Recent evidence indicates that the ACE breakdown product of BK, Arg-Pro-Pro-Gly-Phe (RPPGF), possesses its own unique activities. RPPGF interacts with a-thrombin and protease activated receptor 1 (PAR1) to inhibit thrombin activation of platelets. RPPGF also has been shown to ameliorate the deleterious effects of endotoxin in a rat model of septicemia. These data indicate that this peptide may have its own unique set of activities. The hypothesis that directs this proposal is that RPPGF prevents hypotension associated with sepsis. The specific aims of this proposal are as follows: Specific Aim #1: The mechanism by which RPPGF reduces hypotension and prolongs life in LPS treated rats will be characterized. Specific Aim #2: Structural analogs of RPPGF wil1 are examined to determine if they have the same efficacy as the native sequence to prevent cardiovascular collapse in LPS-treated rats. These studies will characterize new biologic effects of the breakdown product of BK. Since RPPGF has been recognized as a selective thrombin inhibitor, insight gained in investigations on the use of this compound to ameliorate sepsis will further expand knowledge on this agent. The results of the proposed studies also will expand the possible therapeutic use of thrombostatins. The present investigations will be the basis for a Phase II application, which will examine thrombostatins in various animal models for sepsis. Expansion of the therapeutic profile of thrombostatins will hasten its adoption by a large corporate partner for drug development PROPOSED COMMERCIAL APPLICATION: The commercial potential of these investigations is large. These investigations aim to prepare a compound that clinically would be useful 400,000 Amercians who annually are hospitalized with sepsis. Finding a safe and efficacious adjunct to the management of sepsis would be beneficial to medical care
