Failure of L-NAME to cause inhibition of nitric oxide synthesis: role of inducible nitric oxide synthase.
We addressed the hypothesis that administration of nitric oxide synthase inhibitor, NG -nitro-L-arginine methyl ester (L-NAME) does not result in a sustained suppression of nitric oxide (NO) synthesis, because of a compensatory expression of inducible nitric oxide synthase (iNOS). L-NAME was administered in the drinking water (0.1-1.0 mg/ml) for 7 days to guinea pigs and rats. Nitric oxide synthesis was assessed by [1] ex vivo formation of nitrite in blood vessels and intestine [2] tissue levels of cGMP [3] iNOS gene expression by RT-PCR [4] NADPH diaphorase staining [5] direct assessment of NO release in tissue explants using a microelectrode/electrochemical detection system. Chronic L-NAME administration elevated intestinal cGMP and nitrite levels in guinea pigs (p < 0.05). In rats, intestinal nitrite levels were comparable in control and L-NAME treatment groups, whereas direct assessment of NO release defined a marked increase in the L-NAME group. Chronic L-NAME resulted in an induction of iNOS gene expression in rats and guinea pigs and novel sites of NADPH diaphorase staining in the intestine. We conclude that iNOS expression is responsible for a compensatory increase or normalization of NO synthesis during sustained administration of L-NAME.
Miller
M J
MJ
Department of Pediatrics, Louisiana State University Medical Center, New Orleans 70112, USA.
Thompson
J H
JH
Liu
X
X
Eloby-Childress
S
S
Sadowska-Krowicka
H
H
Zhang
X J
XJ
Clark
D A
DA
D000284:Administration, Oral; D000818:Animals; D001483:Base Sequence; D001808:Blood Vessels / Q000187:drug effects / Q000201:enzymology; D006152:Cyclic GMP / Q000378:metabolism; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D006168:Guinea Pigs; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008969:Molecular Sequence Data; D009252:NADPH Dehydrogenase / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology*; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D016133:Polymerase Chain Reaction; D051381:Rats
D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D009566:Nitrates; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D009252:NADPH Dehydrogenase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester