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Relative antihypertensive and glomeruloprotective efficacies of enalapril and candesartan cilexetil in the remnant kidney model

Department of Medicine, Loyola University Medical Center and Hines VA Hospital, prado@research. hines.med.va.gov

Maria M Picken

Pathology, Loyola University Medical Center and Hines VA Hospital, Maywood, IL USA

George Bakris

Department of Preventive Medicine, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL, USA

Anil K Bidani

Department of Medicine, Loyola University Medical Center and Hines VA Hospital

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.

Key Words: experimental hypertension • remnant kidney • glomerulosclerosis • angiotensin II receptor antagonist • angiotensin-converting enzyme inhibitor

Journal of Renin-Angiotensin-Aldosterone System, Vol. 2, No. 1 suppl, S191-S195 (2001)
DOI: 10.1177/14703203010020013301


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