Alpha-2 adrenoceptor blockade protects rats against lipopolysaccharide.
Alpha-2 adrenoceptors are widely distributed in vascular and nonvascular tissue where they mediate diverse physiologic effects. We noted the laboratory anesthetic urethane, which possesses alpha-2 adrenergic blocking activity, protected rats against lethal endotoxemia (1). Therefore, we undertook the present study to examine whether specific alpha-2 adrenoceptor antagonism would protect against lethality and organ injury induced by lipopolysaccharide (LPS). Sprague-Dawley rats were pretreated with doses of the alpha-2 antagonist rauwolscine up to 1 mg/kg, followed by 20 mg/kg LPS. The highest rauwolscine dose decreased mortality from 100% to zero. In contrast, the alpha-2 agonists xylazine or UK 14,304 increased the lethality of a lower, 10-mg/kg dose of LPS from 20% to 80 to 100%. Rauwolscine administered after LPS had no protective effect against mortality. Rauwolscine pretreatment significantly reduced bowel hemorrhage and liver dysfunction induced by 20 mg/kg LPS, but it had no effect on hematologic changes, the rise in plasma creatinine, or lung myeloperoxidase content. Peak tumor necrosis factor-alpha levels were decreased from 1,305 +/- 333 to 493 +/- 155 pg/ml (p < 0.05) in animals pretreated with rauwolscine. Arterial pressure and heart rate was higher after LPS in animals pretreated with rauwolscine. We conclude that alpha-2 adrenergic blockade protects against LPS, either by decreasing tumor necrosis factor-alpha production or through direct effects on the target tissues of endotoxemia.
Fessler
H E
HE
Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Otterbein
L
L
Chung
H S
HS
Choi
A M
AM
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000068438:Brimonidine Tartrate; D003404:Creatinine / Q000097:blood; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014991:Xylazine / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D008070:Lipopolysaccharides; D011810:Quinoxalines; D014409:Tumor Necrosis Factor-alpha; D014991:Xylazine; D015016:Yohimbine; D000068438:Brimonidine Tartrate; D003404:Creatinine; D009195:Peroxidase