Search

The goal of this study was to investigate the sustained sympatho-excitation which occurs in sepsis and which accompanies the fall in blood pressure and to analyze its time-correlation with heart rate and the role of the baro-chemoreflexes. Rats anesthetized with pentobarbital were treated with lipolysaccharide (LPS) 20 mg/kg/20 min i.v. and mean blood pressure (MBP), heart rate (HR), rectal temperature and renal sympathetic nerve activity (RSNA) were recorded. LPS induced a fall in blood pressure, an increase in HR (+20%) and RSNA (+355%); the arterial PO2 and PCO2 remained stable and the injection was fatal within 4 h. Baroreceptor and chemoreceptor denervation accelerated the fall in MBP but did not change the survival time. Under those conditions; RSNA excitation was slightly more pronounced. During treatment with gallamine and under artificial respiration to avoid possible respiratory changes through the chemoreflex pathway, the effects of LPS remained, except for a decrease in arterial PO2. Electrolytic lesioning of the nucleus tractus solitarius or blocking the effects of baroreflex efferents by either an alpha1 or alpha2-adrenoceptor antagonists failed to alter the effects of LPS. After treatment with a beta-adrenoceptor antagonist, LPS increased RSNA but not HR and the survival time of the rats shortened. LPS administered i.c. (1 mg/kg) induced, with a short latency, effects comparable to those produced by i.v. injection. Surprisingly, the time correlation between RSNA and HR rhythms persisted when MBP dropped after LPS and moreover it reappeared in baroreceptor denervated rats after LPS. Thus under these conditions of altered baroreflex pathway and LPS induced sympathetic activation, the sympathetic output from the medulla appears to play a role in the correlation between heart rate and sympathetic nerve activity. These data indicate that the marked RSNA activation and the tachycardia are correlated and that the baroreflex and chemoreflex are not inhibited during sepsis but appear to be of minor importance in the sympathetic activation and in the blood pressure modifications.

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 lipopolysaccharide (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.