Inhibition of kinin breakdown prolongs retention and action of bradykinin in a myocardial B2 receptor compartment

Br J Pharmacol. 2003 Jan;138(2):310-6. doi: 10.1038/sj.bjp.0705036.


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.

MeSH terms

  • Aminopeptidases / antagonists & inhibitors
  • Aminopeptidases / metabolism
  • Animals
  • Bradykinin / antagonists & inhibitors*
  • Bradykinin / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Male
  • Myocardium / metabolism*
  • Peptidyl-Dipeptidase A / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, Bradykinin B2
  • Receptors, Bradykinin / metabolism*


  • Enzyme Inhibitors
  • Receptor, Bradykinin B2
  • Receptors, Bradykinin
  • Aminopeptidases
  • X-Pro aminopeptidase
  • Peptidyl-Dipeptidase A
  • Bradykinin