title: Bradykinin potentiation by angiotensin-(1-7) and ACE inhibitors correlates with ACE C- and N-domain blockade.
abstract: ACE inhibitors block B(2) receptor desensitization, thereby potentiating bradykinin beyond blocking its hydrolysis. Angiotensin (Ang)-(1-7) also acts as an ACE inhibitor and, in addition, may stimulate bradykinin release via angiotensin II type 2 receptors. In this study we compared the bradykinin-potentiating effects of Ang-(1-7), quinaprilat, and captopril. Porcine coronary arteries, obtained from 32 pigs, were mounted in organ baths, preconstricted with prostaglandin F(2alpha), and exposed to quinaprilat, captopril, Ang-(1-7), and/or bradykinin. Bradykinin induced complete relaxation (pEC(50)=8.11+/-0.07, mean+/-SEM), whereas quinaprilat, captopril, and Ang-(1-7) alone were without effect. Quinaprilat shifted the bradykinin curve to the left in a biphasic manner: a 5-fold shift at concentrations that specifically block the C-domain (0.1 to 1 nmol/L) and a 10-fold shift at concentrations that block both domains. Captopril and Ang-(1-7) monophasically shifted the bradykinin curve to the left, by a factor of 10 and 5, respectively. A 5-fold shift was also observed when Ang-(1-7) was combined with 0.1 nmol/L quinaprilat. Repeated exposure of porcine coronary arteries to 0.1 micromol/L bradykinin induced B(2) receptor desensitization. The addition of 10 micromol/L quinaprilat or Ang-(1-7) to the bath, at a time when bradykinin alone was no longer able to induce relaxation, fully restored the relaxant effects of bradykinin. Angiotensin II type 1 or 2 receptor blockade did not affect any of the observed effects of Ang-(1-7). In conclusion, Ang-(1-7), like quinaprilat and captopril, potentiates bradykinin by acting as an ACE inhibitor. Bradykinin potentiation is maximal when both the ACE C- and N-terminal domains are inhibited. The inhibitory effects of Ang-(1-7) are limited to the ACE C-domain, raising the possibility that Ang-(1-7) synergistically increases the blood pressure-lowering effects of N-domain-specific ACE inhibitors.
authors.affiliation: Department of Pharmacology, Erasmus University Rotterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Tom
authors.forename: R
authors.initials: R
authors.lastname: de Vries
authors.forename: P R
authors.initials: PR
authors.lastname: Saxena
authors.forename: A H
authors.initials: AH
authors.lastname: Danser
mesh_terms: D000293:Adolescent; D000328:Adult; D000803:Angiotensin I / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002216:Captopril / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000187:drug effects / Q000378:metabolism; D013552:Swine; D044005:Tetrahydroisoquinolines; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D010446:Peptide Fragments; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D044005:Tetrahydroisoquinolines; C054501:quinaprilat; D000803:Angiotensin I; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; C118790:angiotensin I (1-7); D001920:Bradykinin