Nitric oxide synthase inhibitors affect nitric oxide synthesis in normoxic but not in ischemic organs during intestinal ischemia and early reperfusion.
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.
Kozlov
Andrey V
AV
Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, University of Veterinary Medicine, Vienna, Austria.
Sobhian
Babak
B
Duvigneau
Johanna C
JC
Costantino
Guiseppina
G
Gemeiner
Manfred
M
Nohl
Hans
H
Redl
Heinz
H
Bahrami
Soheyl
S
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*
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