Release of angiotensin-(1-7) from the rat hindlimb: influence of angiotensin-converting enzyme inhibition.
The 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.
Chappell
M C
MC
Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1095, USA. mchappel@wfubmc.edu
Gomez
M N
MN
Pirro
N T
NT
Ferrario
C M
CM
D000803:Angiotensin I / Q000032:analysis / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000032:analysis / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000494:pharmacology; D006614:Hindlimb; D017706:Lisinopril / Q000494:pharmacology*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D010477:Perfusion; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004151:Dipeptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; C060631:Sch 39370; D000803:Angiotensin I; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; C118790:angiotensin I (1-7)