Role of Angiotensin-converting enzyme and neutral endopeptidase in flow-dependent remodeling.
Omapatrilat inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). We compared the effects of omapatrilat (40 mg/kg/day, p.o.) to fosinopril (40 mg/kg/day, p.o.) on flow-induced vascular remodeling in New Zealand genetically hypertensive (GH) rats. Both drugs equally reduced blood pressure (BP) initially, but systolic BP and pulse pressure were reduced more by omapatrilat after 1 week. Carotid remodeling was induced by partial ligation of the left common carotid artery (LCA). There was little remodeling in untreated GH rats - measured as outer diameter to body weight (OD/BW vs. before ligation): 97 +/- 1% of initial LCA (low flow) and 107 +/- 3% of initial right common carotid artery (RCA, high flow). In contrast, OD/BW increased to 118 +/- 5% (p < 0.05) of initial RCA after omapatrilat versus 108 +/- 2% (p = 0.96) after fosinopril. The major change was increased RCA lumen area which was significantly larger in omapatrilat-treated animals (127% vs. control) than fosinopril-treated animals (103% vs. control). The increase in outward remodeling after omapatrilat treatment correlated weakly with vascular cGMP levels and decreased systolic BP. The results suggest that dual inhibition of NEP/ACE may have greater effects than ACE inhibition alone on vessel remodeling in hypertension.
Center for Cardiovascular Research and Department of Medicine, University of Rochester, Rochester, NY 14642, USA.
Vyacheslav A
VA
Korshunov
Michael P
MP
Massett
Robert M
RM
Carey
Bradford C
BC
Berk
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D002940:Circadian Rhythm; D004359:Drug Therapy, Combination; D017328:Fosinopril / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D015260:Neprilysin / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011922:Rats, Mutant Strains; D012039:Regional Blood Flow / Q000187:drug effects; D013841:Thiazepines / Q000494:pharmacology*; D014652:Vascular Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
D000806:Angiotensin-Converting Enzyme Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D017328:Fosinopril