Lipopolysaccharide-induced hypotension and vascular hyporeactivity in the rat: tissue analysis of nitric oxide synthase mRNA and protein expression in the presence and absence of dexamethasone, NG-monomethyl-L-arginine or indomethacin.
The role of inducible nitric oxide synthase (iNOS) was examined in the hypotension and vascular hyporesponsiveness to norepinephrine (NE) invoked by lipopolysaccharide (LPS) in pentobarbital-anesthetized rats. Saline, dexamethasone (DEX), NG-monomethyl-L-arginine (LNMMA) or indomethacin (IND) were administered either pre-LPS (0.5 hr) or post-LPS (4.5 hr) treatment. Rats were then challenged with NE 10 min before LPS injection and 1, 4, and 5 hr after LPS. Administration of LPS produced a biphasic hypotension: an immediate hypotension, which partially recovered within 15 min and was unaffected by any of the pretreatments; and a secondary, more prolonged hypotension which was attenuated by DEX, LNMMA and IND. The NE-induced pressor effects were significantly attenuated 1, 4 and 5 hr post LPS. Pretreatment with LNMMA or DEX significantly attenuated the LPS-induced NE hyporesponsiveness 4 and 5 hr post LPS. LNMMA was the only post-LPS treatment able to reverse the NE hyporesponsiveness. The LPS-induced iNOS mRNA and protein expression was demonstrated in the liver, lung, spleen, heart, kidney and brain by Northern hybridization and Western blot analyses. Low levels of neuronal constitutive NOS mRNA and endothelial cell constitutive NOS mRNA were only detected in brain or myocardial tissue, respectively. Significant induction of iNOS mRNA and protein expression was also observed in the liver, lung and spleen of rats pretreated with DEX, LNMMA or IND. The continued expression of iNOS in the presence of a pharmacologically relevant dose of DEX suggests that DEX may not be an optimal pharmacological agent for defining the in vivo roles of iNOS.(ABSTRACT TRUNCATED AT 250 WORDS)
Hom
G J
GJ
Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey.
Grant
S K
SK
Wolfe
G
G
Bach
T J
TJ
MacIntyre
D E
DE
Hutchinson
N I
NI
D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D019001:Nitric Oxide Synthase; D009638:Norepinephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000378:metabolism*; D014018:Tissue Distribution; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019323:omega-N-Methylarginine; D003907:Dexamethasone; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D009638:Norepinephrine; D007213:Indomethacin