TY - JOUR
T1 - Omapatrilat increases renal endothelin in deoxycorticosterone acetate-salt hypertensive rats
AU - Elmarakby, Ahmed A.
AU - Morsing, Peter
AU - Pollock, Jennifer S.
AU - Pollock, David M.
N1 - Funding Information:
The authors wish to express their appreciation for the expert technical assistance provided by Mr. Hiram Ocasio and Ms. Janet Stewart. These studies were supported by a grant from the National Heart Lung and Blood Institute (HL64776), an Established Investigator Award from the American Heart Association (D. Pollock) and a Predoctoral Fellowship from Southeast Affiliate of the American Heart Association awarded to A. Elmarakby.
PY - 2003/12
Y1 - 2003/12
N2 - Vasopeptidase inhibitors are a new class of antihypertensive drugs that are single molecules having dual inhibitory action on angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The best known drug in this class is omapatrilat, which has been proposed to be more efficacious than ACE inhibitors because of its ability to inhibit NEP and prevent the breakdown of atrial peptides and bradykinin. However, survival of endothelin (ET) may also be enhanced and therefore, NEP inhibitors may have limited efficacy under conditions of low renin and high ET production. The purpose of the current study was to contrast the effects of the ACE inhibitor, enalapril, with omapatrilat in a model of established hypertension where ACE inhibitors are ineffective, the deoxycorticosterone acetate (DOCA)-salt-treated rat. Two weeks after starting DOCA-salt treatment, rats were given either enalapril (10 mg/kg/day) or omapatrilat (30 mg/kg/day) for 5 days. Mean arterial pressure (MAP) measured by radiotelemetry in untreated DOCA-salt rats increased from 102±2 to 181±12 mm Hg (P<.05) as a result of DOCA-salt treatment for 3 weeks. MAP was unaffected by either enalapril (189±3 mm Hg) or omapatrilat (184±8 mm Hg). DOCA-salt treatment significantly increased urinary ET excretion compared to baseline (1.6±0.2 vs. 0.5±0.1 pmol/day). Administration of omapatrilat significantly increased urinary ET excretion in DOCA-salt rats (2.9±0.4 pmol/day) compared to enalapril-treated (1.6±0.2 pmol/day) or untreated (1.5±0.1 pmol/day) rats. These results indicate that combined ACE/NEP inhibition does not lower blood pressure in a model of established hypertension with high ET activity. These results also support the hypothesis that combined ACE/NEP inhibition can increase renal ET production.
AB - Vasopeptidase inhibitors are a new class of antihypertensive drugs that are single molecules having dual inhibitory action on angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The best known drug in this class is omapatrilat, which has been proposed to be more efficacious than ACE inhibitors because of its ability to inhibit NEP and prevent the breakdown of atrial peptides and bradykinin. However, survival of endothelin (ET) may also be enhanced and therefore, NEP inhibitors may have limited efficacy under conditions of low renin and high ET production. The purpose of the current study was to contrast the effects of the ACE inhibitor, enalapril, with omapatrilat in a model of established hypertension where ACE inhibitors are ineffective, the deoxycorticosterone acetate (DOCA)-salt-treated rat. Two weeks after starting DOCA-salt treatment, rats were given either enalapril (10 mg/kg/day) or omapatrilat (30 mg/kg/day) for 5 days. Mean arterial pressure (MAP) measured by radiotelemetry in untreated DOCA-salt rats increased from 102±2 to 181±12 mm Hg (P<.05) as a result of DOCA-salt treatment for 3 weeks. MAP was unaffected by either enalapril (189±3 mm Hg) or omapatrilat (184±8 mm Hg). DOCA-salt treatment significantly increased urinary ET excretion compared to baseline (1.6±0.2 vs. 0.5±0.1 pmol/day). Administration of omapatrilat significantly increased urinary ET excretion in DOCA-salt rats (2.9±0.4 pmol/day) compared to enalapril-treated (1.6±0.2 pmol/day) or untreated (1.5±0.1 pmol/day) rats. These results indicate that combined ACE/NEP inhibition does not lower blood pressure in a model of established hypertension with high ET activity. These results also support the hypothesis that combined ACE/NEP inhibition can increase renal ET production.
KW - Angiotensin-converting enzyme inhibitors
KW - DOCA-salt rats
KW - Urinary endothelin excretion
KW - Vasopeptidase inhibitors
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U2 - 10.1016/j.vph.2004.01.002
DO - 10.1016/j.vph.2004.01.002
M3 - Article
C2 - 15259792
AN - SCOPUS:1642503706
SN - 1537-1891
VL - 40
SP - 253
EP - 259
JO - Vascular Pharmacology
JF - Vascular Pharmacology
IS - 5
ER -