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

We investigated the effects of prolonged treatment with Escherichia co li lipopolysaccharide (LPS) on the responses to sodium nitroprusside ( SNP) in endothelium-denuded rat aortic strips. Incubation of the aorti c strips with LPS for 24 h dramatically attenuated relaxation and guan osine 3',5'-cyclic monophosphate (cGMP) formation by SNP, which were s ignificantly restored by the inhibition of nitric oxide (NO) productio n with Nw-nitro-L-arginine, In the aorta coincubated with LPS and prot ein synthesis inhibitor (dexamethasone or cycloheximide, which prevent s induction of endotoxin-inducible NO synthase), no attenuation of the relaxation was observed and the cGMP formation was significantly rest ored. Relaxation response to 8-bromo-cGMP or papaverine was not attenu ated, even after 24 h of incubation. These results suggest that the at tenuation of SNP responses is mainly associated with a decrease in the activation of guanylate cyclase (GC) as a consequence of the prolonge d exposure to muscle-derived NO. Moreover SNP in the presence of methy lene blue evoked a small but apparent relaxation of 24-h-incubated aor ta without significant elevation of cGMP, suggesting the involvement o f cGMP-independent pathways in the remaining relaxation produced by SN P.