Antimalarial drugs inhibit the acetylcholine-receptor-operated potassium current in atrial myocytes

Abstract

Background: It has been reported that halofantrine, an antimalarial drug, was associated with electrocardiographic prolongation of the QT interval and ventricular arrhythmias. Inhibition of the delayed rectifier potassium channel, a voltage-gated potassium channel, by halofantrine was the likely underlying cellular mechanism for this cardiotoxicity. However, influences of anti-malarial drugs on the ligand-gated potassium channels have not been well-documented. The influences of three different antimalarial drugs, chloroquine, primaquine and pyrimethamine, on the acetylcholine-receptor-operated potassium current (I K.ACh), a ligand-gated potassium current, were compared with the effect of quinidine in isolated guinea pig atrial myocytes using patch-clamp techniques. Methods: The whole-cell patch-clamp method was used in the present studies he I K.ACh was induced by extracellular application of carbachol (1 μmol/L) or intracellular loading of guanosine 5′-O-(3-thiotriphosphate) GTPγS (100 μmol/L) in acutely isolated guinea pig atrial myocytes. Results: The I K.ACh induced by carbachol was inhibited by chloroquine, primaquine, pyrimethamine and quinidine in a concentration-dependent manner, and the concentrations required to produce 50% of the maximal inhibitory effect (IC 50 values) were 0.7, 2.5, 12 and 1.8 μmol/L, respectively. These drugs also inhibited the intracellular GTPγS-activated I K.ACh, and the IC 50 values were 0.8,13,19 and 21 μmol/L, respectively. Conclusions: Chloroquine and pyrimethamine may inhibit I K.ACh by interacting with the muscarinic potassium channel itself and/or associated guanosine 5′-triphosphate-binding proteins, whereas primaquine and quinidine may mainly inhibit the current by the blockade of the muscarinic receptors. These results indicate that antimalarial drugs exert anticholinergic effects via different molecular mechanisms.