Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats.
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 beta-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.
Pilz
Bernhard
B
HELIOS Klinikum-Berlin, Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Germany.
Shagdarsuren
Erdenechimeg
E
Wellner
Maren
M
Fiebeler
Anette
A
Dechend
Ralf
R
Gratze
Petra
P
Meiners
Silke
S
Feldman
David L
DL
Webb
Randy L
RL
Garrelds
Ingrid M
IM
Jan Danser
A H
AH
Luft
Friedrich C
FC
Müller
Dominik N
DN
D000419:Albuminuria / Q000503:physiopathology; D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000000981:diagnostic imaging; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D005650:Fumarates / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006973:Hypertension / Q000175:diagnosis* / Q000401:mortality / Q000503:physiopathology; D007668:Kidney / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D000092502:Renin Inhibitors
D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D000808:Angiotensinogen; D005650:Fumarates; D012083:Renin; D013777:Tetrazoles; D014633:Valine; D000068756:Valsartan; D000092502:Renin Inhibitors; C446481:aliskiren