Pathways for angiotensin-(1-7) metabolism in pulmonary and renal tissues

Two of the primary sites of actions for angiotensin (ANG)-(1-7) are the vas culature and the kidney. Because little information exists concerning the m etabolism of ANG-(1-7) in these tissues, we investigated the hydrolysis of the peptide in rat lung and renal brush-border membrane (BBM) preparations. Radiolabeled ANG-(1-7) was hydrolyzed primarily to ANG-(1-5) by pulmonary membranes. The ANG-converting enzyme (ACE) inhibitor lisinopril abolished t he generation of ANG( 1-5), as well as that of smaller metabolites. Kinetic studies of the hydrolysis of ANG-(1-7) to ANG-(1-5) by somatic (pulmonary) and germinal (testes) forms of rat ACE yielded similar values, suggesting that the COOH-domain is responsible for the hydrolysis of ANG-(1-7). Pulmon ary metabolism of ANG-(1-5) yielded ANG-(3-5) and was independent of ACE bu t may involve peptidyl or dipeptidyl aminopeptidases. In renal cortex BBM, ANG-(1-7) was rapidly hydrolyzed to mono- and dipeptide fragments and ANG-( 1-4). Aminopeptidase (AP) inhibition attenuated the hydrolysis of ANG-(1-7) and increased ANG-(1-4) formation. Combined treatment with AP and neprilys in (Nep) inhibitors abolished ANG-(1-4) formation and preserved ANG-(1-7). ACE inhibition had no effect on the rate of hydrolysis or the metabolites f ormed in the BBM. In conclusion, ACE was the major enzymatic activity respo nsible for the metabolism of ANG-(1-7) in the lung, which is consistent wit h the ability of ACE inhibitors to increase the half-life of circulating AN G-(1-7) and raise endogenous levels of the peptide. An alternate pathway of metabolism was revealed in the renal cortex, where increased AP and Nep ac tivities, relative to ACE activity, promote conversion of ANG-(1-7) to ANG- (1-4) and smaller fragments.