Further evidence of bradykinin involvement in septic shock: Reduction of kinin production in vivo and improved survival in rats by use of polymer tailored SBTI with longer t( 1/4 )

Involvement of bradykinin in septic shock and its therapeutic endeavor using soybean trypsin inhibitor (SBTI, Kunitz type) were investigated in an in vivo model of septic shock induced by pseudomonal elastase. Pseudomonal elastase injection at 0.5 mg/kg i.v. to guinea pigs resulted in elevation level of bradykinin in the blood from <1 ng/ml to 25 ng/ml which was accompanied by a drop of mean arterial blood pressure (MABP) (about 45 mmHg). When native soybean trypsin inhibitor (SBTI, Kunitz type, 20 kDa) was injected into this model, induction of bradykinin generation and hypotension by the bacterial protease treatment was completely obliterated as judged by both the levels of bradykinin and MABP. Specifically, by the treatment with SBTI, bradykinin levels did not increase and the drop of the blood pressure was minimal (<10 mmHg) in this time frame (<30 min). We designed and prepared succinylated gelatin-conjugated SBTI (suc-gel SBTI) with enlarged molecular mass (M(r) ~110,000) and higher area under the curve of the plasma concentration, which exhibits about 6 times longer plasma half-life (t( 1/4 )) and about 4 times larger area under the curve of plasma concentration. Suc-gel-SBTI suppressed the pseudomonal protease-induced shock much more effectively than native SBTI, the conjugate exhibited its effect for more than 3 h, while the native SBTI showed the effect only within 2 h after i.v. injection.