Padmanabhan, N., Jardine, A.G., McGrath, J.C., and Connell, J.M.C. (1999) Angiotensin-converting enzyme: independent contraction to angiotensin I in human resistance arteries. Circulation, 99, pp. 2914-2920. (doi:10.1161/01.CIR.99.22.2914)
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Background: In vitro studies of myocardial tissue suggest that angiotensin II (Ang II) may be generated by both ACE and chymase. A similar dual pathway may exist in the vasculature. We studied the effects of ACE and chymase inhibitors on the contractile response to angiotensin I (Ang I) in human resistance arteries to investigate ACE-independent generation of Ang II.
Methods and Results—Subcutaneous resistance arteries (250 to 350 µm) were obtained from gluteal biopsies from volunteers and New Zealand White rabbits and mounted on a wire myograph. Contractile ability was tested with high-potassium depolarization and norepinephrine 10 µmol/L and endothelial integrity by relaxation to acetylcholine 3 µmol/L. Cumulative concentration-response curves were constructed for Ang I in the presence of enalaprilat 1 µmol/L, chymostatin 10 µmol/L, or both inhibitors together. In the rabbit, enalaprilat completely inhibited the Ang I response. In human vessels, enalaprilat or chymostatin alone had no effect, but the combination of enalaprilat and chymostatin almost completely inhibited the response to Ang I.
Conclusions: A dual pathway for Ang II generation exists in human resistance arteries, mediated by ACE and a chymostatin-sensitive enzyme, probably chymase. We confirm that a marked species difference exists in the mechanism of Ang II generation between the human and the rabbit. More efficacious suppression of the renin-angiotensin system may require development of novel enzyme inhibitors or combinations of currently available drugs.
|Glasgow Author(s) Enlighten ID:||Connell, Professor John|
|Authors:||Padmanabhan, N., Jardine, A.G., McGrath, J.C., and Connell, J.M.C.|
|College/School:||College of Medical Veterinary and Life Sciences > School of Medicine|