Article date: January 2003
By: Andreas Dendorfer, Verena Folkers, Matthias Klinger, Sebastian Wolfrum, Peter Dominiak in Volume 138, Issue 2, pages 310-316
The high efficacy of ACE inhibitors to potentiate the actions of kinins might be explained by a hypothetical compartment in which B2‐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.
Bradykinin‐induced vasodilation and uptake of tritiated bradykinin were studied in perfused rat hearts during inhibition of ACE and aminopeptidase P. B2‐receptors were localized by immuno‐gold labelling and electron‐microscopy.
The EC50 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 B2‐receptors were blocked simultaneously with the termination of bradykinin infusion.
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 B2‐receptor antagonist (NPC 17731) was used as label.
B2‐receptors were localized in plasmalemmal and cytosolic vesicles of capillary endothelium.
Bradykinin is locally incorporated and can associate with B2‐receptors repeatedly when kinin breakdown is inhibited. This is the kinetic and functional consequence of a colocalization of kininases and B2‐receptors in a compartment constituted by endothelial membrane vesicles.
The high efficacy of ACE inhibitors to potentiate the actions of kinins might be explained by a hypothetical compartment in which B2‐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.
Bradykinin‐induced vasodilation and uptake of tritiated bradykinin were studied in perfused rat hearts during inhibition of ACE and aminopeptidase P. B2‐receptors were localized by immuno‐gold labelling and electron‐microscopy.
The EC50 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 B2‐receptors were blocked simultaneously with the termination of bradykinin infusion.
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 B2‐receptor antagonist (NPC 17731) was used as label.
B2‐receptors were localized in plasmalemmal and cytosolic vesicles of capillary endothelium.
Bradykinin is locally incorporated and can associate with B2‐receptors repeatedly when kinin breakdown is inhibited. This is the kinetic and functional consequence of a colocalization of kininases and B2‐receptors in a compartment constituted by endothelial membrane vesicles.
British Journal of Pharmacology (2003) 138, 310–316. doi:10.1038/sj.bjp.0705036
DOI: 10.1038/sj.bjp.0705036
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