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Central rimonabant administration prevents endotoxic hypotension by inhibiting norepinephrine release in the preoptic anterior hypothalamic area
Author(s) -
Yilmaz Mustafa S,
Villanueva Alex,
Millington William R,
Cutrera Rodolfo A,
Cheer Joseph F,
Feleder Carlos
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.938.1
Subject(s) - rimonabant , cannabinoid receptor , endocrinology , medicine , norepinephrine , endocannabinoid system , cannabinoid , preoptic area , blood pressure , receptor , microdialysis , pharmacology , hypothalamus , antagonist , dopamine
Lipopolysaccharide (LPS) is thought to lower arterial pressure by stimulating release of tumor necrosis factor‐α (TNF) and other mediators. However, recent evidence indicates that endotoxic hypotension is initiated through a central mechanism that involves noradrenergic neurotransmission in the preoptic anterior hypothalamic area (POA). In this study, we tested whether cannabinoid‐1 (CB1) receptors participate in the control of arterial pressure during endotoxemia, based on evidence that hypothalamic neurons express CB1 receptors. We found that central administration of the CB1 receptor antagonist rimonabant (250 ng icv) inhibited the initial fall in arterial pressure evoked by LPS (1 mg/kg iv) significantly in both conscious and anesthetized rats. Interestingly, rimonabant also attenuated the second, delayed hypotensive phase that ultimately leads to tissue ischemia and death. Rimonabant also prevented the LPS‐induced rise in extracellular fluid norepinephrine (NE) concentrations in the POA which suggests that rimonabant prevents initiation of LPS hypotension by inhibiting NE release in the POA. The characteristic increase in plasma TNF concentrations was also inhibited significantly. These data indicate that CB1 receptors in the brain mediate endotoxic hypotension. This study supported by American Foundation for Pharmaceutical Education.