Mechanism of neopterin-induced myocardial dysfunction in the isolated perfused rat heart.
Neopterin is a sensitive marker for diseases involving increased activity of the cellular immune system in humans. Many studies, however, provide evidence for neopterin not only as a marker, but also for its characteristic effects. Recently, we were able to demonstrate a considerable influence of exogenous neopterin at a concentration of 100 mumol/l on cardiac performance in the Langendorff model of isolated perfused rat hearts. The present study was designed to investigate its possible mechanism. During co-infusion of neopterin at a concentration of 100 mumol/l with the unspecific nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine monoacetate, the nitric oxide donor PAPA NONOate, the free radical scavenger N-acetylcysteine, or the pro-inflammatory cytokine tumor necrosis factor-alpha the effects on cardiac contractility parameters and coronary vascular resistance were studied in 67 male Sprague-Dawley rats. The temperature-controlled and pressure-constant Langendorff apparatus was used with retrograde perfusion of the aorta and a Krebs-Henseleit buffer. Neither the unspecific nitric oxide synthase inhibitor nor the nitric oxide donor excludes nitric oxide from playing a mechanistic role in our perfusion studies. Tumor necrosis factor-alpha was without any synergistic or antagonistic effects when co-treated with neopterin. N-acetylcysteine was most effective in abolishing neopterin-dependent effects on cardiac function. The negative effects of neopterin on cardiac performance might be due to an enhancement of oxidative stress by neopterin that can be attenuated by the antioxidant N-acetylcysteine. Neopterin has to be considered a pathogenic factor in the development of cardiac dysfunction in chronic disease states with high neopterin levels secondary to activation of the immune system.
Balogh
Agnes
A
Department of Anesthesia and Critical Care Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.
Mittermayr
Markus
M
Schlager
Andreas
A
Balogh
Doris
D
Schobersberger
Wolfgang
W
Fuchs
Dietmar
D
Margreiter
Josef
J
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D019798:Neopterin / Q000008:administration & dosage / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018384:Oxidative Stress; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000975:Antioxidants; D016166:Free Radical Scavengers; D006834:Hydrazines; C112653:PAPA NONOate; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019798:Neopterin; D019001:Nitric Oxide Synthase; D000111:Acetylcysteine