Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan on the Angiotensin II–Renin Feedback Interruption

Azizi, Michel; Ménard, Joël; Bissery, Alvine; Guyenne, Than-Tam; Bura-Rivière, A.; Vaidyanathan, Sujata; Camisasca, R.

doi:10.1097/01.asn.0000146686.35541.29

Cited by 221 publications

(205 citation statements)

References 33 publications

(47 reference statements)

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“…24 In the current studies, PRA in hypertensive patients taking any of the 3 combinations was either similar to or less than baseline untreated values. The fact that the feedback-induced increase in PRA and Ang I seen with diuretics, ACE inhibitors, and ARBs does not occur during renin inhibition may have potentially favorable consequences.…”

Section: Discussionmentioning

confidence: 88%

Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an Angiotensin-Converting Enzyme Inhibitor, or an Angiotensin Receptor Blocker

et al. 2007

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Abstract-Thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers all cause reactive rises in plasma renin activity. We hypothesized that renin inhibition with aliskiren would prevent this reactive rise and also enhance blood pressure lowering. In 3 open-label studies in which blood pressure was assessed with ambulatory measurement, aliskiren was administered to patients with mild-to-moderate hypertension in combination with hydrochlorothiazide (nϭ23), ramipril (nϭ21), or irbesartan (nϭ23). In the diuretic combination study, . Aliskiren (150 mg) alone significantly inhibited plasma renin activity by 65% (PϽ0.0001). Ramipril and irbesartan monotherapy caused 90% and 175% increases in plasma renin activity, respectively. By contrast, when aliskiren was coadministered with hydrochlorothiazide, ramipril, or irbesartan, plasma renin activity did not increase but remained similar to baseline levels or was decreased ( Key Words: aliskiren Ⅲ ambulatory blood pressure measurement Ⅲ combination therapy Ⅲ hypertension Ⅲ plasma renin activity Ⅲ renin inhibitor Ⅲ renin-angiotensin-aldosterone system A ctivation of the renin-angiotensin (Ang)-aldosterone system (RAAS) plays an important role in the development of hypertension and end-organ damage. 1 Indeed, pretreatment plasma renin activity (PRA) has been shown to be a risk factor for myocardial infarction in hypertensive patients. 2,3 RAAS suppression is, therefore, an important goal of antihypertensive therapy, and RAAS inhibitors, such as Ang-converting enzyme (ACE) inhibitors and Ang receptor blockers (ARBs), have proven to be highly successful treatments for hypertension, heart failure, and related cardiovascular disorders. 4 However, optimized RAAS suppression is difficult to achieve with currently available antihypertensive agents, because ACE inhibitors, ARBs, and diuretics all activate compen-

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Section: Discussionmentioning

confidence: 88%

Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an Angiotensin-Converting Enzyme Inhibitor, or an Angiotensin Receptor Blocker

et al. 2007

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“…22 The magnitude of the reactive rise in PRC stimulated by aliskiren/ramipril was numerically greater than the sum of the effects of either monotherapy, indicating synergistic inhibition of the renin system, as demonstrated previously with an aliskiren/ARB combination in healthy volunteers. 23 The reactive rise in PRC stimulated by ramipril was associated with a concomitant increase in PRA, but aliskiren suppressed the rise in PRA in combination with the ACE-inhibitor. This effect of aliskiren may be clinically important, as increased generation of Ang I by renin is associated with 'escape' from ACE-inhibitor monotherapy in patients with diabetes.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension

Üresin

Taylor

Kilo

et al. 2007

J Renin Angiotensin Aldosterone Syst

197

181

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Objective. To assess the antihypertensive efficacy and safety of the combination of the direct renin inhibitor aliskiren and ramipril in patients with diabetes and hypertension. Methods. In this double-blind, multicentre trial, 837 patients with diabetes mellitus and hypertension (mean sitting diastolic blood pressure [BP] > 95 and < 110 mmHg) were randomised to once-daily aliskiren (150 mg titrated to 300 mg after four weeks; n=282), ramipril (5 mg titrated to 10 mg; n=278) or the combination (n=277) for eight weeks. Efficacy variables were cuff mean sitting diastolic BP (msDBP) and mean sitting systolic BP (msSBP); 24-hour ambulatory BP, plasma renin activity (PRA) and plasma renin concentration (PRC) were also assessed.

