title: Angiotensin-converting enzyme-independent contraction to angiotensin I in human resistance arteries.
abstract: 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.
  
  
  RESULTS
  Subcutaneous resistance arteries (250 to 350 microm) 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 micromol/L and endothelial integrity by relaxation to acetylcholine 3 micromol/L. Cumulative concentration-response curves were constructed for Ang I in the presence of enalaprilat 1 micromol/L, chymostatin 10 micromol/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.
authors.affiliation: Department of Medicine and Therapeutics, Western Infirmary, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK. np3n@clinmed.gla.ac.uk
authors.forename: N
authors.initials: N
authors.lastname: Padmanabhan
authors.forename: A G
authors.initials: AG
authors.lastname: Jardine
authors.forename: J C
authors.initials: JC
authors.lastname: McGrath
authors.forename: J M
authors.initials: JM
authors.lastname: Connell
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000803:Angiotensin I / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology; D004338:Drug Combinations; D015773:Enalaprilat / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D014655:Vascular Resistance / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004338:Drug Combinations; D009842:Oligopeptides; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000803:Angiotensin I; C002101:chymostatin; D007703:Peptidyl-Dipeptidase A; D015773:Enalaprilat; D000109:Acetylcholine; D011188:Potassium; D001920:Bradykinin; D009638:Norepinephrine