CONVERTING-ENZYME DETERMINES PLASMA-CLEARANCE OF ANGIOTENSIN-(1-7)

We determined the mechanism accounting for the removal and metabolism of angiotensin-(1-7) [Ang-(1-7)] in 21 anesthetized spontaneously hype rtensive (SHR), 18 age-matched normotensive Sprague-Dawley (SD), and 3 6 mRen-2 transgenic (TG(+)) rats. Animals of all 3 strains were provid ed with tap water or lap water containing losartan, lisinopril, or a c ombination of lisinopril and losartan for 2 weeks. On the day of the e xperiment, 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 b lood were collected rapidly at regular intervals for the assay of plas ma Ang-(1-7) levels by radioimmunoassay. infusion of Ang-(1-7) had a m inimal effect on vehicle-treated SD rats but elicited a biphasic press or/depressor response in vehicle-treated SHR and TG(+) rats. In lisino pril-treated rats, Ang-(1-7) infusion increased blood pressure, wherea s losartan treatment abolished the presser component of the response w ithout altering the secondary fall in arterial pressure. Combined trea tment with lisinopril and losartan abolished the cardiovascular respon se 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 losar tan 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 sign ificantly greater in the untreated SD rats compared with either the SH R or TG+ rat. Lisinopril treatment was associated with reduced clearan ce of Ang-(1-7) in all 3 strains. Concurrent experiments in pulmonary membranes from SD and SWR showed a statistically significant inhibitio n of I-125-Ang-(1-7) metabolism in the presence of lisinopril. These s tudies showed for the first time that the very shea 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 o f the production and metabolism of the two primary active hormones of the renin angiotensin system.