To assess the chronic
antihypertensive and renal protective effects of the specific
angiotensin II receptor antagonist,
CS-866, in the remnant kidney model of
chronic renal failure, we administered it alone or in combination with
temocapril, an
angiotensin converting enzyme inhibitor, to 5/6 nephrectomized spontaneously hypertensive rats (SHR) for 8 weeks. At the age of 10 weeks, 5/6 nephrectomized SHR were allocated to receive two doses of
CS-866 (CS-3; 3 mg/kg/day, or CS-10; 10 mg/kg/day),
temocapril (TEM; 10 mg/kg/day), a combination of
CS-866 (3 mg/kg/day) and
temocapril (10 mg/kg/day) or the vehicle alone via oral gavage for 8 weeks. Systolic blood pressure (SBP) and urinary
protein excretion (UprotV) were measured every two weeks. At the age of 18 weeks, the rats were decapitated and the blood, remnant kidney, aorta and heart were collected and used for biochemical measurements and histopathological studies. There was no significant difference in
body weight among the groups during the study. All
drug treatments significantly reduced SBP, UprotV, glomerular
sclerosis index (GSI), relative interstitial volume (RIV) and the heart weight to
body weight ratio. The hypotensive effects were in the order of combination
therapy > CS-10 = TEM > CS-3. For correlational analysis, we used values for SBP and UprotV derived from the average of values in rats over the age of 12 weeks through 18 weeks. UprotV, GSI and RIV were found to be highly correlated with SBP among the individual rats pooled from all groups (r = 0.511, r = 0.754, r = 0.817, respectively) and the correlation was maintained among the group means (r = 0.945, r = 0.989, r = 0.918, respectively). Furthermore, the heart weight to
body weight ratio was found to be highly correlated with SBP among the individual rats pooled from all groups (r = 0.923) and the correlation was maintained among the group means (r = 0.996). We conclude that organ protective effects of
CS-866, TEM, or combination
therapy are closely related to the magnitude of their
antihypertensive effects.