RO-244736

The role of platelet-activating factor (PAF) in ischemic acute renal failure was evaluated by administering an oral PAF antagonist (Ro-24-4736) to rats prior to or after interruption of blood flow to both kidneys for 30 min. In animals treated with the PAF antagonist prior to ischemia, renal function was less impaired and histological abnormalities was less pronounced when compared with postischemic kidneys from vehicle-treated animals. Serum creatinine (mg/ dl) 24 h following renal ischemia was 1.58 +/- 0.17 in the PAF antagonist-treated rats compared with 2.19 +/- 0.15 in rats given placebo (P < 0.01). There was less necrosis in the outer medulla of kidneys of PAF antagonist-treated animals (P < 0.01). Tissue myeloperoxidase activity at 48 and 72 h postischemia was lower in kidneys of PAF antagonist-treated rats (P < 0.05). The PAF antagonist was also protective when administered 30 min but not 2 h following the ischemic insult. The coincident use of anti-intercellular adhesion molecule-1 monoclonal antibody did not confer additional protection over that observed with the oral PAF antagonist alone. These data suggest that PAF contributes to the pathophysiology of renal ischemic injury, perhaps by its effects on leukocyte-endothelial interactions. An orally active PAF antagonist can protect against the development of ischemic acute renal failure.

A number of studies have suggested that the inflammatory and chemotactic autocoid platelet activating factor (PAF), together with various cytokines, plays an important role in the pathophysiology of trauma, sepsis, and shock. However, little is known about PAF's contribution to the immunosuppression associated with hemorrhage. The aim of our study was, therefore, to determine if the use of a PAF-antagonist following hemorrhage has any salutary effects on splenocyte lymphokine production. To study this, mice were bled to and maintained at a mean arterial pressure of 35 mm Hg for 60 min. The mice were then segregated into three groups and were resuscitated with shed blood plus lactated Ringer's solution (2x the volume of shed blood), containing either a potent PAF-antagonist (Ro 24-4736, a thienodiazepine) in dimethyl sulfoxide (DMSO) or DMSO-vehicle. Sham-operated mice received either DMSO-vehicle in saline or saline alone. Twenty-four hours thereafter the animals were sacrificed and splenocyte cultures established and stimulated for 48 hr with Con A (2.5 micrograms/ml). Supernatant lymphokine levels were determined by bioassay. The cellular release of interleukin-2 and -3 (IL-2 and IL-3) by splenocytes was significantly depressed in the nontreated or vehicle-treated hemorrhaged animals compared to shams. Treatment with the PAF-antagonist Ro 24-4736 restored IL-2 and IL-3 release values to levels comparable to those of the sham-operated animals. Thus, (1) PAF appears to play a significant role in hemorrhage-induced immunosuppression and (2) the use of a PAF-antagonist to uncouple the PAF-generated feedback loops prevents the depression in splenocyte function following hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)