Effect of combined B-1 and B-2 kinin receptor blockade in porcine endotoxin shock

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 mu g/kg/h.i.v. for 8 h) and saline (Group 1). Another group received LPS and the B-2 antagonist CP-0127 (3 mu g/kg/min), beginning 1 h after LPS (Group 2). Group 3 received LPS and the B-2 antagonist in the aforementioned doses, and the B-1 antagonist io Leu(9)-des-Arg(10)-kallidin (3 mu g/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 B-2 blockade attenuates LPS-induced mortality whereas additional B-1 blockade seems to reverse these beneficial effects. This suggests that in this animal model the B-1 receptor does not serve the same purpose as the B-2 receptor, and that up-regulation of B-1 receptors during LPS shock may be an important mechanism of host defence.