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on June 16, 2008

A more recent version of this article appeared on June 24, 2008

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Submitted on November 14, 2007
Accepted on April 7, 2008

Renal and Hormonal Responses to Direct Renin Inhibition With Aliskiren in Healthy Humans

Naomi D.L. Fisher MD^*, A. H. Jan Danser PhD, J. Nussberger MD, William P. Dole MD, and Norman K. Hollenberg MD, PhD

From the Departments of Medicine (N.D.L.F.) and Radiology (N.K.H.), Brigham and Women's Hospital and Harvard Medical School, Boston, Mass; Erasmus Medical Center (A.H.J.D.), Rotterdam, The Netherlands; Centre Hospitalier Universitaire Vaudois (J.N.), Lausanne, Switzerland; and Novartis Institutes for Biomedical Research (W.P.D.), Cambridge, Mass.

^* To whom correspondence should be addressed. E-mail: nfisher{at}partners.org.

Background—Pharmacological interruption of the renin-angiotensin system focuses on optimization of blockade. As a measure of intrarenal renin activity, we have examined renal plasma flow (RPF) responses in a standardized protocol. Compared with responses with angiotensin-converting enzyme inhibition (rise in RPF 95 mL · min^-1 · 1.73 m^-2), greater renal vasodilation with angiotensin receptor blockers (145 mL · min^-1 · 1.73 m^-2) suggested more effective blockade. We predicted that blockade with the direct oral renin inhibitor aliskiren would produce renal vascular responses exceeding those induced by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Methods and Results—Twenty healthy normotensive subjects were studied on a low-sodium (10 mmol/d) diet, receiving separate escalating doses of aliskiren. Six additional subjects received captopril 25 mg as a low-sodium comparison and also received aliskiren on a high-sodium (200 mmol/d) diet. RPF was measured by clearance of para-aminohippurate. Aliskiren induced a remarkable dose-related renal vasodilation in low-sodium balance. The RPF response was maximal at the 600-mg dose (197±27 mL · min^-1 · 1.73 m^-2) and exceeded responses to captopril (92±20 mL · min^-1 · 1.73 m^-2; P<0.01). Furthermore, significant residual vasodilation was observed 48 hours after each dose (P<0.01). The RPF response on a high-sodium diet was also higher than expected (47±17 mL · min^-1 · 1.73 m^-2). Plasma renin activity and angiotensin levels were reduced in a dose-related manner. As another functional index of the effect of aliskiren, we found significant natriuresis on both diets.

Conclusions—Renal vasodilation in healthy people with the potent renin inhibitor aliskiren exceeded responses seen previously with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The effects were longer lasting and were associated with significant natriuresis. These results indicate that aliskiren may provide more complete and thus more effective blockade of the renin-angiotensin system.

Key words: renin • drugs • angiotensin • kidney • hypertension

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Circulation 2008 117: 3161-3162. [Extract] [Full Text]

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