Antagonism of lipopolysaccharide-induced blood pressure attenuation and vascular contractility.
OBJECTIVE
Aim was to assess whether lipopolysaccharide (LPS)-induced decrease of total peripheral resistance depends on Toll-like receptor (TLR)4 signaling and whether it is sensitive to NO-synthase or TLR4 antagonists.


RESULTS
C3H/HeN mice (control), expressing a functional, and C3H/HeJ mice, expressing a nonfunctional TLR4, were compared. LPS (20 mg/kg) was injected i.p. 6 hours before hemodynamic measurements. L-NAME and SMT, inhibitors of NO production, and Eritoran, a TLR4 antagonist, were tested for their impact on vascular contractility. Aortic rings were incubated for 6 hours with or without LPS (1 microg/mL), or with LPS+Eritoran (2 microg/mL) and their phenylephrine-induced contractility was measured using a myograph. The expression of cytokines in aortic tissue was examined by real-time polymerase chain reaction. In control mice LPS induced a significant decrease of blood pressure and an increase of heart rate, whereas C3H/HeJ remained unaffected. LPS induced an increase of cytokine expression and a depression of vascular contractility only in control mice but not in C3H/HeJ. L-NAME and SMT increased contractility in all rings and restored LPS-dependent depression of contractility. Eritoran prevented LPS-induced loss of contractility.


CONCLUSIONS
LPS upregulates cytokine expression via TLR4 and induces attenuation of smooth muscle contractility which can be effectively antagonized.
Institute of Physiology II, Universitätsklinikum Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany.
S
S
Ehrentraut
S
S
Frede
H
H
Stapel
T
T
Mengden
C
C
Grohé
J
J
Fandrey
R
R
Meyer
G
G
Baumgarten
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004187:Disaccharides / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008070:Lipopolysaccharides; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017354:Point Mutation; D012333:RNA, Messenger / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D013403:Sugar Phosphates / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*
D016207:Cytokines; D004187:Disaccharides; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013403:Sugar Phosphates; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C440499:lipopolysaccharide, Escherichia coli O111 B4; D007550:Isothiuronium; D009569:Nitric Oxide; C512420:eritoran; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C027744:S-methylisothiopseudouronium; D019331:NG-Nitroarginine Methyl Ester