title: Nitric oxide synthase inhibitors affect nitric oxide synthesis in normoxic but not in ischemic organs during intestinal ischemia and early reperfusion.
abstract: Inhibition of endogenous nitric oxide (NO) synthesis during early intestinal ischemia/reperfusion (I/R(i)) enhances remote organ damage related to I/R(i). However, the effects of NO synthase (NOS) inhibitors on NO formation in various organs have not yet been specified. We therefore investigated the effects of N-G-monomethyl-L-arginine (L-NMMA), a nonspecific NOS inhibitor, and L-arginine, the NOS substrate, on NO formed in ischemic intestine versus normoxic remote organs (lung and liver). We used electron paramagnetic resonance spectroscopy and a specific NO trap to assay NO in blood, intestine, lung, and liver of rats subjected to local I/R(i), with and without L-NMMA and L-arginine supplementation. We found that I/R(i) increased NO levels in the intestine and blood, but not in the remote organs lung and liver. Administration of L-NMMA before I/R(i) decreased I/R(i)-independent basal NO levels in normoxic lung and liver without influencing I/R(i)-induced increase in NO levels in intestinal tissue or in blood. L-arginine supplementation increased circulating levels of NO, with sensitivity to L-NMMA, without affecting NO levels in normoxic or ischemic tissue. Our data suggest that NOS activity controls the NO generated in normally perfused remote organs during early I/R(i). Hence NOS inhibitors, when administered during I/R(i), decrease physiological NO levels in normoxic remote organs without affecting increased NO levels originating from ischemic intestine. This may explain the harmful effect of nonspecific NOS inhibitors during early I/R(i). In addition, the generation of NO in remote organs is not limited by tissue L-arginine concentrations and, therefore, not influenced by exogenous L-arginine. The protective effect of L-arginine supplementation during I/R(i) is probably related to increasing intravascular NO formation.
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kozlov
authors.forename: Babak
authors.initials: B
authors.lastname: Sobhian
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Duvigneau
authors.forename: Guiseppina
authors.initials: G
authors.lastname: Costantino
authors.forename: Manfred
authors.initials: M
authors.lastname: Gemeiner
authors.forename: Hans
authors.initials: H
authors.lastname: Nohl
authors.forename: Heinz
authors.initials: H
authors.lastname: Redl
authors.forename: Soheyl
authors.initials: S
authors.lastname: Bahrami
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019323:omega-N-Methylarginine / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat