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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.

Angiotensin-Converting Enzyme–Independent Contraction to Angiotensin I in Human Resistance Arteries