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Am J Physiol Renal Physiol 279: F841-F850, 2000;
0363-6127/00 $5.00
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Vol. 279, Issue 5, F841-F850, November 2000

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

Alicia J. Allred, Debra I. Diz, Carlos M. Ferrario, and Mark C. Chappell

Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Two of the primary sites of actions for angiotensin (ANG)-(1---7) are the vasculature and the kidney. Because little information exists concerning the metabolism 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 the 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). Pulmonary metabolism of ANG-(1---5) yielded ANG-(3---5) and was independent of ACE but 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 neprilysin (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 formed in the BBM. In conclusion, ACE was the major enzymatic activity responsible for the metabolism of ANG-(1---7) in the lung, which is consistent with the ability of ACE inhibitors to increase the half-life of circulating ANG-(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 activities, relative to ACE activity, promote conversion of ANG-(1---7) to ANG-(1---4) and smaller fragments.

angiotensin-converting enzyme; neprilysin; lisinopril; SCH-39370; aminopeptidase; amastatin


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