Sepsis is a
systemic inflammatory response syndrome (SIRS) when an
infection is the etiology of SIRS. Our previous studies have indicated that the release of the sympathetic
neurotransmitter,
norepinephrine (NE), from the gut is increased in
sepsis, and that NE potentiates
endotoxin-induced
tumor necrosis factor (
TNF)-alpha upregulation via the A subtype of alpha(2)-adrenoceptors (i.e., alpha(2A)-AR) expressed on the surface of Kupffer cells. A specific antagonist for alpha(2A)-AR, 2-[(4,5-dihydro-1H-imidazol-2-yl) methyl]-2,3-dihydro-1-methyl-1H-
isoindole maleate (BRL-44408 maleate), reduces
TNF-alpha secretion in cultured Kupffer cells. We, therefore, hypothesize that administration of
BRL-44408 maleate inhibits inflammatory responses and reduces organ injury in
sepsis. To study this,
sepsis was induced in male rats by cecal
ligation and
puncture (CLP). At 5 h after CLP,
BRL-44408 maleate (0.3125, 0.625, 1.25, 2.5, or 5.0 mg/kg BW) or vehicle (1-ml
normal saline) were administered intravenously over a period of 30 min. Blood and intestinal samples were collected at 20 h after CLP. Serum levels of
TNF-alpha,
interleukin (IL)-6,
IL-10, keratinocyte-derived
chemokine (KC), macrophage inflammatory protein-2 (MIP-2), liver
enzymes (i.e.,
aspartate aminotransferase (AST) and
alanine aminotransferase (ALT)), and
lactate were measured. The intestinal levels of
TNF-alpha,
IL-6, and
myeloperoxidase (MPO) activities were also analyzed. In additional groups of animals, the necrotic cecum was excised at 20 h post-CLP, and the 10-day survival was recorded. Our results showed that serum levels of proinflammatory
cytokines (TNF-alpha and IL-6), anti-inflammatory
cytokine (IL-10),
chemokines (KC, MIP-2), liver
enzymes (AST and ALT),
lactate, and intestinal levels of
TNF-alpha,
IL-6, and MPO were significantly elevated at 20 h after CLP. Administration of
BRL-44408 maleate significantly reduced serum levels of proinflammatory
cytokines,
chemokines, liver
enzymes, and
lactate, and dramatically decreased
TNF-alpha,
IL-6, and MPO levels in the gut. However, it has no statistical effects on the elevated serum levels of
IL-10. Moreover,
BRL-44408 maleate at the doses of 2.5 or 5.0 mg/kg BW significantly increased the survival rate after CLP and cecal excision. In conclusion, modulation of the sympathetic nervous system by blocking alpha(2A)-AR appears to be a novel treatment for inflammatory conditions such as
sepsis.