A metabolic fragment of bradykinin, Arg-Pro-Pro-Gly-Phe, protects against the deleterious effects of lipopolysaccharide in rats

Abstract

Extensive research has provided few therapeutic agents for the treatment of septicemia. Bradykinin, an endogenous vasodepressor hormone, is a key mediator in the hypotension seen with septicemia. The present investigation shows that a stable metabolic fragment of bradykinin, arginine-proline-proline-glycine-phenylalanine (RPPGF), prevents the deleterious effects of endotoxin [lipopolysaccharide (LPS); a component of the membrane of Gram negative bacteria], the signaling agent responsible for the effects of septicemia, in both anesthetized rats and in isolated rat aortic segments. Survival time of rats treated with LPS (12 mg/kg) was significantly (p < 0.05) prolonged by pretreatment with RPPGF [140.3 +/- 16 min (n = 10)] compared with rats receiving saline and LPS [93.2 +/- 8 min (n = 39)]. Prolongation of survival was not seen when rats were pretreated with either bradykinin or with PRGFP (proline-arginine-glycine-phenylalanine-proline). Isolated aortic segments treated with LPS (30 microg/ml) showed a significantly reduced ability to contract in response to phenylephrine compared with control segments not receiving LPS. Pretreatment of the segments with RPPGF significantly reversed the LPS-induced reduction in contractile response of the segments. Removal of the endothelial layer did not alter the protection provided by RPPGF. These results demonstrate the ability of a stable metabolic fragment of bradykinin, RPPGF, to protect against the deleterious effects produced by LPS. The findings presented here may provide the basis for a new developmental area for novel therapeutic agents in the treatment of septicemia.