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

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.

The whole-cell patch-clamp method was used in the present studies he I(K.ACh) was induced by extracellular application of carbachol (1 micromol/L) or intracellular loading of guanosine 5'-O-(3-thiotriphosphate) GTPgammaS (100 micromol/L) in acutely isolated guinea pig atrial myocytes.

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 micromol/L, respectively. These drugs also inhibited the intracellular GTPgammaS-activated I(K.ACh), and the IC(50) values were 0.8,13,19 and 21 micromol/L, respectively.

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.