title: Metalloendopeptidases EC 3.4.24.15/16 regulate bradykinin activity in the cerebral microvasculature.
abstract: Bradykinin is a vasoactive peptide that has been shown to increase the permeability of the cerebral microvasculature to blood-borne macromolecules. The two zinc metalloendopeptidases EC (EP 24.15) and EC (EP 24.16) degrade bradykinin in vitro and are highly expressed in the brain. However, the role that these enzymes play in bradykinin metabolism in vivo remains unclear. In the present study, we investigated the role of EP 24.15 and EP 24.16 in the regulation of bradykinin-induced alterations in microvascular permeability. Permeability of the cerebral microvasculature was assessed in anesthetized Sprague-Dawley rats by measuring the clearance of 70-kDa FITC dextran from the brain. Inhibition of EP 24.15 and EP 24.16 by the specific inhibitor N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA-2) resulted in the potentiation of bradykinin-induced increases in cerebral microvessel permeability. The level of potentiation was comparable to that achieved by the inhibition of angiotensin-converting enzyme. These findings provide the first evidence of an in vivo role for EP 24.15/EP 24.16 in brain function, specifically in regulating alterations in microvessel permeability induced by exogenous bradykinin.
authors.affiliation: Baker Heart Research Institute, Melbourne, Victoria 8008, Australia.
authors.forename: M Ursula
authors.initials: MU
authors.lastname: Norman
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Lew
authors.forename: A Ian
authors.initials: AI
authors.lastname: Smith
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D002199:Capillary Permeability / Q000187:drug effects; D002550:Cerebral Veins / Q000187:drug effects / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003911:Dextrans; D004305:Dose-Response Relationship, Drug; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008833:Microcirculation / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2
chemical_list: D065168:Bradykinin Receptor Antagonists; D003911:Dextrans; D011480:Protease Inhibitors; D043782:Receptor, Bradykinin B2; C015219:fluorescein isothiocyanate dextran; C065679:icatibant; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase; C062316:neurolysin; D016650:Fluorescein-5-isothiocyanate; D001920:Bradykinin