Converting Enzyme Determines Plasma Clearance of Angiotensin-(1–7)

Abstract —We determined the mechanism accounting for the removal and metabolism of angiotensin-(1–7) [Ang-(1–7)] in 21 anesthetized spontaneously hypertensive (SHR), 18 age-matched normotensive Sprague-Dawley (SD), and 36 mRen-2 transgenic (TG + ) rats. Animals of all 3 strains were provided with tap water or tap water containing losartan, lisinopril, or a combination of lisinopril and losartan for 2 weeks. On the day of the experiment, Ang-(1–7) was infused for a period of 15 minutes at a rate of 278 nmol · kg −1 · min −1 . After this time, samples of arterial blood were collected rapidly at regular intervals for the assay of plasma Ang-(1–7) levels by radioimmunoassay. Infusion of Ang-(1–7) had a minimal effect on vehicle-treated SD rats but elicited a biphasic pressor/depressor response in vehicle-treated SHR and TG + rats. In lisinopril-treated rats, Ang-(1–7) infusion increased blood pressure, whereas losartan treatment abolished the pressor component of the response without altering the secondary fall in arterial pressure. Combined treatment with lisinopril and losartan abolished the cardiovascular response to Ang-(1–7) in all 3 strains. In vehicle-treated SD, SHR and TG + the half-life (t 1/2 ) of Ang-(1–7) averaged 10±1, 10±1, and 9±1 seconds, respectively. Lisinopril alone or in combination with losartan produced a statistically significant rise in the half-life of Ang-(1–7) in all 3 strains of rats. Plasma clearance of Ang-(1–7) was significantly greater in the untreated SD rats compared with either the SHR or TG + rat. Lisinopril treatment was associated with reduced clearance of Ang-(1–7) in all 3 strains. Concurrent experiments in pulmonary membranes from SD and SHR showed a statistically significant inhibition of 125 I-Ang-(1–7) metabolism in the presence of lisinopril. These studies showed for the first time that the very short half-life of Ang-(1–7) in the circulation is primarily accounted for peptide metabolism by ACE. These findings suggest a novel role of ACE in the regulation of the production and metabolism of the two primary active hormones of the renin angiotensin system.