Vasopeptidase inhibitor restores the balance of vasoactive hormones in progressive nephropathy.
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
Twenty-one days after 5/6 nephrectomy, after the onset of hypertension and overt proteinuria, rats were divided in 3 groups (N= 7-8) and given daily by gavage: vehicle, the vasopeptidase inhibitor AVE7688 (3 mg/kg bid), or enalapril (5 mg/kg bid) until day 90. Normal rats (N= 5) served as control rats.


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).


CONCLUSIONS
The superior renoprotection achieved by AVE7688 over enalapril in progressive renal injury is due to the correction of the altered balance of vasoconstrictor/vasodilator mediators in the kidney.
Benigni
Ariela
A
Mario Negri Institute for Pharmacological Research, Bergamo, Italy. abenigni@marionegri.it
Zoja
Carla
C
Zatelli
Cristina
C
Corna
Daniela
D
Longaretti
Lorena
L
Rottoli
Daniela
D
Maggioni
Paola
P
Todeschini
Marta
M
Noris
Marina
M
Remuzzi
Giuseppe
G
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000652:urine; D004656:Enalapril / Q000494:pharmacology; D019332:Endothelin-1 / Q000378:metabolism* / Q000652:urine; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009392:Nephrectomy; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism* / Q000652:urine; D009573:Nitrites / Q000652:urine; D011507:Proteinuria / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
C479877:AVE 7688; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D019332:Endothelin-1; D006575:Heterocyclic Compounds, 3-Ring; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D004656:Enalapril; D015260:Neprilysin; D006152:Cyclic GMP