title: Bj-PRO-5a, a natural angiotensin-converting enzyme inhibitor, promotes vasodilatation mediated by both bradykinin B₂and M1 muscarinic acetylcholine receptors.
abstract: Bradykinin-potentiating peptides (BPPs) or proline-rich oligopeptides (PROs) isolated from the venom glands of Bothrops jararaca (Bj) were the first natural inhibitors of the angiotensin-converting enzyme (ACE) described. Bj-PRO-5a (<EKWAP), a member of this structurally related peptide family, was essential for the development of captopril, the first site-directed ACE inhibitor used for the treatment of human hypertension. Nowadays, more Bj-PROs have been identified with higher ACE inhibition potency compared to Bj-PRO-5a. However, despite its modest inhibitory effect of ACE inhibition, Bj-PRO-5a reveals strong bradykinin-potentiating activity, suggesting the participation of other mechanisms for this peptide. In the present study, we have shown that Bj-PRO-5a induced nitric oxide (NO) production depended on muscarinic acetylcholine receptor M1 subtype (mAchR-M1) and bradykinin B₂ receptor activation, as measured by a chemiluminescence assay using a NO analyzer. Intravital microscopy based on transillumination of mice cremaster muscle also showed that both bradykinin B₂ receptor and mAchR-M1 contributed to the vasodilatation induced by Bj-PRO-5a. Moreover, Bj-PRO-5a-mediated vasodilatation was completely blocked in the presence of a NO synthase inhibitor. The importance of this work lies in the definition of novel targets for Bj-PRO-5a in addition to ACE, the structural model for captopril development.
authors.affiliation: Center for Applied Toxinology CAT-CEPID, Instituto Butantan, SP, Brazil.
authors.forename: K L P
authors.initials: KL
authors.lastname: Morais
authors.forename: M A F
authors.initials: MA
authors.lastname: Hayashi
authors.forename: F M
authors.initials: FM
authors.lastname: Bruni
authors.forename: M
authors.initials: M
authors.lastname: Lopes-Ferreira
authors.forename: A C M
authors.initials: AC
authors.lastname: Camargo
authors.forename: H
authors.initials: H
authors.lastname: Ulrich
authors.forename: C
authors.initials: C
authors.lastname: Lameu
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D017837:Bothrops; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003435:Crotalid Venoms / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D055232:Proline-Rich Protein Domains / Q000502:physiology*; D043782:Receptor, Bradykinin B2 / Q000502:physiology*; D043643:Receptor, Muscarinic M1 / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D003435:Crotalid Venoms; D043782:Receptor, Bradykinin B2; D043643:Receptor, Muscarinic M1