deltibant and Shock--Septic

In order to investigate the contribution of kinin receptor antagonism in the treatment of LPS-induced shock we conducted a randomized study with anaesthetized piglets. Before randomization the animals were stratified according to predetermined health criteria under baseline conditions. One group of control animals received LPS from S. abortus equi (2 micrograms/kg/h i.v. for 8 h) and saline (Group 1). Another group received LPS and the B2 antagonist CP-0127 (3 micrograms/kg/min), beginning 1 h after LPS (Group 2). Group 3 received LPS and the B2 antagonist in the aforementioned doses, and the B1 antagonist Leu9-des-Arg10-kallidin (3 micrograms/kg/min), also beginning 1 h after LPS. Overall survival figures after 8 h of LPS infusion were: Group 1, 10/22 (45%); Group 2, 10/17 (59%); Group 3, 10/28 (36%). Fifty percent (29/58) of animals that were healthy at baseline survived, but only 11% (1/9) of sick animals survived (Log Rank p = 0.0001). In the subset of healthy animals, survival rates for Groups 2 and 3 were 77% and 38%, respectively (p = 0.0519). It appears, therefore, that B2 blockade attenuates LPS-induced mortality whereas additional B1 blockade seems to reverse these beneficial effects. This suggests that in this animal model the B1 receptor does not serve the same purpose as the B2 receptor, and that up-regulation of B1 receptors during LPS shock may be an important mechanism of host defence.

Topics: Animals; Bradykinin Receptor Antagonists; Disease Models, Animal; Drug Interactions; Kallidin; Lipopolysaccharides; Peptides; Random Allocation; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Shock, Septic; Swine

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.

Topics: Animals; Blood Pressure; Bradykinin; Disease Models, Animal; Escherichia coli; Male; Peptides; Rabbits; Rats; Rats, Sprague-Dawley; Shock, Septic

Topics: Amino Acid Sequence; Animals; Bradykinin; Humans; Kinins; Molecular Sequence Data; Oligopeptides; Peptides; Shock, Septic