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.
Ehrentraut
S
S
Institute of Physiology II, Universitätsklinikum Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany.
Frede
S
S
Stapel
H
H
Mengden
T
T
Grohé
C
C
Fandrey
J
J
Meyer
R
R
Baumgarten
G
G
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