Aminoethyl-isothiourea inhibits the increase in plasma endothelin-1 causedby serogroup A streptococci and prolongs survival in rat peritoneal sepsis

To elucidate the possible roles of nitric oxide (NO), endothelin-1 (ET-1), and reactive oxygen species (ROS) in the pathophysiology of serogroup A str eptococcal (GAS) peritoneal sepsis, we investigated the effects of aminoeth ylisothiourea (AE-ITU), an inducible NO synthase (iNOS) inhibitor, and a RO S scavenger, and the ET-1 receptor antagonist bosentan. In rats, live GAS i nocula, 3 x 10(8) and 1 x 10(9) cfu/kg, entailed a 24-h mortality of 10% an d 90%, respectively. GAS caused increases in tissue iNOS activity (9 h), in serum nitrite/nitrate (9-24 h), and in intracellular leukocyte ROS levels (3-6 h). These changes were all prevented by the pre-treatment with AE-ITU. A novel finding was that AE-ITU also prevented the GAS-induced marked incr ease in plasma ET-1 at 6 h. Short-term (7-h) survival was improved by both AE-ITU and by bosentan. The mechanism(s) for the beneficial effects of AE-I TU may possibly be a combined mode of action; iNOS inhibition, ROS scavengi ng. and inhibition of the increase in plasma ET-1 caused by GAS.