Chronic endopeptidase inhibition in DOCA-salt hypertension: Mechanism of cardiovascular protection

Mohammad A. Newaz, Zivar Yousefipour, Hantz Hercule, Luan Truong, Adebayo Oyekan

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

These studies examined the interactions of neutral endopeptidase (NEP), endothelin-1 (ET-1), and nitric oxide (NO) in deoxycorticosterone acetate (DOCA)-induced hypertension. Male Sprague-Dawley rats (n=35) were uninephrectomized (UNx) or uninephrectomized and treated with DOCA (25 mg pellet implanted subcutaneously). Candoxatril (30 mg/kg day-1), a NEP inhibitor, was given orally for 3 weeks in UNx or DOCA rats. Sham nephrectomized rats (SHAM) served as controls. Except SHAM, all other groups received 1% NaCl in drinking water ad libitum. Measurements were taken of systolic blood pressure (SBP), left ventricle (LV), and aortic weight (AW), plasma ET-1, and urinary excretion of nitrite and Na+. Whole body vascular hypertrophy and morphometric analysis of histological sections of the heart were also determined. In DOCA rats, SBP increased from 113 ± 5 to 170 ± 5 mmHg without significant changes in body weight (BW). Candoxatril reduced the increase in SBP to 135 ± 9 mmHg (P < 0.05), abolished the increased LV wall thickness (P < 0.05), and increased the reduced LV lumen diameter (P < 0.05) in DOCA-salt rats. Candoxatril also reduced plasma ET-1 by 88 ± 9% and 89 ± 17% (P < 0.05) in UNx and DOCA rats, respectively, and elicited increases in urinary excretion of nitrite. These effects were accompanied by a marked increase in urinary excretion of Na+ (UNaV) (P < 0.05) and a blunting of the proteinuria (32 ± 5%; P < 0.05) in DOCA rats. We conclude that endopeptidase inhibition in DOCA-salt hypertension reduced the increase in blood pressure and the attendant tissue hypertrophy and renal injury. These effects suggest a correlation between endopeptidase-related reduction in ET-1 production and protection in DOCA-salt hypertension.

Original languageEnglish (US)
Pages (from-to)335-347
Number of pages13
JournalClinical and Experimental Hypertension
Volume25
Issue number6
DOIs
StatePublished - Aug 1 2003

Keywords

  • Blood pressure
  • Candoxatril
  • DOCA
  • Endothelin-1
  • Hypertrophy
  • NEP

ASJC Scopus subject areas

  • Internal Medicine

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