title: Chronic endopeptidase inhibition in DOCA-salt hypertension: mechanism of cardiovascular protection.
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+ (U(Na)V) (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.
authors.affiliation: Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004, USA.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Newaz
authors.forename: Zivar
authors.initials: Z
authors.lastname: Yousefipour
authors.forename: Hantz
authors.initials: H
authors.lastname: Hercule
authors.forename: Luan
authors.initials: L
authors.lastname: Truong
authors.forename: Adebayo
authors.initials: A
authors.lastname: Oyekan
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone; D019332:Endothelin-1 / Q000097:blood; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism; D007189:Indans / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D019332:Endothelin-1; D007189:Indans; D011422:Propionates; D009569:Nitric Oxide; D003900:Desoxycorticosterone; D012964:Sodium; C062766:candoxatril; D015260:Neprilysin