title: Selective angiotensin-converting enzyme C-domain inhibition is sufficient to prevent angiotensin I-induced vasoconstriction.
abstract: Somatic angiotensin-converting enzyme (ACE) contains 2 domains (C-domain and N-domain) capable of hydrolyzing angiotensin I (Ang I) and bradykinin. Here we investigated the effect of the selective C-domain and N-domain inhibitors RXPA380 and RXP407 on Ang I-induced vasoconstriction of porcine femoral arteries (PFAs) and bradykinin-induced vasodilation of preconstricted porcine coronary microarteries (PCMAs). Ang I concentration-dependently constricted PFAs. RXPA380, at concentrations >1 mumol/L, shifted the Ang I concentration-response curve (CRC) 10-fold to the right. This was comparable to the maximal shift observed with the ACE inhibitors (ACEi) quinaprilat and captopril. RXP407 did not affect Ang I at concentrations < or =0.1 mmol/L. Bradykinin concentration-dependently relaxed PCMAs. RXPA380 (10 micromol/L) and RXP407 (0.1 mmol/L) potentiated bradykinin, both inducing a leftward shift of the bradykinin CRC that equaled approximately 50% of the maximal shift observed with quinaprilat. Ang I added to blood plasma disappeared with a half life (t(1/2)) of 42+/-3 minutes. Quinaprilat increased the t(1/2) approximately 4-fold, indicating that 71+/-6% of Ang I metabolism was attributable to ACE. RXPA380 (10 micromol/L) and RXP407 (0.1 mmol/L) increased the t(1/2) approximately 2-fold, thereby suggesting that both domains contribute to conversion in plasma. In conclusion, tissue Ang I-II conversion depends exclusively on the ACE C-domain, whereas both domains contribute to conversion by soluble ACE and to bradykinin degradation at tissue sites. Because tissue ACE (and not plasma ACE) determines the hypertensive effects of Ang I, these data not only explain why N-domain inhibition does not affect Ang I-induced vasoconstriction in vivo but also why ACEi exert blood pressure-independent effects at low (C-domain-blocking) doses.
authors.affiliation: Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Joep H M
authors.initials: JH
authors.lastname: van Esch
authors.forename: Beril
authors.initials: B
authors.lastname: Tom
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Batenburg
authors.forename: Dimitris
authors.initials: D
authors.lastname: Georgiadis
authors.forename: Athanasios
authors.initials: A
authors.lastname: Yiotakis
authors.forename: Jeanette M G
authors.initials: JM
authors.lastname: van Gool
authors.forename: René J A
authors.initials: RJ
authors.lastname: de Bruijn
authors.forename: René
authors.initials: R
authors.lastname: de Vries
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
mesh_terms: D000293:Adolescent; D000328:Adult; D000803:Angiotensin I / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000378:metabolism* / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D009928:Organ Specificity; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D010721:Phosphinic Acids / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000187:drug effects; D012995:Solubility; D013329:Structure-Activity Relationship; D034421:Sus scrofa; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; D010721:Phosphinic Acids; C118733:RXP 407; C476531:RXPA380; D044005:Tetrahydroisoquinolines; C054501:quinaprilat; D000803:Angiotensin I; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin