Aldosterone antagonist facilitates the cardioprotective effects of angiotensin receptor blockers in hypertensive rats

Tanabe, Akiyo; Naruse, Mitsuhide; Hara, Yoshiko; Sato, Aiko; Tsuchiya, Ken; Nishikawa, Toshio; Imaki, Toshihiro; Takano, Kazue

doi:10.1097/00004872-200405000-00025

Cited by 24 publications

(21 citation statements)

References 29 publications

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“…It has been reported that the combined treatment with an ARB and SPRL improves the expression of collagen mRNA and cardiac interstitial and perivascular fibrosis compared with both ARB and SPRL monotherapy in stroke-prone spontaneous hypertensive rats. 25 The RALES showed the clinical significance of SPRL in almost all patients with severe heart failure who were receiving an ACE inhibitor before the randomization, therefore, this evidence indicated the beneficial effects of the combined treatment of ACE inhibitor and SPRL. 11 Recently, Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS trial) showed the efficacy of a new selective aldosterone blocker, eprelenone, in patients with heart failure.…”

Section: Discussionmentioning

confidence: 92%

Effects of Spironolactone During an Angiotensin II Receptor Blocker Treatment on the Left Ventricular Mass Reduction in Hypertensive Patients With Concentric Left Ventricular Hypertrophy

Taniguchi

Kikuchi

Date

et al. 2006

Circ J

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he blockade of the renin -angiotensin -aldosterone system has beneficial effects on cardiovascular remodeling. Many patients with hypertension, heart failure, and post-myocardial infarction have been treated with angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) to prevent cardiovascular events. 1-3 ARB blocks the action of angiotensin II (Ang II) and subsequently suppresses the secretion of aldosterone from the adrenal gland, and prevent the development of cardiovascular remodeling. Recently, aldosterone has been recognized to play a crucial role in the pathophysiology of myocardial remodeling in cardiovascular diseases. [4][5][6] It has been reported that an aldosterone breakthrough during ACE inhibitor or ARB treatment might reverse some of the beneficial effects on cardiovascular remodeling. 7,8 We reported that an ARB treatment is less Circulation Journal Vol.70, August 2006 effective for preventing cardiac fibrosis in left ventricular (LV) hypertrophy in renovascular hypertensive rats than an ACE inhibitor, despite similar changes in blood pressure (BP). 9 It is not clear whether ACE inhibitors or ARB sufficiently inhibit the action of intrinsic aldosterone, which is involved in the development of cardiac remodeling. However, LV hypertrophy is an independent risk factor in cardiovascular events. 10 The regression of LV hypertrophy is an important target to treat hypertension. A randomized clinical study, The Randomized Aldactone Evaluation Study (RALES), indicated that an aldosterone blocker, spironolactone (SPRL), reduced the risk of both morbidity and death in the patients with severe heart failure. 11 The combined treatment of ACE inhibitor and SPRL has been reported to have beneficial effects on LV remodeling in hypertensive patients. 12 Also, we have reported that ARB monotherapy reduced the plasma aldosterone concentration (PAC) levels for the first 6 months; however, some patients experienced a rise in the PAC levels during the late phase of treatment. 13 We studied the additional effects of SPRL during an ARB treatment and conventional treatments on LV remodeling to strongly inhibit the action of aldosterone in patients with essential hypertension. Background Angiotensin II receptor blockers (ARB) are now commonly used to treat hypertension because of their beneficial effects on cardiovascular remodeling. However, ARB treatment can not inhibit the left ventricular (LV) remodeling sufficiently, which may be related with aldosterone secretion. To inhibit the action of aldosterone during ARB treatment, the additional effects of an aldosterone blocker and spironolactone (SPRL) on LV hypertrophy in patients with essential hypertension was studied. Methods and ResultsThe patients with essential hypertension were randomly divided into 2 groups; 1 group was treated with an ARB, candesartan (8 mg/day), for 1 year (ARB group) and other group was treated with the ARB for the first 6 months and with the ARB plus SPRL (25 mg/day) for the next 6 months (combination group...

