CP-0127, a novel potent bradykinin antagonist, increases survival in rat and rabbit models of endotoxin shock

Abstract

The bradykinin antagonist dimer CP-0127 was found to be a potent and selective inhibitor of the depressor response to bradykinin in the anaesthetized rat and rabbit. When given as a single dose s.c. (3.6 mumol/kg), the depressor response to bradykinin was blocked for the duration of the experiment (4 hours). In anaesthetized control rats, LPS from E. coli produced a profound and immediate hypotensive response, while in rats infused with CP-0127, the response to LPS was almost totally reversed. In addition, CP-0127 given as a single subcutaneous dose (3.6 mumol/kg) to rats 1 hour before LPS challenge produced a 93% survival rate, compared to 14% in control animals. Finally, a survival rate of 86% was achieved in rabbits infused with CP-0127 at 0.36 nmol/kg/min i.v., compared to 45.5% in saline-infused control animals given LPS (500 micrograms/kg i.v.). The results of these experiments provide evidence for a significant role for the kallikrein-kinin system in these models of endotoxic shock, and indicate the therapeutic potential of a bradykinin antagonist such as CP-0127 for treating this disorder in man.