Omapatrilat increases renal endothelin in deoxycorticosterone acetate-salt hypertensive rats

Ahmed Abdelrazik Elmarakby, Peter Morsing, Jennifer S. Pollock, David M. Pollock

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)253-259
Number of pages7
JournalVascular Pharmacology
Volume40
Issue number5
DOIs
StatePublished - Dec 1 2003

Fingerprint

Desoxycorticosterone
Endothelins
Neprilysin
Acetates
Enalapril
Salts
Kidney
Peptidyl-Dipeptidase A
Angiotensin-Converting Enzyme Inhibitors
Arterial Pressure
Hypertension
Bradykinin
Protease Inhibitors
Renin
Antihypertensive Agents
omapatrilat
Blood Pressure
Pharmaceutical Preparations

Keywords

  • Angiotensin-converting enzyme inhibitors
  • DOCA-salt rats
  • Urinary endothelin excretion
  • Vasopeptidase inhibitors

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

Cite this

Omapatrilat increases renal endothelin in deoxycorticosterone acetate-salt hypertensive rats. / Elmarakby, Ahmed Abdelrazik; Morsing, Peter; Pollock, Jennifer S.; Pollock, David M.

In: Vascular Pharmacology, Vol. 40, No. 5, 01.12.2003, p. 253-259.

Research output: Contribution to journalArticle

Elmarakby, Ahmed Abdelrazik ; Morsing, Peter ; Pollock, Jennifer S. ; Pollock, David M. / Omapatrilat increases renal endothelin in deoxycorticosterone acetate-salt hypertensive rats. In: Vascular Pharmacology. 2003 ; Vol. 40, No. 5. pp. 253-259.
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