Exogenous neopterin causes cardiac contractile dysfunction in the isolated perfused rat heart

Neopterin is known in humans as a sensitive marker for diseases associated with increased activity of the cellular immune system. Recent studies report neopterin also to exhibit distinct effects: neopterin induces inducible nitric oxide synthase expression in rat vascular smooth muscle cells and activates translocation of nuclear factor- kappa B. Neopterin may also induce oxidative stress causing apoptotic cell death, or superinduce tumor necrosis factor- alpha -mediated apoptosis. Observing these effects in cell cultures, we were interested in possible consequences of neopterin on cardiac function in the isolated perfused rat heart. The influence of neopterin in three different concentrations (10 micromol/l, 50 micromol/l, 100 micromol/l) on cardiac contractility parameters and coronary vascular resistance were studied in 67 male Sprague-Dawley rats using the temperature-controlled and pressure-constant Langendorff apparatus with retrograde perfusion of the aorta with a Krebs-Henseleit buffer. Treatment with 100 micromol/l neopterin resulted in a significant decrease in coronary flow and cardiac contractility. Coronary flow decreased from 15.2 to 9.5 ml/min (P=0.002), left ventricular pressure from 80 to 52 mmHg (P=0. 002), rate of pressure fall from 1605 to 923 mmHg/s (P=0.001) and rate of pressure rise from 2862 to 1709 mmHg/s (P=0.001). Concentrations lower than 100 micromol/l neopterin had no significant effect on cardiac function. Our study demonstrates a considerable influence of exogenous neopterin on cardiac performance in the Langendorff model of isolated perfused rat hearts. This has to be considered a potential pathogenic factor of cardiac disturbances in diseases in which high concentrations of neopterin are released due to immune activation. At present the exact mechanism remains unclear.