Effects of omapatrilat on the renin-angiotensin system in salt-sensitive hypertension.
The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which omapatrilat induces an antihypertensive response in salt sensitive hypertension.
Ferrario
Carlos M
CM
Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. cferrari@wfubmc.edu
Smith
Ronald D
RD
Brosnihan
Bridget
B
Chappell
Mark C
MC
Campese
Vito M
VM
Vesterqvist
Ole
O
Liao
Wei-chi
WC
Ruddy
Michael C
MC
Grim
Clarence E
CE
D000293:Adolescent; D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000809:Angiotensins / Q000097:blood / Q000652:urine; D009320:Atrial Natriuretic Factor / Q000187:drug effects* / Q000652:urine; D018660:Blood Pressure Monitoring, Ambulatory; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D017706:Lisinopril / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012982:Sodium, Dietary / Q000009:adverse effects; D013841:Thiazepines / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D011725:Pyridines; D012982:Sodium, Dietary; D013841:Thiazepines; C106266:omapatrilat; D009320:Atrial Natriuretic Factor; D017706:Lisinopril