The present studies were performed to investigate whether the differences described between the two modalities for interruption of the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin AT 1receptor antagonists (AIIA) result in differences in renoprotective efficacy in the rat remnant kidney model. Male Sprague-Dawley rats with an initial body weight of 225—300 g, underwent 5/6 renal ablation and had radiotransmitters installed for radiotelemetric blood pressure (BP) measurements, owing to the known limitations of periodic tail-cuff BP measurements to adequately reflect ambient BP profiles. After renal ablation surgery, the rats received no treatment (n=10); enalapril (n=11) or candesartan (n=9) after the first week, both administered initially at a dose of 50 mg/l of drinking water (~10 mg/kg). However, the dose of candesartan had to be reduced to 10—25 mg/l in 4/9 rats to avoid excessive hypotension. Both enalapril and candesartan produced significant reductions in average systolic BP during the subsequent approximately six weeks of observations as compared with untreated rats (187±4 mmHg, p<0.001), but candesartan was significantly more effective at these relative doses (121±3 vs. 133±4 mmHg, p<0.05). At approximately seven weeks, serum creatinine and proteinuria were measured before sacrifice for morphologic assessment of percentage glomerulosclerosis (GS). Despite the described differences between ACE-I and AIIA after acute administration, the percentage GS was reduced similarly by enalapril (down to 6.8±2.8%) and candesartan (down to 2.9±1.5%) as compared with untreated rats (37.2±4.3%). Moreover, GS in individual animals paralleled the BP reductions achieved. Proteinuria was reduced in parallel to the decrease in % GS. These data indicate that, at least in the 5/6 renal ablation model, RAAS blockade by either ACE-I or AIIA provides protection by BPdependent rather than BP-independent mechanisms. This may reflect the primarily hypertensive pathogenesis of GS in this model, and the fact that hypertension is also very angiotensin II-dependent in this model. Thus, these data suggest that models other than the 5/6 ablation model may be more appropriate to demonstrate the BP-independent protective effects of RAAS blockade.