title: Angiotensin-(1-7) potentiates responses to bradykinin but does not change responses to angiotensin I.
abstract: Angiotensin-(1-7) (Ang-(1-7)), a bioactive peptide in the renin-angiotensin system, has counterregulatory actions to angiotensin II (Ang II). However, the mechanism by which Ang-(1-7) enhances vasodepressor responses to bradykinin (BK) is not well understood. In the present study, the effects of Ang-(1-7) on responses to BK, BK analogs, angiotensin I (Ang I), and Ang II were investigated in the anesthetized rat. The infusion of Ang-(1-7) (55 pmol/min i.v.) enhanced decreases in systemic arterial pressure in response to i.v. injections of BK and the BK analogs [Hyp3, Tyr(Me)8]-bradykinin (HT-BK) and [Phe8psi (CH2-NH) Arg9]-bradykinin (PA-BK) without altering pressor responses to Ang I or II, or depressor responses to acetylcholine and sodium nitroprusside. The angiotensin-converting enzyme (ACE) inhibitor enalaprilat enhanced responses to BK and the BK analog HT-BK without altering responses to PA-BK and inhibited responses to Ang I. The potentiating effects of Ang-(1-7) and enalaprilat on responses to BK were not attenuated by the Ang-(1-7) receptor antagonist A-779. Ang-(1-7)- and ACE inhibitor-potentiated responses to BK were attenuated by the BK B2 receptor antagonist Hoe 140. The cyclooxygenase inhibitor sodium meclofenamate had no significant effect on responses to BK or Ang-(1-7)-potentiated BK responses. These results suggest that Ang-(1-7) potentiates responses to BK by a selective B2 receptor mechanism that is independent of an effect on Ang-(1-7) receptors, ACE, or cyclooxygenase product formation. These data suggest that ACE inhibitor-potentiated responses to BK are not mediated by an A-779-sensitive mechanism and are consistent with the hypothesis that enalaprilat-induced BK potentiation is due to decreased BK inactivation.
authors.affiliation: Department of Pharmacology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: A Joel
authors.initials: AJ
authors.lastname: Greco
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Master
authors.forename: Alex
authors.initials: A
authors.lastname: Fokin
authors.forename: Syed R
authors.initials: SR
authors.lastname: Baber
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kadowitz
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology*; D002342:Carotid Artery, External / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015773:Enalaprilat / Q000494:pharmacology; D008297:Male; D008469:Meclofenamic Acid / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2 / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C092006:7-Ala-angiotensin (1-7); D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D016861:Cyclooxygenase Inhibitors; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043782:Receptor, Bradykinin B2; D043562:Receptors, G-Protein-Coupled; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D008469:Meclofenamic Acid; C065679:icatibant; D000803:Angiotensin I; D015773:Enalaprilat; C118790:angiotensin I (1-7); D001920:Bradykinin