ATTENUATION OF SODIUM-NITROPRUSSIDE RESPONSES AFTER PROLONGED INCUBATION OF RAT AORTA WITH ENDOTOXIN

We investigated the effects of prolonged treatment with Escherichia coli lipopolysaccharide (LPS) on the responses to sodium nitroprusside (SNP) in endothelium-denuded rat aortic strips. Incubation of the aortic strips with LPS for 24 h dramatically attenuated relaxation and guanosine 3',5'-cyclic monophosphate (cGMP) formation by SNP, which were significantly restored by the inhibition of nitric oxide (NO) production with Nw-nitro-L-arginine, In the aorta coincubated with LPS and protein synthesis inhibitor (dexamethasone or cycloheximide, which prevents induction of endotoxin-inducible NO synthase), no attenuation of the relaxation was observed and the cGMP formation was significantly restored. Relaxation response to 8-bromo-cGMP or papaverine was not attenuated, even after 24 h of incubation. These results suggest that the attenuation of SNP responses is mainly associated with a decrease in the activation of guanylate cyclase (GC) as a consequence of the prolonged exposure to muscle-derived NO. Moreover SNP in the presence of methylene blue evoked a small but apparent relaxation of 24-h-incubated aorta without significant elevation of cGMP, suggesting the involvement of cGMP-independent pathways in the remaining relaxation produced by SNP.