ENDOTHELIUM-DERIVED KININS ACCOUNT FOR THE IMMEDIATE RESPONSE OF ENDOTHELIAL-CELLS TO BACTERIAL LIPOPOLYSACCHARIDE

We have recently shown that cultured endothelial cells produce kinins that can stimulate endothelial nitric oxide (NO) production in an autocrine manner. Because both the kallikrein-kinin system and the L-arginine/NO pathway have been implicated in the pathogenesis of septic shock, we investigated the possible involvement of endothelium-derived kinins in the response of cultured endothelial cells to bacterial lipopolysaccharide (LPS). In primary cultures of human umbilical vein and porcine aortic endothelial cells, LPS (0.3 to 3 mug/ml) induced significant concentration-dependent increases in cyclic GMP and 6-keto-PGF1alpha, both of which were abolished in the presence of the selective bradykinin B2-receptor antagonist HOE 140 (0.1 muM). These LPS-induced increases in cyclic GMP and 6-keto-PGF1alpha were short lived, being maximal after 5 min but were not apparent after 60 min. In parallel with these effects, LPS (30 mug/ml) induced a distinct, HOE 140-sensitive increase in the intracellular calcium concentration of human endothelial cells loaded with indo-1. In summary, these data suggest that the release of endothelium-derived kinin and subsequent stimulation of endothelial cells. followed by the enhanced production of NO and prostacyclin (PGI2), are implicated in the immediate hypotension induced by LPS in vivo.