Calpain inhibitors improve myocardial dysfunction and inflammation induced by endotoxin in rats.
Excessive activation of calpains has been implicated in the pathophysiology of inflammation, trauma, and ischemia reperfusion injury. Here, we investigated the effects of calpain inhibition on myocardial dysfunction and inflammation induced by endotoxin in rats. Rats were treated i.v. with endotoxin (10 mg/kg) or endotoxin plus calpain inhibitors and were then prepared after 4 h for myocardial contractility assessment, detection of endothelium leukocyte interactions, and plasma TNF-alpha, nitrite/nitrate, and endocan levels. Compared with vehicle-treated rats, hearts from endotoxin-treated rats had reduced systolic performance that was partially prevented by calpain inhibitors, i.e., acetyl-leucyl-leucyl-arginal (leupeptin), carbobenzoxy-valyl-phenylalanial (calpain inhibitor III), and N-acetyl-leucinyl-leucinyl-norleucinal (ALLN). Leupeptin and calpain inhibitor III reduced plasma TNF-alpha levels in endotoxin-treated rats. ALLN reduced plasma TNF-alpha and nitrite/nitrate levels in endotoxin-treated rats. Endotoxin treatment increased mesenteric venule leukocyte rolling (10 +/- 3 leukocytes/min vs. 44 +/- 10 leukocytes/min; P < 0.01) and adhesion (2 +/- 2 leukocytes/min vs. 15 +/- 3 leukocytes/min; P < 0.01), which was reduced by calpain inhibitors. Attenuation of leukocyte endothelium interactions observed in calpain inhibitor-treated rats with sepsis was associated with increases in plasma anti-adhesion molecule endocan. In conclusion, calpain inhibitors improved endotoxin-induced cardiac dysfunction, which may be attributed to the modulation of endothelium leukocyte interactions in the inflamed vasculature.
Tissier
Stephanie
S
Université de Lille 2, Lille, France.
Lancel
Steve
S
Marechal
Xavier
X
Mordon
Serge
S
Depontieu
Florence
F
Scherpereel
Arnaud
A
Chopin
Claude
C
Neviere
Remi
R
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D004731:Endotoxins / Q000494:pharmacology*; D006023:Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy*; D007275:Injections, Intravenous; D036904:Leukocyte Rolling / Q000187:drug effects; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D004731:Endotoxins; D006023:Glycoproteins; D007976:Leupeptins; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; C039304:calpain inhibitors; C063261:acetylleucyl-leucyl-norleucinal; C032854:leupeptin