title: Endothelium-accelerated hyporesponsiveness of norepinephrine-elicited contraction of rat aorta in the presence of bacterial lipopolysaccharide.
abstract: The role of the endothelium in the hyporesponsiveness of alpha-adrenoceptor-mediated contractions of the rat aorta was investigated. The norepinephrine-induced maximal contraction was diminished after repeated addition of the agonist. The hyporesponsiveness of the maximal contraction was endothelium dependent, being prevented by NG-monomethyl-L-arginine (0.5 mM), L-argininosuccinic acid (0.5 mM), puromycin (IC50 = 100 microM), actinomycin D (IC50 = 80 nM) but not by indomethacin, which suggests that nitric oxide (NO) synthase is induced. The sensitivity of the rings to NO-induced relaxation remained unchanged. The above-mentioned hyporesponsiveness of norepinephrine-induced maximal contractions of aorta rings was also observed after a 5-h incubation without norepinephrine. The agonist-independent hyporesponsiveness was also prevented by NG-monomethyl-L-arginine, puromycin and actinomycin D, which suggests that NO synthase is induced. Moreover, the norepinephrine-independent hyporesponsiveness was prevented by polymyxin B (10 micrograms/ml), which suggests that bacterial lipopolysaccharide (LPS) might be involved. The concentration of contaminating LPS was 89 +/- 11 ng/ml. When the concentration of contaminating LPS was reduced to 40-70 pg/ml, the hyporesponsiveness of the maximal contraction did not occur after repeated addition of norepinephrine or alter a 5-h incubation without the agonist. An addition of 30 or 100 ng/ml of E. coli lipopolysaccharide to the organ bath reproduced the hyporesponsiveness of the maximal contraction. After a 5-h incubation of aortic rings with 30 ng/ml LPS, only the endothelium-intact ring showed a reduced contraction. However, a 24-h incubation reduced the contraction even in the absence of endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakaki
authors.forename: Y
authors.initials: Y
authors.lastname: Otsuka
authors.forename: M
authors.initials: M
authors.lastname: Nakayama
authors.forename: R
authors.initials: R
authors.lastname: Kato
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D000818:Animals; D001011:Aorta; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001125:Argininosuccinic Acid / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D004926:Escherichia coli / Q000737:chemistry; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019001:Nitric Oxide Synthase; D009638:Norepinephrine / Q000494:pharmacology*; D011112:Polymyxin B / Q000494:pharmacology; D011691:Puromycin / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects*; D019323:omega-N-Methylarginine
chemical_list: D008070:Lipopolysaccharides; D003609:Dactinomycin; D001125:Argininosuccinic Acid; D019323:omega-N-Methylarginine; D011691:Puromycin; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D011112:Polymyxin B; D009638:Norepinephrine