Antihypertensive and antihypertrophic effects of omapatrilat in SHR.
Vasopeptidase inhibitors, such as omapatrilat are single molecules that simultaneously inhibit neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). In normotensive rats, a single dose of oral omapatrilat (10 mg/kg) and 1 mg/kg inhibited plasma ACE (P < .01) for 24 h and increased plasma renin activity for 8 h (P < .01). In vitro autoradiography using the specific NEP inhibitor radioligand 125I-RB104 and the specific ACE inhibitor radioligand 125I-MK351A showed omapatrilat (10 mg/kg) caused rapid and potent inhibition of renal NEP and ACE, respectively, for 24 h (P < .01). In spontaneously hypertensive rats, 10 days of oral omapatrilat (40 mg/kg/day) reduced blood pressure (vehicle 237 +/- 4 mm Hg; omapatrilat, 10 mg/kg, 212 +/- 4 mm Hg; omapatrilat 40 mg/kg, 197 +/- 4 mm Hg, P < .01) in a dose-dependent manner (10 v 40 mg/kg, P < .01). Left ventricular hypertrophy was significantly reduced by high-dose omapatrilat (vehicle 2.76 +/- 0.03 mg/g body weight; omapatrilat, 10 mg/kg, 2.71 +/- 0.02 mg/g; omapatrilat 40 mg/kg, 2.55 +/- 0.02 mg/g, P < .01) and omapatrilat also increased kidney weight compared to vehicle (both doses, P < .01). Omapatrilat caused significant inhibition of plasma ACE and increased plasma renin activity (both doses, P < .01), and in vitro autoradiographic studies indicated sustained inhibition of renal ACE and NEP (both doses, P < .01). Omapatrilat is a potent vasopeptidase inhibitor, and its antihypertensive effects are associated with inhibition of NEP and ACE at the tissue level and beneficial effects on cardiovascular structure. Relating the degree of tissue inhibition to physiologic responses may allow further definition of the role of local renin angiotensin and natriuretic peptide systems in the beneficial effects of vasopeptidase inhibitors.
Burrell
L M
LM
Department of Medicine, The University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia. burrell@austin.unimelb.edu.au
Droogh
J
J
Man in't Veld
O
O
Rockell
M D
MD
Farina
N K
NK
Johnston
C I
CI
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007668:Kidney / Q000201:enzymology; D008297:Male; D009206:Myocardium / Q000473:pathology; D015260:Neprilysin / Q000037:antagonists & inhibitors; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D013841:Thiazepines / Q000627:therapeutic use*; D013997:Time Factors
D000959:Antihypertensive Agents; D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D015260:Neprilysin