title: Inhibition of kinin breakdown prolongs retention and action of bradykinin in a myocardial B2 receptor compartment.
abstract: 1. The high efficacy of ACE inhibitors to potentiate the actions of kinins might be explained by a hypothetical compartment in which B(2)-receptors are colocalized with kinin degrading enzymes. To demonstrate the functional consequence of such a compartment we compared the myocardial uptake and the persistence of action of bradykinin under the influence of kininase inhibitors. 2. Bradykinin-induced vasodilation and uptake of tritiated bradykinin were studied in perfused rat hearts during inhibition of ACE and aminopeptidase P. B(2)-receptors were localized by immuno-gold labelling and electron-microscopy. 3. The EC(50) of bradykinin-induced vasodilation (5.1+/-0.8 nM) was shifted to 14 fold lower concentrations during inhibition of both kininases. The maximum persistence of vasodilation after termination of bradykinin application (half-life 112+/-20 s) was increased by kininase inhibitors to 398+/-130 s. This prolongation was reversed when B(2)-receptors were blocked simultaneously with the termination of bradykinin infusion. 4. Tritiated bradykinin (perfused for 1 min) was partially (1.7+/-0.24%) retained by the myocardium and consecutively released with a half-life of 70+/-9 s. Kinin uptake was increased during kininase inhibition (7.7+/-2.6%), and was normalized by HOE 140 (2.0+/-0.34%), or when a tritiated B(2)-receptor antagonist (NPC 17731) was used as label. 5. B(2)-receptors were localized in plasmalemmal and cytosolic vesicles of capillary endothelium. 6. Bradykinin is locally incorporated and can associate with B(2)-receptors repeatedly when kinin breakdown is inhibited. This is the kinetic and functional consequence of a colocalization of kininases and B(2)-receptors in a compartment constituted by endothelial membrane vesicles.
authors.affiliation: Institute of experimental and clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. dendorfe@medinf.mu-luebeck.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Dendorfer
authors.forename: Verena
authors.initials: V
authors.lastname: Folkers
authors.forename: Matthias
authors.initials: M
authors.lastname: Klinger
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wolfrum
authors.forename: Peter
authors.initials: P
authors.lastname: Dominiak
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin