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J. S. Williams and G. H. Williams 50th Anniversary of Aldosterone J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2364 - 2372. [Full Text] [PDF]
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N. J. Brown Eplerenone: Cardiovascular Protection Circulation, May 20, 2003; 107(19): 2512 - 2518. [Abstract] [Full Text] [PDF]
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T.-Y. Chun, L. J. Bloem, and J. H. Pratt Aldosterone Inhibits Inducible Nitric Oxide Synthase in Neonatal Rat Cardiomyocytes Endocrinology, May 1, 2003; 144(5): 1712 - 1717. [Abstract] [Full Text] [PDF]
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 J Song, I Narita, S Goto, N Saito, K Omori, F Sato, J Ajiro, D Saga, D Kondo, M Sakatsume, et al. Gender specific association of aldosterone synthase gene polymorphism with renal survival in patients with IgA nephropathy J. Med. Genet., May 1, 2003; 40(5): 372 - 376. [Full Text] [PDF]
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J. M. Flack, S. Oparil, J. H. Pratt, B. Roniker, S. Garthwaite, J. H. Kleiman, Y. Yang, S. L. Krause, D. Workman, and E. Saunders Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1148 - 1155. [Abstract] [Full Text] [PDF]
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S. Kasama, T. Toyama, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi Effect of spironolactone on cardiacsympathetic nerve activity and left ventricular remodeling in patients with dilated cardiomyopathy J. Am. Coll. Cardiol., February 19, 2003; 41(4): 574 - 581. [Abstract] [Full Text] [PDF]
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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]
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R. Rocha, C. L. Martin-Berger, P. Yang, R. Scherrer, J. Delyani, and E. McMahon Selective Aldosterone Blockade Prevents Angiotensin II/Salt-Induced Vascular Inflammation in the Rat Heart Endocrinology, December 1, 2002; 143(12): 4828 - 4836. [Abstract] [Full Text] [PDF]
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 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]
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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]
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S. Kasama, T. Toyama, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi Spironolactone Improves Cardiac Sympathetic Nerve Activity and Symptoms in Patients with Congestive Heart Failure J. Nucl. Med., October 1, 2002; 43(10): 1279 - 1285. [Abstract] [Full Text] [PDF]
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A. Virdis, M. F. Neves, F. Amiri, E. Viel, R. M. Touyz, and E. L. Schiffrin Spironolactone Improves Angiotensin-Induced Vascular Changes and Oxidative Stress Hypertension, October 1, 2002; 40(4): 504 - 510. [Abstract] [Full Text] [PDF]
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M. G. Mohaupt and F. J. Frey Mineralocorticoid receptor malfunction: further insights from rare forms of hypertension Nephrol. Dial. Transplant., April 1, 2002; 17(4): 539 - 542. [Full Text] [PDF]
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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]
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 K. T. Weber Aldosterone in Congestive Heart Failure N. Engl. J. Med., December 6, 2001; 345(23): 1689 - 1697. [Full Text] [PDF]
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A. D Struthers Review: Aldosterone-induced vasculopathy: a new reversible cause of cardiac death Journal of Renin-Angiotensin-Aldosterone System, December 1, 2001; 2(4): 211 - 214. [PDF]
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C. Ngarmukos and R. J. Grekin Nontraditional aspects of aldosterone physiology Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1122 - E1127. [Abstract] [Full Text] [PDF]
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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]
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J. A. Florian, A. Dorrance, R. C. Webb, and S. W. Watts Mineralocorticoids upregulate arterial contraction to epidermal growth factor Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2001; 281(3): R878 - R886. [Abstract] [Full Text] [PDF]
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