Alternative pathways of angiotensin II production in the human saphenous vein.
1. The aim of our study was to demonstrate the existence, location and functional importance of an alternative angiotensin II-forming pathway other than angiotensin converting enzyme (ACE) in the human saphenous vein (SV). 2. Vascular reactivity studies using an in vitro organ bath technique showed that the SV (n=20) produced similar maximum contractions in response to angiotensin I (41.5+/-5.4 mN) compared to those observed to angiotensin II (46.7+/-10.9 mN). The response to angiotensin I could be significantly inhibited (P<0.05) by incubation with the AT1 receptor antagonist losartan (1 microM). 3. Prior incubation of segments of SV with either captopril (1 microM) (n=6), quinaprilat (1 microM) (n=7), or the chymase inhibitor soya bean trypsin inhibitor (SBTI) (10 microM) (n=7) singularly failed to have any inhibitory effect on the response to angiotensin I. However when vessel segments (n=7) were co-incubated with quinaprilat (1 microM) and SBTI (10 microM), the SV exhibited a rightward shift in curve profile to angiotensin I and a markedly reduced maximum response 12.5+/-2.4 mN, when compared to control (30.4+/-7.6 mN), quinaprilat (24.5+/-9.4 mN), and SBTI (31.6+/-10.7 mN) on their own. 4. An immunohistochemical technique employing streptavidin biotin peroxidase localised ACE to both endothelial cells and smooth muscle cells while chymase was confined to mast cells in the adventitia of the vessel wall. 5. In conclusion, our results demonstrate the existence of an alternative angiotensin I converting pathway to that of ACE, involving chymase. Therefore, there is the capacity for a continuation of angiotensin II formation, in the presence of ACE inhibition.
Borland
J A
JA
Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of Science Technology and Medicine, Heart Science Centre, Harefield Hospital, Uxbridge, UK.
Chester
A H
AH
Morrison
K A
KA
Yacoub
M H
MH
D000804:Angiotensin II / Q000096:biosynthesis*; D053818:Chymases; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D012501:Saphenous Vein / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000502:physiology
D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases