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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.

M7 (5,6-dihydroxy-2-dimethylaminotetralin) produces in anesthetized rats a hypotensive response previously attributed to peripheral dopaminergic mechanisms. We re-examined the effects of this drug on arterial blood pressure, heart rate and sympathetic nerve activity in anesthetized rats and dogs. M7 (1-100 micrograms/kg i.v.) produced in the rats transient dose-dependent pressor effects, with bradycardia and sympatho-inhibition, followed by long-lasting dose-dependent hypotension, bradycardia and sympatho-inhibition. The sympatho-inhibitory and hypotensive effects were comparable in baroreceptor-denervated rats and were reversed by idazoxan (0.1 mg/kg i.v.). The sympatho-inhibitory response induced by M7 (1-100 micrograms/kg) was prevented by treatment with the specific alpha 2-adrenoceptor antagonist, 2-methoxy-idazoxan (0.03 mg/kg i.v.). This central effect of M7 was not altered by treatment with the alpha 1-adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.), and was reduced by treatment with the alpha 2-adrenoceptor antagonists, yohimbine (1 mg/kg i.v.) or idazoxan (0.3 mg/kg i.v.), and the dopaminergic antagonists, haloperidol (0.5 mg/kg i.v.) or sulpiride (3 mg/kg i.v.). Bilateral microinjections of M7 (0.3-3 nmol) into the rostroventral medulla in the rat produced dose-dependent hypotension, bradycardia and sympathetic nerve inhibition which were reversed and prevented by bilateral microinjection of 2-methoxy-idazoxan (1 nmol) into the same sites. Microinjections of 2-methoxy-idazoxan into the rostroventral medulla also inhibited the central effects of M7 at 0.03 mg/kg i.v. In anesthetized dogs, M7 administered into the cisterna magna (1-10 micrograms/kg) reduced arterial blood pressure, heart rate and sympathetic nerve activity; these effects were reversed by administration of 2-methoxy-idazoxan (0.03 mg/kg i.v.). In conclusion, M7, a rigid catecholamine, produces a potent central sympatho-inhibitory and hypotensive effect by activation of alpha 2-adrenoceptors.

The medullary structures involved in the central Bezold-Jarisch reflex pathway were studied by recording unit activity of sympatho-excitatory (SE) or inhibitory (SI) cardiovascular neurons in pentobarbital-anesthetized cats. The neurons were selected based upon their spontaneous activity and upon their sensitivity to baroreceptor reflex activation by L-phenylephrine. The Bezold-Jarisch reflex was induced by i.v. injection of chlorophenylbiguanide 10 micrograms/kg which produced a short-lasting decrease in blood pressure, heart rate and renal nerve activity. 76 neurons were studied. In 10 out of 12 SE neurons of the rostral ventrolateral medulla the activity was inhibited by chlorophenylbiguanide whereas in 10 out of 11 SI neurons and 6 out of 6 baroreflex-insensitive cells of the caudal ventrolateral medulla it was activated. The others cells were insensitive. Three types of neurons: excitatory, inhibitory or non-barosensitive, were recorded in the lateral tegmental field (27 cells) and the medullary raphe (20 cells). These neurons were either activated, inhibited or insensitive to Bezold-Jarisch reflex activation. Microinjection of the glutamate receptor antagonist kynurenic acid (2.5 nmol/site) or the GABAergic agonist muscimol (1 nmol/site) into the nucleus tractus solitarii abolished the effects of both L-phenylephrine and chlorophenyl-biguanide on heart rate and renal nerve activity. These results indicate that the cardiovascular neurons (sympatho-excitatory and sympatho-inhibitory) located in the medullary areas, involved in cardiovascular and baroreflex mechanisms, are implicated in the central Bezold-Jarish reflex pathway.

1. The recovery of the clonidine-induced hypotension, bradycardia and sympatho-inhibition produced by several putative alpha 2-adrenoceptor antagonists was investigated in pentobarbitone anaesthetized rats. The activity of four substances containing an imidazoline structure: idazoxan, methoxy-idazoxan, BRL44408 and atipamezole was compared with the effect of fluparoxan, yohimbine and L-657,743; in addition the effect of the alpha 1-adrenoceptor antagonist, prazosin, was also studied. 2. Prazosin (0.03-1 mg kg-1, i.v.) failed to alter the sympatho-inhibitory and hypotensive effects of clonidine (10 micrograms kg-1, i.v.). L-657,743 (0.01-1 mg kg-1, i.v.) induced a recovery of blood pressure, heart rate and renal sympathetic nerve activity. Yohimbine (0.03-3 mg kg-1, i.v.) completely reversed the sympatho-inhibitory effect of clonidine but did not alter its hypotensive effect. 3. The four imidazoline drugs: idazoxan (10-300 micrograms kg-1, i.v.), methoxy-idazoxan (1-100 micrograms kg-1, i.v.), BRL44408 (0.1-3 mg kg-1, i.v.) and atipamezole (0.03-1 mg kg-1, i.v.) and fluparoxan (10-300 micrograms kg-1, i.v.) reversed the clonidine-induced hypotension but produced only a partial recovery of the renal sympathetic nerve activity and of the heart rate. After pretreatment with prazosin (0.1 mg kg-1, i.v.), the recovery of the sympathetic nerve activity elicited by these compounds was significantly higher. In hexamethonium (10 mg kg-1, i.v.) pretreated rats, these five drugs induced dose-related hypertension which was reduced by pretreatment with prazosin (0.1 mg kg-1, i.v.). 4. Our results indicate that the putative alpha 2-adrenoceptor antagonists idazoxan, methoxy-idazoxan, BRL44408, atipamezole and fluparoxan also have a peripheral hypertensive effect which is mediated through activation of vascular alpha 1-adrenoceptors; this property of the compounds may be partly responsible for the reversal of the hypotensive action of clonidine. Considering the structure and the affinities of the drugs tested, our data indirectly suggest that alpha 2A-adrenoceptors may be implicated in the central sympatho-inhibitory effects of clonidine.