Primacy of angiotensin converting enzyme in angiotensin-(1–12) metabolism

Abstract

Angiotensin-(1–12) [ANG-(1–12)], a new member of the renin-angiotensin system, is recognized as a renin independent precursor for ANG II. However, the processing of ANG-(1–12) in the circulation in vivo is not fully established. We examined the effect of angiotensin converting enzyme (ACE) and chymase inhibition on angiotensin peptides formation during an intravenous infusion of ANG-(1–12) in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). WKY and SHR were assigned to a short ANG-(1–12) infusion lasting 5, 15, 30, or 60 min ( n = 4–10 each group). In another experiment WKY and SHR were assigned to a continuous 15-min ANG-(1–12) infusion with pretreatment of saline, lisinopril (10 mg/kg), or chymostatin (10 mg/kg) ( n = 7–13 each group). Saline or lisinopril were infused intravenously 15 min before the administration of ANG-(1–12) (2 nmol·kg−1·min−1), whereas chymostatin was given by bolus intraperitoneal injection 30 min before ANG-(1–12). Infusion of ANG-(1–12) increased arterial pressure and plasma ANG-(1–12), ANG I, ANG II, and ANG-(1–7) levels in WKY and SHR. Pretreatment with lisinopril caused increase in ANG-(1–12) and ANG I and large decreases in ANG II compared with the other two groups in both strains. Pretreatment of chymostatin had no effect on ANG-(1–12), ANG I, and ANG II levels in both strains, whereas it increased ANG-(1–7) levels in WKY. We conclude that ACE acts as the primary enzyme for the conversion of ANG-(1–12) to smaller angiotensin peptides in the circulation of WKY and SHR and that chymase may be an ANG-(1–7) degrading enzyme.