Chloroquine interacts with muscarinic receptors and inhibits cholinergic effects in the heart

Abstract

Binding and electrophysiological studies were carried out in order to investigate the mechanisms underlying the cardiac anticholinergic action of chloroquine. Muscarinic receptors of guinea-pig heart homogenates were labeled with tritiated quinuclidinyl-benzilate ( | ?H |- QNB) in the absence and in the presence of chloroquine. Chloroquine (10~S— 10" 4 M) produced a shift of the Q N B saturation binding curve to the right. Increasing the chloroquine concentration in the presence of a constant QNB concentration produced a progressive decrease in QNB binding, but the QNB - chloroquine competition curves were shallow (Hill coefficients = 0.65). Chloroquine also shifted the QNB-carbachol competition curve to the right without changing its Hill slope. In electrophysiological experiments, chloroquine inhibited the negative chronotropic effect of carbacholin Langendorff-perfused hearts. This inhibitory effect of chloroquine was obtained at concentrations lower than those expected to produce significant binding to muscarinic receptors and was not completely reversible. It is concluded that the binding of chloroquine to cardiac muscarinic receptors is complex and that in addition to the interaction at the receptor, other mechanisms are involved in the inhibition of the muscarinic agonist-induced negative chronotropic effect.