Thrombin, the central regulatory enzyme in coagulation, when incubated in nanomolar concentrations with murine neuroblastoma cells produced a rapid and marked increase in tritiated guanosine 3′,5′-monophosphate (cyclic GMP) formation that was blocked by hirudin and competitively antagonized by dansylarginine N-(3-ethyl-1,5-pentanediyl)amide. Diisopropylphosphofluoridate- inactivated thrombin as well as the serine protease trypsin were markedly less potent and less effective than α-thrombin in producing this effect. Thrombin-stimulated cyclic GMP formation was inhibited by mepacrine and nordihydroguaiaretic acid but unaffected by indomethacin, suggesting that lipoxygenase metabolites of arachidonic acid are involved in the response. These results suggest that a thrombin-like protease in the brain may be involved with the function of neurons or that thrombin interactions with nerve cells, such as those following cerebral hemorrhage or other trauma of the central nervous system, may be important in the subsequent neuropathology.
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