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.