Characterisation of recombinant HERG K+ channel blockade by the Class Ia antiarrhythmic drug procainamide
Section snippets
Methods
Maintenance of mammalian cell line stably expressing HERG. Measurements of HERG current (IHERG) were made from a cell line (human embryonic kidney; HEK 293) stably expressing HERG that was generously donated by Professor Craig January, University of Wisconsin [24]. Cells were maintained in culture as described previously [17].
Electrophysiological recordings. Coverslip fragments on which cultured HEK 293 cells were plated were placed in a bath mounted on an inverted microscope (Nikon Diaphot)
Results and discussion
In order to assess IHERG blockade by PROC, the voltage protocol shown in Fig. 1A (lower trace) was employed and IHERG tail amplitude was measured on repolarisation to −40 mV after voltage commands to +20 mV. A range of drug concentrations were examined; Fig. 1A shows representative data with 100 μM PROC. Fig. 1B shows the concentration-dependence of the inhibitory action of PROC. For each cell and each drug concentration studied, blockade was quantified by determining the fractional inhibition of
Acknowledgements
J.M.R. was supported by a University of Bristol Ph.D. studentship, H.J.W. and J.T.M. were supported by the British Heart Foundation (PG/2001104 and PG/2000123). J.C.H. also acknowledges research fellowship support from the Wellcome Trust. The authors also gratefully appreciate technical assistance from Mrs. Lesley Arberry.
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2017, Journal of Pharmacological and Toxicological MethodsCitation Excerpt :Second, class Ia and Ic agents decrease outward K+ currents, thus prolonging APD. For example, both flecainide and procainamide at therapeutic concentrations were reported to reduce IKr in hERG-expressing cell lines (Melgari, Zhang, El Harchi, Dempsey, & Hancox, 2015; Paul, Witchel, & Hancox, 2002; Ridley et al., 2003), and single ventricular myocytes (Follmer, Cullinan, & Colatsky, 1992; Iost, Virag, Varro, & Papp, 2003; Wang, Kiyosue, Sato, & Arita, 1996). Quinidine inhibits several repolarizing K+ currents, including the delayed rectifier, the inward rectifier, and the transient outward K+ current (Iost et al., 2003; Paul et al., 2002; Salata & Wasserstrom, 1988).