Abstract | BACKGROUND: The mechanism(s) underlying greater renoprotection of combined blockade of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) by vasopeptidase over ACE inhibitors are ill defined. We previously found that progressive renal disease is associated with increased renal synthesis of endothelin-1 (ET-1) in the face of reduced generation of renal nitric oxide (NO) in the remnant kidney model. Here we compared changes in urinary excretion of ET-1 and nitrite/ nitrate, markers of renal ET-1, and NO synthesis, respectively, and urinary cGMP, an indirect index of renal atrial natriuretic peptide ( ANP) synthesis, after administration of vasopeptidase or ACE inhibitor in rats with renal mass reduction (RMR). METHODS: RESULTS: Systolic blood pressure in RMR rats was equally controlled by AVE7688 and enalapril. AVE7688 resulted in a significant antiproteinuric effect, with urinary protein levels being reduced on average by 83% in respect to vehicle (88 +/- 28 vs. 518 +/- 27 mg/day, P < 0.0001). Enalapril achieved a 47% reduction in proteinuria (277 +/- 81 mg/day, P < 0.01 vs. vehicle) to levels that remained higher (P < 0.01), however, than those after AVE7688. Renal function impairment and glomerular and tubular changes were significantly (P < 0.05 vs. vehicle) ameliorated by AVE7688, and partially affected by enalapril. AVE7688 reduced the abnormal urinary excretion of ET-1 of RMR animals (98 +/- 8 vs. vehicle: 302 +/- 50 pg/24 h, P < 0.001) more than enalapril (159 +/- 14 pg/24 h, P < 0.05 vs. AVE7688). Consistently, AVE7688 was more effective than enalapril in augmenting renal synthesis of NO (2487 +/- 267 and 1519 +/- 217 vs. vehicle: 678 +/- 71 nmol/15 h; P < 0.001, AVE7688 vs. vehicle, P < 0.01 AVE7688 vs. enalapril). AVE7688 significantly increased urinary cGMP (78 +/- 6 vs. vehicle 45 +/- 9 nmol/24 h; P < 0.01). CONCLUSION:
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Authors | Ariela Benigni, Carla Zoja, Cristina Zatelli, Daniela Corna, Lorena Longaretti, Daniela Rottoli, Paola Maggioni, Marta Todeschini, Marina Noris, Giuseppe Remuzzi |
Journal | Kidney international
(Kidney Int)
Vol. 66
Issue 5
Pg. 1959-65
(Nov 2004)
ISSN: 0085-2538 [Print] United States |
PMID | 15496167
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- AVE 7688
- Angiotensin-Converting Enzyme Inhibitors
- Antihypertensive Agents
- Endothelin-1
- Heterocyclic Compounds, 3-Ring
- Nitrates
- Nitrites
- Nitric Oxide
- Enalapril
- Neprilysin
- Cyclic GMP
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Topics |
- Angiotensin-Converting Enzyme Inhibitors
(pharmacology)
- Animals
- Antihypertensive Agents
(pharmacology)
- Blood Pressure
(drug effects)
- Cyclic GMP
(urine)
- Enalapril
(pharmacology)
- Endothelin-1
(metabolism, urine)
- Heterocyclic Compounds, 3-Ring
(pharmacology)
- Kidney
(pathology, physiopathology)
- Kidney Diseases
(metabolism, pathology, physiopathology)
- Male
- Nephrectomy
- Neprilysin
(antagonists & inhibitors)
- Nitrates
(urine)
- Nitric Oxide
(metabolism, urine)
- Nitrites
(urine)
- Proteinuria
(urine)
- Rats
- Rats, Sprague-Dawley
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