Persistent antihypertensive effect of aliskiren is accompanied by reduced proteinuria and normalization of glomerular area in Ren-2 transgenic rats.
The effects of the human renin inhibitor aliskiren on blood pressure (BP), end-organ damage, proteinuria, and tissue and plasma angiotensin (ANG) II levels in young and adult heterozygous Ren-2 transgenic rats (TGR) were evaluated and compared with the effect of the ANG type 1 (AT(1)) receptor blocker losartan during treatment and after 12 days after the withdrawal of drug treatments. BP was monitored by telemetry from the age of 32 days on (young rats) and at 100 days (adult rats). Aliskiren (10 mg·kg(-1)·day(-1) in osmotic minipumps) or losartan (5 mg·kg(-1)·day(-1) in drinking water) treatment was applied for 28 days in young rats and for 70 days in adult rats. In young untreated TGR, severe hypertension rapidly evolved. Adult untreated TGR exhibited stable established hypertension. Both aliskiren and losartan fully prevented the development of hypertension and cardiac hypertrophy in young TGR and normalized BP and cardiac hypertrophy in adult TGR. After cessation of aliskiren treatment in both young and adult TGR BP and cardiac hypertrophy were persistently reduced, while after losartan withdrawal BP and cardiac hypertrophy rapidly increased. In adult aliskiren-treated rats proteinuria was significantly reduced compared with losartan (the effect persisting after withdrawal of treatment), and this decrease strongly correlated with normalization of glomerular size in these animals. In conclusion, aliskiren and losartan had similar antihypertensive effects during chronic treatment, but the antihypertensive and organoprotective effects of aliskiren were persistent even after the 12-day washout period. The durable effect on proteinuria can possibly be attributed to the normalization of glomerular morphology.
Rakusan
Dan
D
Section of Nephrology, 1st Medical Faculty, Department of Medicine, Charles University, Prague, Czech Republic.
Kujal
Petr
P
Kramer
Herbert J
HJ
Husková
Zuzana
Z
Vanourková
Zdenka
Z
Vernerová
Zdenka
Z
Mrázová
Iveta
I
Thumová
Monika
M
Cervenka
Ludek
L
Vanecková
Ivana
I
D000577:Amides / Q000494:pharmacology*; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000517:prevention & control; D004195:Disease Models, Animal; D005650:Fumarates / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000517:prevention & control; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D011507:Proteinuria / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; C535029:Ren2 protein, rat; D000804:Angiotensin II; C446481:aliskiren; D012083:Renin; D019808:Losartan