Vol. 296, Issue 1, 71-76, January 2001

A Metabolic Fragment of Bradykinin, Arg-Pro-Pro-Gly-Phe, Protects against the Deleterious Effects of Lipopolysaccharide in Rats

Thomas A. Morinelli, Jerry G. Webb, Ayad A. Jaffa , Philip J. Privitera and Harry S. Margolius

Departments of Cell and Molecular Pharmacology and Experimental Therapeutics (T.A.M., J.G.W., A.A.J., P.J.P., H.S.M.) and Medicine (A.A.J., H.S.M.), Medical University of South Carolina, Charleston, South Carolina

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 µg/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.