Abstract 235: Role of Angiotensin Converting Enzyme on the Production of Angiotensins From Angiotensin-(1-12) In Normotensive Wistar-kyoto Rats and Spontaneously Hypertensive Rats
We investigated the metabolic pathways contributing to angiotensin II (Ang II) formation from Ang-(1-12) in WKY and SHR. Intravenous infusion of Ang-(1-12) (2 nmol/kg/min) induced a significant pressor response (+ 48 ± 5 mm Hg). Pretreatment with lisinopril [angiotensin converting enzyme (ACE) inhibitor, 10mg/kg] abolished the pressor response by Ang-(1-12) while chymostatin (chymase inhibitor, 10mg/kg) had no effect on the blood pressure rise by Ang-(1-12). ACE inhibition increased plasma Ang-(1-12) from an average of 6,750 ± 2,871 to 23,345 ± 4,509 fmol/mL in vehicle and lisinopril-treated WKY (P < 0.01), respectively (Figure), whereas in SHR plasma Ang-(1-12) rose to 14,334 ± 5,971 in lisinopril-treated compared to 432 ± 142 fmol/mL in vehicle-treated SHR (P < 0.01). The degradation of Ang-(1-12) into Ang I following lisinopril treatment resulted in plasma Ang I averaging 4,762 ± 746 in WKY versus 2,724 ± 657 fmol/mL in SHR compared to plasma Ang I of 744 ± 149 and 580 ± 81 fmol/mL in vehicle-treated WKY and SHR (all P < 0.01). ACE inhibition suppressed Ang II formation from Ang-(1-12) to almost the detectable level of the assay. In contrast, chymostatin increased plasma Ang-(1-7) (138% of control, P<0.05) while having no effect on Ang-(1-12), Ang I or Ang II following Ang-(1-12) infusion compared to control in WKY but not SHR. The data shows that Ang-(1-12) metabolism or plasma clearance is significantly augmented in SHR compared to WKY and that in both strains ACE acts as the primary source for the direct circulatory conversion of Ang-(1-12) into Ang II. Furthermore, we now show for the first time a role of chymase in acting as an Ang-(1-7) degrading enzyme in WKY.
- © 2012 by American Heart Association, Inc.