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“…The efficacy of the RAS-targeting drugs is often compromised by the reactive renin increase caused by disruption of the renin feedback inhibition (26,32). This clinical problem is not solved even with the use of the new renin inhibitor aliskiren (39), which blocks the enzymatic activity but not the production of renin. Patients treated with aliskiren had plasma immunoreactive renin increased to a level higher than that when valsartan (an ARB) was used (39).…”

Section: Discussionmentioning

confidence: 99%

Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

Zhang

Ning

et al. 2008

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

261

225

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The renin-angiotensin system (RAS) plays a critical role in the development of diabetic nephropathy, and blockade of the RAS is currently used for treatment of diabetic nephropathy. One major problem for the current RAS inhibitors is the compensatory renin increase, which reduces the efficacy of RAS inhibition. We albuminuria ͉ glomerulosclerosis ͉ renin-angiotensin system D iabetic nephropathy is the most common renal complication that often leads to end-stage kidney disease and high mortality (1). Previous studies have suggested the renin-angiotensin system (RAS) as a major mediator of progressive renal injury in diabetic nephropathy. Drugs targeting the RAS including angiotensin (Ang)-converting enzyme inhibitors (ACEIs) and Ang II type 1 receptor blockers (ARBs) have been shown to reduce the progression of glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria (2-6). The systemic components of the RAS are actually down-regulated in diabetic mellitus (7), whereas renal interstitial Ang II levels are estimated to be 1,000-fold higher than in the plasma (8); therefore, intrarenal RAS is thought to play the major damaging role. In fact, all components of the RAS are present within the kidney (9). Cells in the kidney are able to synthesize renin, prorenin/renin receptor (10), angiotensinogen, and Ang II receptors independent of the systemic RAS (11), making the kidney capable of maintaining a high level of intrarenal Ang II. Intrarenal renin and angiotensinogen levels are induced in diabetic animals (12, 13), and high glucose has been shown to stimulate renin and Ang II synthesis in mesangial cells and podocytes (14-16). Intrarenal Ang II exerts multiple effects on the kidney that promote the progression of renal injury; these include an increase in glomerular capillary pressure, induction of profibrotic and proinflammatory cytokine production, promotion of immune cell infiltration, stimulation of cell proliferation and hypertrophy, up-regulation of extracellular matrix (ECM) synthesis, and damaging of podocytes (17)(18)(19) (21), and null mutant mice lacking the vitamin D receptor (VDR) gene develop hyperreninemia, high blood pressure, and cardiac hypertrophy (22)(23)(24). Our recent studies showed that in diabetic state VDR-null mice developed more severe nephropathy than wild-type mice (25), suggesting that vitamin D plays a protective role against hyperglycemia-induced renal injury by regulation of the RAS. However, whether vitamin D or vitamin D analogs have therapeutic effects in intervention or prevention of diabetic nephropathy remains to be tested.Although RAS inhibitors, including ACEIs and ARBs, are widely used in the therapy of renal and cardiovascular diseases, the major problem of these drugs is the compensatory renin rise due to the disruption of the feedback inhibition of renin production (26). The increase in renin activity stimulates the conversion of Ang I and ultimately Ang II, which largely limits the efficacy of RAS inhibition (27,28). The increased renin can also act through the...

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Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan on the Angiotensin II–Renin Feedback Interruption

Cited by 221 publications

References 33 publications

Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an Angiotensin-Converting Enzyme Inhibitor, or an Angiotensin Receptor Blocker

Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an Angiotensin-Converting Enzyme Inhibitor, or an Angiotensin Receptor Blocker

Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension

Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

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