The angiotensin receptor antagonist, irbesartan, reduces renal injury in experimental chronic renal failure.
The effects of chronic treatment with the specific AT1 angiotensin receptor antagonist, irbesartan, or the angiotensin converting enzyme inhibitor, enalapril, were assessed in uninephrectomized fawn-hooded hypertensive rats (FHH) and compared with vehicle treatment. Three days after uninephrectomy, irbesartan (240 mg/liter), enalapril (80 mg/liter) or vehicle were administered via the drinking water. Systolic blood pressure (SBP) and protein excretion rates (UprotV) were determined monthly. In rats receiving irbesartan (N = 7) and enalapril (N = 6) SBP (132 +/- 3 mm Hg and 133 +/- 6, respectively) was essentially normalized at 12 weeks when compared with vehicle (169 +/- 6 mm Hg (N = 6); all comparisons were P < 0.05 by ANOVA). Similarly, proteinuria was lower in irbesartan (44 +/- 12 mg/day) and enalapril (19 +/- 2) groups versus vehicle (123 +/- 10 mg/day). Treatment with both drugs was associated with marked reduction in glomerulosclerosis at 12 weeks (both < 5% vs. vehicle, 43 +/- 9%) without effect on glomerular volume. In identically prepared rats, glomerular capillary hydraulic pressure (PGC, estimated from stop-flow pressure, Psf) was lower in FHH receiving irbesartan (58 +/- 1 mm Hg, N = 6) or enalapril (54 +/- 2, N = 6) than in vehicle-treated rats, in whom PGC was greatly elevated (68 +/- 2 mm Hg; N = 7). Despite this, GFR and single nephron GFR were well maintained. These data support a critical role for AT1 receptor-mediated, angiotensin-dependent processes in the pathogenesis of hypertension in FHH, and further implicate elevated PGC as a major determinant of glomerular injury in this model.
Ziai
F
F
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Ots
M
M
Provoost
A P
AP
Troy
J L
JL
Rennke
H G
HG
Brenner
B M
BM
Mackenzie
H S
HS
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004656:Enalapril / Q000494:pharmacology*; D000077405:Irbesartan; D007676:Kidney Failure, Chronic / Q000188:drug therapy; D007678:Kidney Glomerulus / Q000187:drug effects / Q000503:physiopathology; D009392:Nephrectomy; D011507:Proteinuria / Q000517:prevention & control*; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D013777:Tetrazoles; D004656:Enalapril; D000077405:Irbesartan