Transcriptional up-regulation of nitric oxide synthase II by nuclear factor-kappaB at rostral ventrolateral medulla in a rat mevinphos intoxication model of brain stem death.
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-kappaB (NF-kappaB) 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-kappaB in RVLM neurons induced by microinjection of Mev into the bilateral RVLM. However, NF-kappaB inhibitors (diethyldithiocarbamate or pyrrolidine dithiocarbamate) or double-stranded kappaB 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-kappaB 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.
Chan
Julie Y H
JY
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, and Center for Neuroscience, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, Republic of China.
Wu
Carol H Y
CH
Tsai
Ching-Yi
CY
Cheng
Hsiao-Lei
HL
Dai
Kuang-Yu
KY
Chan
Samuel H H
SH
Chang
Alice Y W
AY
D000818:Animals; D001794:Blood Pressure; D001926:Brain Death / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D003959:Diamines / Q000494:pharmacology; D004195:Disease Models, Animal; D004050:Ditiocarb / Q000494:pharmacology; D004790:Enzyme Induction; D006339:Heart Rate; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008799:Mevinphos; D018727:Muscarinic Antagonists / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043588:Receptor, Muscarinic M4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015203:Reproducibility of Results; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014331:Tropicamide / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D003959:Diamines; D018727:Muscarinic Antagonists; D016328:NF-kappa B; D011759:Pyrrolidines; D043585:Receptor, Muscarinic M2; D043588:Receptor, Muscarinic M4; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D008799:Mevinphos; D004050:Ditiocarb; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; D017869:Cyclic GMP-Dependent Protein Kinases; D014331:Tropicamide; C054938:methoctramine