Protective effect of 3-deazaadenosine in a rat model of lipopolysaccharide-induced myocardial dysfunction.
Severe sepsis is accompanied by a profound depression of myocardial contractility. Leukocyte adhesion with subsequent local excess nitric oxide and reactive oxygen species production play major roles for this deleterious effect. We hypothesized that 3-deazaadenosine (c3Ado), an adenosine analogue with anti-inflammatory properties, prevents endotoxin-induced myocardial dysfunction. Wistar rats (8 per group) were treated with Escherichia coli lipopoly-saccharide (LPS, 1 mg/kg, i.p., strain 0111:B4) +/- c3Ado (10 mg/kg, i.p.) 8 h before their hearts were harvested for isolated perfusion, histochemical analysis, or electrophoretic mobility shift assay. LPS induced a marked depression of left ventricular contractility. Immunohistochemistry revealed an upregulation of the adhesion molecules VCAM-1, ICAM-1, and P-selectin within the postcapillary venules. c3Ado inhibited VCAM-1 and ICAM-1 upregulation, but not P-selectin, and prevented cardiodepression. Electrophoretic mobility shift assay revealed inactivation of the transcription factor nuclear factor-kappaB and immunohistochemical staining for gp91phox, ED1, and CD11b demonstrated that c3Ado prevented local recruitment of monocytes and polymorph nuclear neutrophils to the myocardium. Accordingly, significantly fewer leukocytes producing nitric oxide or reactive oxygen species accumulated within the myocardium. Intravital microscopy of intestinal venules confirmed that LPS-induced adhesion of leukocytes was prevented by c3Ado. Additionally, c3Ado prevented LPS-induced elevation of serum tumor necrosis factor-alpha levels. Our results imply that c3Ado may prove to have clinical relevance for inflammatory disease processes.
Braun-Dullaeus
Ruediger C
RC
Department of Internal Medicine/Cardiology, Giessen University, Giessen, Germany.
Dietrich
Simon
S
Schoaff
Michael J
MJ
Sedding
Daniel G
DG
Leithaeuser
Boris
B
Walker
Gerhard
G
Seay
Ulrike
U
Matthias
Reinhard F
RF
Kummer
Wolfgang
W
Tillmanns
Harald
H
Haberbosch
Werner
W
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D007536:Isomerism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000139:chemically induced / Q000517:prevention & control*; D014372:Tubercidin / Q000627:therapeutic use*
D015815:Cell Adhesion Molecules; D008070:Lipopolysaccharides; C018258:3-deazaadenosine; D014372:Tubercidin