title: ACE-versus chymase-dependent angiotensin II generation in human coronary arteries: a matter of efficiency?
abstract: OBJECTIVE
  The objective of this study was to investigate ACE- and chymase-dependent angiotensin I-to-II conversion in human coronary arteries (HCAs).
  
  
  RESULTS
  HCA rings were mounted in organ baths, and concentration-response curves to angiotensin II, angiotensin I, and the chymase-specific substrate Pro(11)-D-Ala(12)-angiotensin I (PA-angiotensin I) were constructed. All angiotensins displayed similar efficacy. For a given vasoconstriction, bath (but not interstitial) angiotensin II during angiotensin I and PA-angiotensin I was lower than during angiotensin II, indicating that interstitial (and not bath) angiotensin II determines vasoconstriction. PA-angiotensin I increased interstitial angiotensin II less efficiently than angiotensin I. Separate inhibition of ACE (with captopril) and chymase (with C41 or chymostatin) shifted the angiotensin I concentration-response curve approximately 5-fold to the right, whereas a 10-fold shift occurred during combined ACE and chymase inhibition. Chymostatin, but not captopril and/or C41, reduced bath angiotensin II and abolished PA-Ang I-induced vasoconstriction. Perfused HCA segments, exposed luminally or adventitially to angiotensin I, released angiotensin II into the luminal and adventitial fluid, respectively, and this release was blocked by chymostatin.
  
  
  CONCLUSIONS
  Both ACE and chymase contribute to the generation of functionally active angiotensin II in HCAs. However, because angiotensin II loss in the organ bath is chymase-dependent, ACE-mediated conversion occurs more efficiently (ie, closer to AT(1) receptors) than chymase-mediated conversion.
authors.affiliation: Department of Pharmacology, Thoracic Surgery and Heart Valve Bank, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Beril
authors.initials: B
authors.lastname: Tom
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Scalbert
authors.forename: Alexander P A
authors.initials: AP
authors.lastname: Stegmann
authors.forename: Frans
authors.initials: F
authors.lastname: Boomsma
authors.forename: Pramod R
authors.initials: PR
authors.lastname: Saxena
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
mesh_terms: D000293:Adolescent; D000328:Adult; D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism* / Q000502:physiology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D053818:Chymases; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D005110:Extracellular Space / Q000737:chemistry; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007552:Isotonic Solutions; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D010477:Perfusion; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013379:Substrate Specificity / Q000187:drug effects; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007552:Isotonic Solutions; C051865:Krebs-Ringer solution; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D000804:Angiotensin II; D000803:Angiotensin I; C002101:chymostatin; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases