kallidin and Shock--Septic

Topics: Anaphylaxis; Angioedema; Arthritis; Bradykinin; Burns; Dumping Syndrome; Half-Life; Humans; Inflammation; Kallidin; Kallikreins; Kinins; Malignant Carcinoid Syndrome; Pancreatitis; Shock; Shock, Septic; Vascular Diseases

Previous experiments in anesthetized pigs have demonstrated that blockade of the bradykinin B2 receptor in experimental endotoxin shock attenuates LPS-induced organ failure, lung dysfunction and mortality. Additional B1 receptor blockade in this situation seems to counteract the beneficial effects of B2 blockade. This suggests that the upregulation of B1 receptors during porcine LPS shock may be a useful mechanism of host defense. Furthermore, infusion of a B1 agonist during septic shock may be of therapeutic benefit. In order to prepare an experiment with B1 stimulation in LPS shock, we conducted a study in anesthetized pigs, in which the B1 receptor has been upregulated by infusion of bacterial lipopolysaccharide (LPS), by evaluating the effect of constant intravenous infusions of the B1 agonist des-Arg10-kallidin on the hypotensive response to bolus doses of this agonist. Following infusions of lipopolysaccharide from S. abortus equi, anesthetised pigs received repeated intra-arterial bolus injections of des-Arg10-kallidin before and during continuous infusions of this agonist in doses of 3, 10, 30 and 100 ng/kg/min. We found that all doses greater than 3 ng/kg/min produced attenuation of the hypotensive response produced by bolus administration of the B1 agonist des-Arg10-kallidin. We conclude that tachyphylaxis is an important feature to be considered in experiments with continuous administration of a B1 agonist in LPS shock.

Topics: Animals; Blood Pressure; Bradykinin Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Infusions, Intravenous; Injections, Intra-Arterial; Kallidin; Lipopolysaccharides; Receptor, Bradykinin B1; Receptors, Bradykinin; Shock, Septic; Swine; Tachyphylaxis; Up-Regulation

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 selective competitive bradykinin (BK) antagonist (B4148) produced significant inhibition of the hypotensive effect of BK in rats. Using a rat model of endotoxin shock, the fall in mean arterial blood pressure to an intravenous injection of lipopolysaccharide from E. coli was significantly attenuated by the B4148 as compared to controls. These findings suggest that kinins are involved in the hypotensive response to endotoxin shock in rats. The development of potent BK antagonists offers a new experimental approach for evaluating the role of kinins in this and other disease states.

Topics: Animals; Bradykinin; Escherichia coli; Hypotension; Kallidin; Kinetics; Lipopolysaccharides; Male; Rats; Rats, Inbred Strains; Shock, Septic

The selective competitive bradykinin (Bk) antagonist, B4148 (Lys-Lys-[Hyp2, Thi5,8, DPhe7]-Bk) infused at 100 micrograms kg-1 min-1 into rats produced a significant inhibition of the hypotensive effect of Bk and had no effect against acetylcholine-induced responses. In a rat model of endotoxin shock, the fall in mean arterial blood pressure in response to an intravenous injection of lipopolysaccharide from E. coli was significantly attenuated by the same infusion of B4148 compared to controls. These findings suggest that kinins are involved in the hypotensive response to endotoxin shock in rats. The development of potent Bk antagonists offers a new experimental approach for evaluating the role of kinins in this and other disease states and potential therapy in such disorders.

Topics: Animals; Blood Pressure; Bradykinin; Kallidin; Male; Rats; Rats, Inbred Strains; Shock, Septic

Topics: Angioedema; Animals; Blood Coagulation Factors; Bradykinin; Carboxypeptidases; Carcinoid Tumor; Catecholamines; Chemical Phenomena; Chemistry; Colchicine; Complement System Proteins; Female; Glucocorticoids; Guinea Pigs; Haplorhini; Humans; Inflammation; Kallidin; Kallikreins; Kidney; Kinins; Muscle Contraction; Phenothiazines; Rats; Salicylates; Sheep; Shock, Septic; Stimulation, Chemical; Uterus; Vascular Diseases; Vascular Resistance; Vasodilator Agents