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Section: Discussionmentioning

confidence: 92%

Effects of Spironolactone During an Angiotensin II Receptor Blocker Treatment on the Left Ventricular Mass Reduction in Hypertensive Patients With Concentric Left Ventricular Hypertrophy

Taniguchi

Kikuchi

Date

et al. 2006

Circ J

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“…The current understanding of the increasingly appreciated involvement of aldosterone in hypertension acting through BP elevation, vascular damage, and cardiac fibrosis and the realization that aldosterone has complex interactions with Ang II have provided justification for the use of combined angiotensin and mineralocorticoid blockade in the treatment of hypertension and cardiac failure. 76,77 …”

Section: Discussionmentioning

confidence: 99%

Effects of Aldosterone on the Vasculature

2006

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“…Several studies show that ANG II is central in inflammatory processes (31). The treatment of the prehypertensive SHRs for 10 wk with losartan abolished or significantly ameliorated renal injury indicating a pivotal role in renal damage observed in SHRs.…”

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confidence: 92%

Changes in angiotensin receptors expression play a pivotal role in the renal damage observed in spontaneously hypertensive rats

Landgraf

Wengert

Silva

et al. 2011

American Journal of Physiology-Renal Physiology

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The renal renin-angiotensin system plays a central role in the development of hypertension. The aim of this work was to verify the expression of angiotensin II receptors AT 1R and AT2R in the microsomal fraction of renal cortex and correlate this with the development of hypertension and renal damage in spontaneously hypertensive rats (SHR) using Wistar-Kyoto rats (WKY) as controls. AT 1R expression increased (126%) and AT 2R expression decreased (66%) in 4-wk-old SHR; AT2 expression decreased in 14-wk-old SHR (61%) compared with respective agematched WKY. These modifications were correlated to the increase in protein kinase C activity and decrease in protein kinase A activity. Four-week-old SHR showed large accumulations of macrophages in kidney glomerulus and the tubulointerstitial area, dense cortical collagen deposition, and arterial proliferative changes in the walls of arterioles and medium-sized vessels. Similar modifications were also observed in 14-wk-old SHR. Four-week-old SHR treated with losartan (30 mg·kg Ϫ1 ·day Ϫ1 ) or hydralazine (15 and 30 mg·kg Ϫ1 ·day Ϫ1 ) by gavage for 10 wk did not develop hypertension. The decrease in AT 2R expression and renal damage observed in SHR remained even after treatment with hydralazine. On the other hand, losartan treatment prevented the modifications observed in 14-wk-old SHR, indicating that renal injuries are caused specifically by AT1 rather than an increase in blood pressure. Our results indicate that the imbalance in AT1R and AT2R expression is associated with an inflammatory process that contributes to renal injury in adult SHR and to the development of hypertension.renin-angiotensin system; kidney; angiotensin II receptors; inflammation THE KEY ROLE OF THE KIDNEY in primary hypertension pathogenesis has been proposed based on measurements of renal function and renal transplantation studies in spontaneously hypertensive rats (SHR) and human patients (10,14). Renal damage is commonly caused by hypertension, which is a key to morbidity and mortality (23). On the other hand, renal damage could be involved in the genesis of hypertension, showing the dangerous loop in this correlation.Some studies showed functional alterations in tissues that precede the development of hypertension (17,27,32). Based on these observations, one attractive hypothesis is that asymptomatic alterations in renal function at an early stage could be contributed to development of the primary hypertension. Identification of the mechanisms responsible for these events becomes very attractive as an early marker of primary hypertension development and in prevention of hypertension. One candidate could be the renin-angiotensin system (RAS), which plays an important role in renal function and regulation of blood pressure.The effects of angiotensin II (ANG II) are mediated mainly by two receptors: angiotensin type 1 receptor (AT 1 R) or angiotensin type 2 receptor (AT 2 R) (11). AT 1 R activation is involved in vasoconstriction and proinflammatory action; AT 2 R counteracts the effects triggered...

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Aldosterone antagonist facilitates the cardioprotective effects of angiotensin receptor blockers in hypertensive rats

Abstract: These results demonstrate that residual aldosterone has a significant impact on target-organ damage in hypertension, even during chronic administration of an ARB. The addition of an aldosterone antagonist has an advantage in facilitating the cardioprotective effects of ARBs.

Cited by 24 publications

References 29 publications

Effects of Spironolactone During an Angiotensin II Receptor Blocker Treatment on the Left Ventricular Mass Reduction in Hypertensive Patients With Concentric Left Ventricular Hypertrophy

Effects of Spironolactone During an Angiotensin II Receptor Blocker Treatment on the Left Ventricular Mass Reduction in Hypertensive Patients With Concentric Left Ventricular Hypertrophy

Effects of Aldosterone on the Vasculature

Changes in angiotensin receptors expression play a pivotal role in the renal damage observed in spontaneously hypertensive rats

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