THE ANGIOTENSIN RECEPTOR ANTAGONIST, IRBESARTAN, REDUCES RENAL INJURYIN EXPERIMENTAL CHRONIC-RENAL-FAILURE

The effects of chronic treatment with the specific AT(1) angiotensin r eceptor antagonist, irbesartan, or the angiotensin converting enzyme i nhibitor, enalapril, were assessed in uninephrectomized fawn-hooded hy pertensive rats (FHH) and compared with vehicle treatment. Three days after uninephrectomy, irbesartan (240 mg/liter), enalapril (80 mg/lite r) or vehicle were administered via the drinking water. Systolic blood pressure (SBP) and protein excretion rates UprotV) were determined mo nthly. In rats receiving irbesartan (N = 7) and enalapril (N = 6) SBP (132 +/- 3 mm Hg and 133 +/- 6, respectively) was essentially normaliz ed at 12 weeks when compared with vehicle (169 +/- 6 mm Hg (N = 6): al l comparisons were P < 0.05 by ANOVA). Similarly, proteinuria was lowe r in irbesartan (44 +/- 10 mg/day). Treatment with both drugs was asso ciated with marked reduction in glomerulosclerosis at 12 weeks (both < 5% vs. vehicle, 43 +/- 9%) without effect on glomerular volume. In id entically prepared rats, glomerular capillary hydraulic pressure (P-GC , estimated from stop-flow pressure P-4) was lower in FHH receiving ir besartan (58 +/- 1 mm lig, N = 6) or enalapril (54 +/- 2, N = 6) than in vehicle-treated rats, in whom P-GC was greatly elevated (68 +/- 2 m m Hg; N = 7). Despite this, GFR and single nephron GFR were well maint ained. These data support a critical role for AT(1) receptor-mediated, angiotensin-dependent processes in the pathogenesis of hypertension i n FHH, and further implicate elevated P-GC as a major determinant of g lomerular injury in this model.