Transcriptional up-regulation of nitric oxide synthase II by nuclear factor-κB at rostral ventrolateral medulla in a rat mevinphos intoxication model of brain stem death

Julie Y.H. Chan, Carol H.Y. Wu, Ching Yi Tsai, Hsiao Lei Cheng, Kuang Yu Dai, Samuel H.H. Chan, Alice Y.W. Chang

研究成果: Article同行評審

24 引文 斯高帕斯(Scopus)

摘要

As the origin of a 'life-and-death' signal that reflects central cardiovascular regulatory failure during brain stem death, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this vital phenomenon. Using a clinically relevant animal model that employed the organophosphate pesticide mevinphos (Mev) as the experimental insult, we evaluated the hypothesis that transcriptional up-regulation of nitric oxide synthase I or II (NOS I or II) gene expression by nuclear factor-κB (NF-κB) on activation of muscarinic receptors in the RVLM underlies brain stem death. In Sprague-Dawley rats maintained under propofol anaesthesia, co-microinjection of muscarinic M2R (methoctramine) or M4R (tropicamide), but not M1R (pirenzepine) or M3R (4-diphenylacetoxy-N-dimethylpiperidinium) antagonist significantly reduced the enhanced NOS I-protein kinase G signalling ('pro-life' phase) or augmented NOS II-peroxynitrite cascade ('pro-death' phase) in ventrolateral medulla, blunted the biphasic increase and decrease in baroreceptor reflex-mediated sympathetic vasomotor tone that reflect the transition from life to death, and diminished the elevated DNA binding activity or nucleus-bound translocation of NF-κB in RVLM neurons induced by microinjection of Mev into the bilateral RVLM. However, NF-κB inhibitors (diethyldithiocarbamate or pyrrolidine dithiocarbamate) or double-stranded κB decoy DNA preferentially antagonized the augmented NOS II-peroxynitrite cascade and the associated cardiovascular depression exhibited during the 'pro-death' phase. We conclude that transcriptional up-regulation of NOS II gene expression by activation of NF-κB on selective stimulation of muscarinic M2 or M4 subtype receptors in the RVLM underlies the elicited cardiovascular depression during the 'pro-death' phase in our Mev intoxication model of brain stem death.

原文English
頁(從 - 到)1293-1307
頁數15
期刊Journal of Physiology
581
發行號3
DOIs
出版狀態Published - 2007 六月 1

All Science Journal Classification (ASJC) codes

  • Physiology

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