Dual angiotensin-converting enzyme/neutral endopeptidase inhibition on cardiac and renal fibrosis and inflammation in DOCA-salt hypertensive rats.
OBJECTIVE
The relative roles of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) inhibition on cardiac and renal fibrosis in deoxycorticosterone acetate (DOCA)-salt hypertensive rats were studied.


METHODS
The ACE/NEP inhibitor omapatrilat (40 mg/kg per day), the ACE inhibitor enalapril (10 mg/kg per day) and the NEP inhibitor CGS 25462(100 mg/kg per day) were administrated for 3 weeks to DOCA rats. Collagen was stained with Sirius red, and mediators of inflammation were identified by immunolabeling (vascular cell adhesion molecule, nuclear factor-kappaB, infiltrating ED-1-positive macrophages and monocyte chemotactic protein-1) or by western blot (platelet-endothelial cell adhesion molecule-1).


RESULTS
Elevated systolic blood pressure of DOCA rats was significantly reduced (P < 0.05) by omapatrilat and CGS 25462. Omapatrilat and CGS 25462 significantly (P < 0.05) decreased interstitial collagen density in the left ventricle of DOCA rats compared with untreated DOCA rats. Enalapril only decreased the subepicardial collagen of DOCA rats. Omapatrilat significantly (P < 0.05) decreased renal mesangial collagen deposition in DOCA rats. Cardiac and renal expression of surface adhesion molecules, nuclear factor-kappaB, monocyte chemotactic protein and ED-1-positive cells were decreased in omapatrilat-treated DOCA rats compared with untreated DOCA rats. Enalapril and CGS 25462 did not alter mesangial collagen of DOCA rats.


CONCLUSIONS
Dual ACE/NEP inhibition was more effective than ACE or NEP inhibition in decreasing inflammatory mediators, and improving cardiac and renal fibrosis. This suggests a role for NEP inhibition added to blockade of the renin-angiotensin system that may explain the greater efficacy of omapatrilat.
Pu
Qian
Q
Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada.
Amiri
Farhad
F
Gannon
Philippe
P
Schiffrin
Ernesto L
EL
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003900:Desoxycorticosterone; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000627:therapeutic use; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D006331:Heart Diseases / Q000188:drug therapy / Q000473:pathology; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy / Q000473:pathology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D063065:Organophosphonates / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013841:Thiazepines / Q000627:therapeutic use
D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D015815:Cell Adhesion Molecules; D016328:NF-kappa B; D063065:Organophosphonates; D011725:Pyridines; D013841:Thiazepines; C086165:CGS 25462; C106266:omapatrilat; D003900:Desoxycorticosterone; D004656:Enalapril; D003094:Collagen; D008666:Metalloendopeptidases; D015260:Neprilysin