Release of Angiotensin-(1-7) From the Rat Hindlimb: Influence of Angiotensin-Converting Enzyme Inhibition

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 35; no. 1, Part 2 Suppl; p. 348
• Main Authors: Chappell, Mark C, Gomez, Martina N, Pirro, Nancy T, Ferrario, Carlos M
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.01.2000
• Subjects: Angiotensin I - analysis; Angiotensin I - metabolism; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Antihypertensive Agents - analysis; Antihypertensive Agents - metabolism; Chromatography, High Pressure Liquid; Dipeptides - pharmacology; Hindlimb; Lisinopril - pharmacology; Male; Neprilysin - antagonists & inhibitors; Peptide Fragments - analysis; Peptide Fragments - metabolism; Peptidyl-Dipeptidase A - metabolism; Perfusion; Protease Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin - metabolism; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - physiology
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.35.1.348

ABSTRACTThe results of recent studies have demonstrated that angiotensin (Ang)-(1-7) contributes to the antihypertensive actions of either combined ACE/Ang II type 1 receptor blockade or ACE inhibition alone. The vasculature is a key site of action for either drug regimen, and evidence favors a local Ang system within these tissues. Because ACE may degrade Ang-(1-7), we determined whether ACE inhibition alters Ang-(1-7) release from the rat hindlimb perfused with Krebs-Ringer buffer containing Ficoll. Ang-(1-7) release averaged 36±13 fmol (period 1, 15-minute collection) and 44±11 fmol (period 2) in the control buffer. The addition of the ACE inhibitor lisinopril to the perfusion buffer augmented levels of Ang-(1-7) in periods 3 (144±39 fmol) and 4 (163±35 fmol;P <0.05 versus 1 or 2, n=8). HPLC and radioimmunoassay of effluent from control or lisinopril treatment demonstrated a single immunoreactive peak with a retention time identical to that of Ang-(1-7). The addition of the neprilysin inhibitor SCH 39370 reduced Ang-(1-7) release in the lisinopril buffer from 177±32 (period 1) and 173±39 (period 2) fmol to 112±24 (period 3) and 87±23 fmol (period 4;P <0.05 versus 1 or 2, n=6). Ang I metabolism in the collected perfusate revealed the formation of Ang-(1-7) that was sensitive only to thimet oligopeptidase inhibition; Ang II generation was not detected. The present study demonstrates the recovery of endogenous Ang-(1-7) from the perfused hindlimb. The release of Ang-(1-7) is significantly influenced by inhibition of ACE, which may reflect both increased substrate (Ang I) levels and reduced metabolism of the peptide. Neprilysin inhibition reduced but did not abolish Ang-(1-7) release, which suggests that other endopeptidases may contribute to the release of the peptide.