Candoxatril reduced systolic blood pressure to 135 +/- 9 mmHg compared to 170 +/- 5 mmHg in untreated DOCA-salt rats (P<0.05), and attenuated tissue hypertrophy and renal injury.
Does candoxatril reduce blood pressure and cardiovascular hypertrophy in a DOCA-salt hypertension rat model?
Endopeptidase inhibition with candoxatril reduces blood pressure, tissue hypertrophy, and renal injury in DOCA-salt hypertensive rats, likely via reduction in ET-1 production.
Absolute Event Rate: 135% vs 170%
p-value: p=<0.05
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.
Newaz et al. (Wed,) conducted a other in DOCA-induced hypertension (n=35). Candoxatril vs. Untreated DOCA rats and SHAM controls was evaluated on Systolic blood pressure (SBP) (p=<0.05). Candoxatril reduced systolic blood pressure to 135 +/- 9 mmHg compared to 170 +/- 5 mmHg in untreated DOCA-salt rats (P<0.05), and attenuated tissue hypertrophy and renal injury.