NITRIC OXIDE-INDEPENDENT ACTIVATION OF SOLUBLE GUANYLYL CYCLASE CONTRIBUTES TO ENDOTOXIN-SHOCK IN RATS

We investigated whether a complete inhibition of nitric oxide (NO) for mation caused by bacterial endotoxin (lipopolysaccharide, LPS) in vivo prevents the hypotension and restores the vascular hyporeactivity to normal in vivo and ex vivo. The combination of dexamethasone (Dex; 3 m g/kg at 30 min before LPS) plus aminoguanidine (AG; 15 mg/kg at 2 h af ter LPS) inhibited the overproduction of nitrate (an indicator of NO) in the plasma and aortic smooth muscle and also prevented the developm ent of the delayed hypotension in rats treated with LPS for 6 h. Howev er, the vascular hyporeactivity to norepinephrine (NE) was only partia lly improved either in vivo or ex vivo in endotoxemic rats treated wit h Dex plus AG. Pretreatment of aortic rings with N-omega-nitro-L-argin ine methyl ester (L-NAME) or 1H-[1,2,4]oxidazolo[4,3-a]quinoxalin-1-on e (ODQ) enhanced the contraction to NE in rings obtained from LPS-trea ted rats, but not in those from Dex plus AG-treated endotoxemic rats. Methylene blue, an inhibitor of soluble guanylyl cyclase (CTC), comple tely restored contractions to NE and aortic cGMP levels to normal eith er in LPS-treated rats or in Dex plus AG-treated endotoxemic rats, whe reas the cGMP level was partially inhibited by ODQ in LPS-treated rats only. These results suggest that non-NO mediator(s) also activates so luble GC during endotoxemia. Interestingly, we found that in the prese nce of tetraethylammonium (an inhibitor of Kt channels) plus L-NAME or charybdotoxin [a specific inhibitor of large-conductance Ca2+- activa ted K+ (K-Ca) channels] plus ODQ, the vascular hyporeactivity to NE in the LPS-treated group was also completely restored to normal. In addi tion, in the presence of L-NAME or ODQ, the vascular hyporeactivity to high K+ was abolished in rings from the LPS-treated group. These resu lts suggest that LPS causes the production of other mediator(s), in ad dition to NO, which also stimulates soluble GC (i.e., increases the fo rmation of cGMP) and then activates the large-conductance K-Ca channel s in the vascular smooth muscle causing vascular hyporeactivity.