Renal effects of omapatrilat and captopril in salt-loaded, nitric oxide-deficient rats.
Inhibition of nitric oxide synthases causes systemic hypertension and renal injury in rats. Our objective was to examine whether omapatrilat, a vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase, could induce better regression of renal injury than ACE inhibitor alone. Ten groups of rats were studied. They were fed either a normal (0.8% NaCl) or a high (4% NaCl) sodium diet. Eight of these groups received NG-nitro-L-arginine methyl ester (L-NAME, 20 mg x kg(-1) x d(-1)) in their drinking water. After 4 weeks, 1 group on each diet was killed and considered the L-NAME group, whereas the others received L-NAME alone, captopril (200 mg x kg(-1) x d(-1)) plus L-NAME, or omapatrilat (80 mg x kg(-1) x d(-1)) plus L-NAME for 4 additional weeks. In rats receiving L-NAME alone for 8 weeks, the mortality rate was approximately 90%, irrespective of the diet. In contrast, all rats survived in the captopril and the omapatrilat groups. In rats fed a normal-sodium diet, captopril and omapatrilat normalized systolic blood pressure and induced a complete regression of renal injury. Creatinine clearance and proteinuria were also normalized. In the high-sodium-diet groups, both treatments were less efficient: blood pressure remained elevated, and the regression of renal fibrosis was only partial. Although proteinuria decreased significantly with captopril or omapatrilat, creatinine clearance remained lower than in the controls. These results demonstrate that, in nitric oxide-deficient rats fed a normal-sodium diet, ACE and vasopeptidase inhibitors exhibit a marked renoprotective effect, whereas these treatments are less efficient in rats fed a high-sodium diet.
INSERM U489, Hôpital Tenon, 4, rue de la Chine, 75970 Paris cedex 20, France.
Lu
L
Ying
Martin
M
Flamant
Sophie
S
Vandermeersch
Jean-Jacques
JJ
Boffa
Christos
C
Chatziantoniou
Jean-Claude
JC
Dussaule
Dominique
D
Chansel
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000473:pathology; D002216:Captopril / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000097:blood; D019332:Endothelin-1 / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D006977:Hypertension, Renal / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D015996:Survival Rate; D013841:Thiazepines / Q000627:therapeutic use*
D000806:Angiotensin-Converting Enzyme Inhibitors; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; D009569:Nitric Oxide; C106266:omapatrilat; D012965:Sodium Chloride; D002216:Captopril; D019001:Nitric Oxide Synthase; D015260:Neprilysin; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester