EFFECTS OF COMBINATION THERAPY WITH ENALAPRIL AND LOSARTAN ON THE RATE OF PROGRESSION OF RENAL INJURY IN RATS WITH 5 6 RENAL MASS ABLATION/

Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II rec eptor antagonists (AT(1)RA) slow the rate of progression of experiment al renal disease. Although the end result of both classes of drugs is to block the renin-angiotensin system (RAS), ACEI and AT(1)RA act at d ifferent sites in the RAS cascade. The aim of this study was to compar e the effects of an ACEI (enalapril) and AT(1)RA (losartan), alone or in combination, in slowing the progression of experimental renal disea se in a model of reduced renal mass. Two weeks after 5/6 renal ablatio n, rats were divided into five groups matched for body weight, systoli c BP (SBP), and urinary protein excretion rate (UprotV). The effects o n SBP and UprotV of treatment with 25 and 40 mg/L enalapril (groups I and II; both n = 7), 180 mg/L losartan (group III, n = 8), or a combin ation of enalapril (25 mg/L) + losartan (180 mg/L) (group IV, n = 9) v ersus vehicle (group V, n = 9) were studied for 12 wk. Remnant kidneys were then assessed histologically for evidence of focal and segmental glomerulosclerosis and hyalinosis (FSGS), and interstitial fibrosis, There wore no significant differences (NSD) in body weight among the g roups at any time. Combination therapy reduced SEP (122 +/- 8 mmHg) si gnificantly at 12 wk to levels similar to losartan (127 +/- 3 mmHg) or enalapril (40 mg/L) alone (124 +/- 5 mmHg) (P < 0.05 versus vehicle c ontrols). With equivalent antihypertensive effects, no differences in frequency of FSGS were discerned among the treatment groups (groups II through IV; F = 1.7, NSD). Tubulointerstitial injury scores followed a similar pattern. BP was highly correlated with the extent of FSGS, b oth among individual rats (r = 0.68, P = 0.05) and the group means (r = 0.99, P = 0.001). We conclude that the renoprotective effects of ena lapril, losartan, or combination therapy are similar in this model ove r the 12 wk of the study, and are closely related to the magnitude of their antihypertensive effects.