Role of nitric oxide and K+-channels in vascular hyporeactivity induced by endotoxin

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• 作者：Shiu-Jen Chen ; C.-C. Wu and Mao-Hsiung Yen
• 关键词：Key words Nitric oxide ; Potassium channels ; Vascular hyporeactivity ; Lipopolysaccharide ; Rat aortas
• 刊名：Naunyn-Schmiedeberg's Archives of Pharmacology
• 出版年：1999
• 出版时间：June 1999
• 年：1999
• 卷：359
• 期：6
• 页码：493-499
• 全文大小：100 KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Neurosciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1912

文摘

This study was to investigate possible mechanisms associated with vascular hyporeactivity to vasoconstrictor agents in rats with endotoxaemia. Wistar-Kyoto rats were anaesthetised and injected with endotoxin [E. coli lipopolysaccharide (LPS); 10 mg/kg, i.v.] for 4 h. Pressor responses to noradrenaline (NA; 1 μg/kg, i.v.) were determined prior to and at every hour after LPS injection. After the in vivo experiment, rat thoracic aortas were excised and prepared as rings 3–4 mm in width. The endothelium was mechanically removed to evaluate K+-channel activity and the effects of nitric oxide (NO) on the vascular smooth muscle. Our results demonstrated that: (1) injection of LPS caused a significant fall in blood pressure and a severe vascular hyporeactivity to NA in the anaesthetised rat, (2) the relaxation induced by the K+-channel opener cromakalim was greater in rings obtained from endotoxaemic rats and this enhanced relaxation was partially inhibited by pretreatment of these rings with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of the NO/cGMP pathway, (3) endotoxaemia for 4 h was also associated with a profound vascular hyporeactivity to NA ex vivo and this vascular hyporesponsiveness was partially inhibited by ODQ, tetraethylammonium (TEA, a non-selective inhibitor of K+-channels) and charybdotoxin [CTX, a selective inhibitor of large conductance calcium-activated K+ channels (BK_Ca)], but not by apamin, and (4) the combination of TEA or CTX with ODQ completely restored that vascular responsiveness to normal. These results suggest that activation of BK_Ca and overproduction of NO in the vascular smooth muscle simultaneously contribute to vascular hyporeactivity to vasoconstrictor agents in endotoxaemia.