N-n-butyl haloperidol iodide (F-2), a novel quaternary ammonium salt derivative of haloperidol, was reported to antagonize myocardial ischemia/reperfusion injuries. To investigate its mechanisms, we characterized the effects of F-2 on Na+/Ca2+ exchanger currents (I-NCX) and the L-type Ca2+ channel current (I-Ca,I-L) of cardiomyocytes during either hypoxia/reoxygenation or exposure to H2O2. Using whole-cell patch-clamp techniques, the I-NCX and I-Ca,I-L were recorded from isolated rat ventricular myocytes. Exposure of cardiomyocytes to hypoxia/reoxygenation or H2O2 enhanced the amplitude of the inward and outward of I-NCX and I-Ca,I-L. F-2 especially inhibited the outward current of Na+/Ca2+ exchanger, as well as the I-Ca,I-L, in a concentration-dependent manner. F-2 inhibits cardiomyocyte I-NCX and I-Ca,I-L after exposure to hypoxia/reoxygenation or H2O2 to antagonize myocardial ischemia/reperfusion injury by inhibiting Ca2+ overload. (C) 2012 Elsevier Inc. All rights reserved.