Vasopeptidase inhibition and Ang-(1-7) in the spontaneously hypertensive rat

Abstract

Omapatrilat, a new vasopeptidase inhibitor, inhibits the activity of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP). Because these two enzymes participate in the degradation of the vasodilator and natriuretic peptide, angiotensin-(1-7) [Ang-(1-7)], we assessed whether omapatrilat treatment is associated with changes in the plasma and urinary excretion rates of the angiotensins. We investigated in spontaneously hypertensive rats (SHR) (0.24 kg body weight) the effect of omapatrilat on plasma and urinary concentrations of angiotensin (Ang) I, Ang II and Ang-(1-7) during 17 days of administration of either the drug (N = 15, 100 micromol/kg/day) or vehicle (N = 14) in the drinking water. Hemodynamic and renal excretory function studies were associated with histological examination of the expression of Ang-(1-7) in the kidneys of both vehicle and omapatrilat-treated SHRs. Omapatrilat induced a sustained lowering of systolic blood pressure (-68 mm Hg) without changes in cardiac rate. The mild positive water balance produced by omapatrilat did not cause natriuresis or kaliuresis, although it was associated with a significant decrease in urine osmolality. Blood pressure normalization was accompanied by increases in plasma Ang I (2969%), Ang II (57%), and Ang-(1-7) (163%) levels, paralleling pronounced increases in urinary excretion rates of Ang I and Ang-(1-7) but not Ang II. Detection of Ang-(1-7) immunostaining in the kidneys of five other SHR exposed either to vehicle (N = 3) or omapatrilat (N = 2) ascertained the source of the Ang-(1-7) found in the urine. Intense Ang-(1-7) staining, more pronounced in omapatrilat-treated SHR, was found in renal proximal tubules throughout the outer and inner regions of the renal cortex and the thick ascending loop of Henle, whereas no Ang-(1-7)-positive immunostaining was found in glomeruli and distal tubules. Omapatrilat antihypertensive effects caused significant activation of the renin-angiotensin system associated with increases in urinary excretion rates of Ang I and Ang-(1-7). Combined studies of Ang-(1-7) metabolism in urine and immunohistochemical studies in the kidney revealed the existence of an intrarenal source, which may account for the pronounced increase in the excretion rate of the vasodilator heptapeptide. These findings provide further evidence for a contribution of Ang-(1-7) to the regulation of renal function and blood pressure.