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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2170.)
© 2007 American Heart Association, Inc.

Vascular Biology

Antagonism of Lipopolysaccharide-Induced Blood Pressure Attenuation and Vascular Contractility

S. Ehrentraut; S. Frede; H. Stapel; T. Mengden; C. Grohé; J. Fandrey; R. Meyer; G. Baumgarten

From the Institute of Physiology II (S.E., H.S., R.M.), the Department of Anesthesiology and Intensive Care Medicine (G.B.), Medizinische Universitätspoliklinik (T.M., C.G.), Universitätsklinikum Bonn, Germany; and the Institute of Physiology (S.F., J.F.), University Duisburg-Essen, Germany.

Correspondence to Rainer Meyer, PhD, Institute of Physiology II, Universitätsklinikum Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany. E-mail rainer.meyer{at}ukb.uni-bonn.de

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.

Methods and 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 µg/mL), or with LPS+Eritoran (2 µg/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.

LPS decreases blood pressure as well as vascular contractility and increases vascular cytokine expression via a Toll-like receptor 4 (TLR4) pathway in mice. This local vascular Signaling contributes to septic shock. Lowered vascular contractility can be restored by inhibition of iNOS or prevented by the application of a TLR4 antagonist.

Key Words: blood pressure • sepsis • toll-like receptor 4 antagonism • vascular contractility