Involvement of COX and NOS induction in the sympatho-activation during sepsis

Abstract

The role of NOS and/or COX induction on sympathetic nerve activation induced by sepsis was investigated in pentobarbital anesthetized rats. Sepsis was induced by i.v. administration of lipopolyssaccharide (LPS) in control experiments and during treatment with anti-inflammatory drugs or inhibitors of NOS and COX (five to six rats per group). Mean arterial blood pressure (MBP), rectal temperature (RT) and renal sympathetic nerve activity (RSNA) were recorded for up to 6 h after LPS infusion. LPS administration induced profound increases in RSNA and decreases in MBP. The corticosteroid anti-inflammatory drug dexamethasone had a potent protector effect on blood pressure and survival of the LPS-treated animals and inhibited the RSNA increase. The nonsteroid anti-inflammatory compound indomethacin inhibited the sympathetic activation but did not alter the hypotensive action of LPS. The nonselective NOS inhibitor nitroarginine methyl ester ( l-NAME) accelerated the fall in MBP and death of the animals while the inducible NOS inhibitor l-NIL delayed the fall in MBP and reduced the sympatho-activation without affecting survival time in LPS rats. The neuronal NOS inhibitor 7-nitroindazole (7-NINA) did not improve the hypotensive effect and survival of the LPS animals but potentiated the RSNA increase. The COX-1 inhibitor SC560 accelerated hypotension and death of the LPS animals without affecting the RSNA increase. The COX-2 inhibitor NS398 did not modify the effect of LPS on blood pressure but reduced its sympatho-excitatory effect; NS398 also abolished the LPS-induced increase in RT. The results indicate that different mechanisms are involved in the effects of sepsis on MBP, sympathetic activation and fever. Sympathetic nerve activation during sepsis appears to depend on the induction of NOS and COX; the COX pathway is involved in the elevation of temperature and in the activation of sympathetic nerve activity but not in the hypotension. The potent effect of dexamethasone suggests that a NOS- and COX-independent arachidonic acid pathway also plays a role.