Omapatrilat, a dual angiotensin-converting enzyme and neutral endopeptidase inhibitor, prevents fatty streak deposit in apolipoprotein E-deficient mice.
Angiotensin-converting enzyme (ACE) is mainly responsible for converting angiotensin I (AI) to angiotensin II (AII), and ACE inhibitors prevent atherosclerosis in animal models. Neutral endopeptidase 24.11 (NEP) degrades substance P, kinins and atrial natriuretic peptide (ANP), and aortic wall NEP activity was found to be increased in atherosclerosis. In the present study, we have evaluated the effect of candoxatril, a NEP inhibitor, and of omapatrilat, a dual ACE and NEP inhibitor, on the development of fatty streak in apolipoprotein E (apoE)-deficient mice. Groups of ten male apoE-deficient mice were given either placebo, candoxatril 50 mg/kg per day, or omapatrilat 10, or 100 mg/kg per day for 4 months. None of the treatments influenced body weight, serum total or HDL-cholesterol. Compared with the placebo, candoxatril did not protect the mice from fatty streak deposit. In contrast, omapatrilat dose dependently inhibited the constitution of fatty streak in apoE-deficient mice. The precise advantages of the dual ACE and NEP inhibition versus the inhibition of only ACE should now be considered in the prevention of atherosclerosis as well as in the occurrence of its complications.
INSERM U397 et laboratoire de Physiologie, Institut L. Bugnard, CHU Rangueil, 31403, Toulouse, France. arnal@rangueil.inserm.fr
J F
JF
Arnal
C
C
Castano
E
E
Maupas
A
A
Mugniot
B
B
Darblade
P
P
Gourdy
J B
JB
Michel
F
F
Bayard
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D001161:Arteriosclerosis / Q000201:enzymology / Q000517:prevention & control*; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001920:Bradykinin / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D004353:Drug Evaluation, Preclinical; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000494:pharmacology / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D013373:Substance P / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D007189:Indans; D011422:Propionates; D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; D014280:Triglycerides; D013373:Substance P; C106266:omapatrilat; D009320:Atrial Natriuretic Factor; D002784:Cholesterol; C062766:candoxatril; D015260:Neprilysin; D001920:Bradykinin