Effects of a platelet-activating factor antagonist, CV-3988, on different shock models in the rat

Research in recent years has implicated many vasoactive mediators in causing or maintaining the shock process. One of the newer mediators to be considered is platelet-activating factor (PAF). The present group of experiments examined the effects of a PAF antagonist, CV-3988, on PAF, endotoxin, and hemorrhagic hypotension in rats. Sprague Dawley male rats (250-350 g) were lightly anesthetized with halothane and instrumented to measure mean arterial pressure (MAP). Hypotension induced by PAF (3.0 micrograms/kg) (iv) was attenuated only by CV-3988 (10 mg/kg). The other compounds tested which were unsuccessful were MK-771, TRH, benoxaprofen, fenoprofen, FPL-55712, naloxone, diphenhydramine, verapamil, and methylprednisolone. In another set of rats, hypotension was induced by endotoxin (E. coli 0127:B8) (40 mg/kg) (iv). Animals were pretreated with saline or CV-3988 (10 mg/kg) (iv) 5 min prior to endotoxin administration. CV-3988 was able to attenuate the drop in MAP. Representative MAP (mmHg) measured 60 min after endotoxin administration was 72 +/- 7 for the saline group (n = 6) and 99 +/- 5 (P less than or equal to .05) for the CV-3988 group. No animal in either group survived 24 hours. In another series of animals which were pithed and vagotomized, hypotension, induced by endotoxin (6 mg/kg) (iv) could be attenuated by CV-3988. Representative MAP (mmHg) difference from baseline measured 30 min after endotoxin administration was -17 +/- 3 for the saline group (n = 7) and 0 +/- 2 (P less than or equal to .05) for the CV-3988 group. Hypotension induced by another endotoxin (Salmonella abortus equi) could also be attenuated by CV-3988. In the final set of experiments, hypotension was induced by an acute hemorrhage (30 cc/kg). In these animals, CV-3988, however, had no effect in attenuating the drop in MAP. These data demonstrate that CV-3988 can attenuate the hypotension of PAF and endotoxemia but not of hemorrhage. Also, the data suggest that PAF works directly in the rat to cause hypotension and not through other mediators. The hemodynamic effects of CV-3988 in the endotoxin model are partially mediated through peripheral mechanisms. Further work is needed to better characterize the effects of CV-3988 and other PAF antagonists in different shock models.