Published Online
on August 15, 2005

A more recent version of this article appeared on September 1, 2005

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Submitted on April 4, 2005
Revised on April 26, 2005

Aliskiren, a Human Renin Inhibitor, Ameliorates Cardiac and Renal Damage in Double-Transgenic Rats

Bernhard Pilz; Erdenechimeg Shagdarsuren; Maren Wellner; Anette Fiebeler; Ralf Dechend; Petra Gratze; Silke Meiners; David L. Feldman; Randy L. Webb; Ingrid M. Garrelds; A. H. Jan Danser; Friedrich C. Luft; and Dominik N. Müller^*

From the HELIOS Klinikum-Berlin (B.P., E.S., M.W., A.F., R.D., S.M., F.C.L., D.N.M.), Franz Volhard Clinic and Medical Faculty of the Charité, Humboldt University of Berlin, Germany; Max-Delbrück-Center for Molecular Medicine (P.G., F.C.L., D.N.M.), Berlin-Buch, Germany; Novartis Institutes for Biomedical Research (D.L.F., R.L.W.), East Hanover, NJ; and Department of Pharmacology (I.M.G., A.H.J.D.), Erasmus MC, Rotterdam, The Netherlands.

^* To whom correspondence should be addressed. E-mail: mueller{at}fvk-berlin.de.

Abstract--We tested the hypothesis that the renin inhibitor aliskiren ameliorates organ damage in rats transgenic for human renin and angiotensinogen genes (double transgenic rat [dTGR]). Six-week-old dTGR were matched by albuminuria (2 mg per day) and divided into 5 groups. Untreated dTGR were compared with aliskiren (3 and 0.3 mg/kg per day)-treated and valsartan (Val; 10 and 1 mg/kg per day)-treated rats. Treatment was from week 6 through week 9. At week 6, all groups had elevated systolic blood pressure (BP). Untreated dTGR showed increased BP (202±4 mm Hg), serum creatinine, and albuminuria (34±5.7 mg per day) at week 7. At week 9, both doses of aliskiren lowered BP (115±6 and 139±5 mm Hg) and albuminuria (0.4±0.1 and 1.6±0.6 mg per day) and normalized serum creatinine. Although high-dose Val lowered BP (148±4 mm Hg) and albuminuria (2.1±0.7 mg per day), low-dose Val reduced BP (182±3 mm Hg) and albuminuria (24±3.8 mg per day) to a lesser extent. Mortality was 100% in untreated dTGR and 26% in Val (1 mg/kg per day) treated rats, whereas in all other groups, survival was 100%. dTGR treated with low-dose Val had cardiac hypertrophy (4.4±0.1 mg/g), increased left ventricular (LV) wall thickness, and diastolic dysfunction. LV atrial natriuretic peptide and -myosin heavy chain mRNA, albuminuria, fibrosis, and cell infiltration were also increased. In contrast, both aliskiren doses and the high-dose Val lowered BP to a similar extent and more effectively than low-dose Val. We conclude that in dTGR, equieffective antihypertensive doses of Val or aliskiren attenuated end-organ damage. Thus, renin inhibition compares favorably to angiotensin receptor blockade in reversing organ damage in dTGR.

Key words: renin • rats, transgenic • hypertrophy

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