Histamine H1 antagonists block M-currents in dissociated rat cortical neurons

We investigated the effects of histamine H1 antagonists on acutely dissociated neurons from the rat cortex using the patch-clamp technique. First-generation antihistamines, such as pyrilamine, d-chlorpheniramine, diphenhydramine, and ketotifen, suppressed M-currents in a concentration-dependent manner with respective half-inhibition concentrations (C50) of 35.9, 48.5, 34.8, and 47.8 μM at a holding potential of −26.5 mV. Astemizole, a second-generation antihistamine, inhibited M-currents with a C50 of 18.1 μM, but cetirizine did not do so, up to a concentration of 300 μM. Neither ranitidine nor cimetidine, both H2 antagonists, suppressed M-currents. The C50 of pyrilamine significantly decreased with membrane hyperpolarization, suggesting that it acts directly on M channel pores. The inhibition of M channels may be involved in the neurotoxic effects of histamine H1 antagonist overdose.