Expression and preferential inhibition of inducible nitric oxide synthase in aortas of endotoxemic rats.
Septic shock is associated with high mortality. There is in vitro evidence that the induction of nitric oxide synthase (iNOS) in vascular smooth muscle cells may be an important mediator of the systemic vasodilation and hypotension associated with sepsis. In this study, an in vivo murine model of sepsis was used to further examine this important question. Lipopolysaccharide (LPS), the major wall component of gram-negative bacteria, was administered to rats. By the use of a selective cDNA probe for iNOS, mRNA for iNOS was demonstrated in the aortas of these rats. The functional significance of this iNOS was then examined with aminoguanidine, a preferential inhibitor of iNOS. Aminoguanidine reversed the blunted phenylephrine-evoked contraction of endothelium-denuded aortic rings from LPS-treated rats or rings exposed to LPS in vitro. Aminoguanidine did not impair the relaxation of aortic rings with endothelium to acetylcholine, a known stimulator of endothelial NOS. The reversal of LPS-induced vascular hyporesponsiveness by aminoguanidine therefore strongly supports the functional importance of iNOS mRNA expression in the aorta of endotoxemic rats. Future clinical trials in treating septic shock should therefore consider the preferential inhibition of iNOS while maintaining the integrity of endothelial NOS.
Weigert
A L
AL
Department of Medicine, University of Colorado, Denver 80262, USA.
Higa
E M
EM
Niederberger
M
M
McMurtry
I F
IF
Raynolds
M
M
Schrier
R W
RW
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology*; D018076:DNA, Complementary / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000201:enzymology*
D018076:DNA, Complementary; D006146:Guanidines; D008070:Lipopolysaccharides; D009124:Muscle Proteins; D010656:Phenylephrine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C004479:pimagedine