Contribution of peroxynitrite to fatal cardiovascular depression induced by overproduction of nitric oxide in rostral ventrolateral medulla of the rat.
We evaluated the contribution of peroxynitrite to the fatal cardiovascular depression induced by overproduction of nitric oxide (NO) after activation of inducible NO synthase (iNOS) in the rostral ventrolateral medulla (RVLM), the origin of sympathetic vasomotor tone. In Sprague-Dawley rats maintained under propofol anesthesia, microinjection of E. coli lipopolysaccharide (LPS) bilaterally into the RVLM elicited significant hypotension, bradycardia, reduction in sympathetic vasomotor tone and mortality. There was also a discernible elevation of iNOS expression in the ventrolateral medulla, followed by a massive production of nitrotyrosine, an experimental index for peroxynitrite. Co-administration bilaterally into the RVLM of the selective iNOS inhibitor, S-methylisothiourea (50, 100 or 250 pmol), an active peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis- (N-methyl-4'-pyridyl)-porphyrinato iron (III) (10 or 50 pmol), a peroxynitrite scavenger, L-cysteine (5, 50 or 100 pmol), or a superoxide dismutase mimetic, Mn(III)-tetrakis-(4-benzoic acid) porphyrin (1 or 10 pmol), significantly prevented mortality, reduced nitrotyrosine production and reversed the NO-induced cardiovascular suppression after application of LPS into the RVLM. We conclude that the formation of peroxynitrite by a reaction between superoxide anion and NO is primarily responsible for the fatal cardiovascular depression induced by overproduction of NO after activation of iNOS at the RVLM.
Chan
S H H
SH
Center for Neuroscience, National Sun Yat-sen University, 804, Kaohsiung, Taiwan, ROC.
Wang
L-L
LL
Ou
C-C
CC
Chan
J Y H
JY
D000818:Animals; D015153:Blotting, Western; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000401:mortality*; D006152:Cyclic GMP / Q000378:metabolism; D003864:Depression, Chemical; D006162:Guanylate Cyclase / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008845:Microinjections; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism* / Q000633:toxicity*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D013997:Time Factors
D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006162:Guanylate Cyclase; D006152:Cyclic GMP