Effects of TCV-309, a novel PAF antagonist, on circulatory shock and hematological abnormality induced by endotoxin in dogs.

We investigated the effects of TCV-309, a novel platelet activating factor (PAF) antagonist, on circulatory dysfunction and hematological abnormalities in experimental canine endotoxin (ET) shock. ET caused biphasic hypotension with a decrease in cardiac output (CO), left ventricular systolic pressure (LVP) and its dp/dt(max). The first hypotensive phase occurred within 15 min, and the second phase between 90 and 180 min following the injection of ET. Pulmonary vascular resistance (PVR) abruptly increased at 15 min with a partial recovery, and was then sustained at twice the basal value throughout the experiment. TCV-309 attenuated the hypotension, the decrease in CO, LVP and its dp/dt(max), and the increase in PVR. TCV-309 had no significant effect on the increase in TPR. The decrease in plasma fibrinogen and the increase in hematocrit and plasma lactate were significantly attenuated by TCV-309. These data suggest that PAF may be a key mediator leading to shock in sepsis.