CNI-1493 ATTENUATES HEMODYNAMIC AND PRO-INFLAMMATORY RESPONSES TO LPS

The increased production of pro-inflammatory cytokines and nitric oxid e have been postulated to contribute to the deleterious sequella of LP S administration. To date, clinical strategies to control these respon ses using individual specific inhibitors have been disappointing, The aim of the present study was to determine whether a tetravalent guanyl hydrazone compound (CNI-1493) attenuates LPS-induced stress responses by suppressing multiple inflammatory mediators. Rats were injected int ravenously with either CNI-1493 (10 mg/kg) or vehicle (1 mL NaCl) 60 m in prior to the injection of LPS (100 mu g/100 g body weight). LPS pro duced a 20% decrease in mean arterial blood pressure and a significant increase in circulating TNF-alpha levels as well as in tissue content of TNF-alpha, IL-1 beta, and IL-6. This was associated with a marked increase in lung and gut apoptosis and myeloperoxidaae (MPO) activitie s as well as with an increase in lung and spleen nitric oxide end prod ucts (NOx). Pretreatment with CNI-1493 attenuated the LPS-induced drop in mean arterial blood pressure (MABP) and blunted (40%) the rise in circulating TNF-alpha levels. CNI-1493 attenuated the LPS-induced incr ease in tissue cytokine (TNF-alpha, IL-1 beta, and IL-6) content in lu ng and spleen but did not alter that of liver or gut. CNI-1493 pretrea tment protected both lung and gut from LPS-induced apoptosis and in ad dition attenuated the rise in MPO activity in the gut. These results s uggest diverse effects of CNI-1493 that are tissue specific and that c onfer protection against the hemodynamic and inflammatory responses to LPS.