Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656

Abstract

The anticholinergic antiparkinson drug orphenadrine is an antagonist at central and peripheral muscarinic receptors. Orphenadrine intake has recently been linked to QT prolongation and Torsade-de-Pointes tachycardia. So far, inhibitory effects on I (Kr) or cloned HERG channels have not been examined. HERG channels were heterologously expressed in a HEK 293 cell line and in Xenopus oocytes and HERG current was measured using the whole cell patch clamp and the double electrode voltage clamp technique. Orphenadrine inhibits cloned HERG channels in a concentration dependent manner, yielding an IC(50) of 0.85 microM in HEK cells. Onset of block is fast and reversible upon washout. Orphenadrine does not alter the half-maximal activation voltage of HERG channels. There is no shift of the half-maximal steady-state-inactivation voltage. Time constants of direct channel inactivation are not altered significantly and there is no use-dependence of block. HERG blockade is attenuated significantly in mutant channels lacking either of the aromatic pore residues Y652 and F656. In conclusion, we show that the anticholinergic agent orphenadrine is an antagonist at HERG channels. These results provide a novel molecular basis for the reported proarrhythmic side effects of orphenadrine.

Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine

“…Low dose of orphenadrine was also shown to precipitate long QT and Torsades-de-Pointes tachycardia in a patient with congenital long QT syndrome [32]. Recent studies suggest that cardiac and neuronal toxicity may be linked to the action of orphenadrine on HERG channels, which contribute to the action potential repolarization phase in the heart and to spike-frequency accommodation in the nervous system [43,47]. Our results show that orphenadrine inhibits the sodium channel subtypes expressed in heart and central neurons.…”

Anesthetic drug midazolam inhibits cardiac human ether-à-go-go-related gene channels: mode of action

“… 23 As published previously, two different voltage protocols were applied in order to qualitatively analyze the state dependence of hERG channel inhibition. 20 , 24 , 25 For each voltage protocol, a measurement before and after drug incubation was performed, and development of block was calculated by division. First, using a long depolarizing voltage step to 0 mV (6 seconds), cells were depolarized ( Figure 4A ).…”

Assessment of drug-induced arrhythmic risk using limit cycle and autocorrelation analysis of human iPSC-cardiomyocyte contractility

“…Our automated high-throughput approach is a powerful qualitative and quantitative method to rank order compounds according to their predictive cardiac risk and aims to bridge the gap between assay throughput and clinical relevance. (Aarons et al, 1998;Zhou et al, 1998;Teschemacher et al, 1999;Tie et al, 2000;Paul et al, 2002;Kirsch et al, 2004;Guo et al, 2005;Tarantino et al, 2005;Scholz et al, 2007;Luo et al, 2008;Huang et al, 2010;Zhang et al, 2010;Gintant, 2011;Lee et al, 2011;Vigneault et al, 2011;El Harchi et al, 2012;Crumb, 2014;Gualdani et al, 2015;Yun et al, 2015).…”