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.