Species dependent cardiac electrophysiological effects elicited by various potassium channel blocking drugs: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle

Rodents are commonly used as models in electrophysiology. However, distinct differences exist between large animals and rodents in terms of their ion channel expression and action potential shapes, possibly limiting the translational value of findings obtained in rodents. We aimed for a direct comparison of the possible impact of selective inhibition of ion channels on the cardiac repolarization in preparations from human hearts and from model species. We applied the standard microelectrode technique at 37°C on cardiac ventricular preparations (papillary muscles and trabecules) from human (n = 63), dog (n = 47), guinea pig (n = 53), rat (n = 43), and rabbit (n = 16) hearts, paced at 1 Hz. To selectively block the I_Kur current, 1 µM XEN-D101; I_K1 current, 10 µM barium chloride; I_Kr current, 50 nM dofetilide; I_Ks current, 500 nM HMR-1556; and I_to current, 100 µM chromanol-293B were applied directly to the tissue bath. The block of I_Kur and I_K1 elicited significantly more prominent prolongation of APD in rats (35.6% and 67.9%, respectively) when compared with the other species, including that of human (1.0% and 2.6%, respectively). On the other hand, I_Kr block did not affect APD in rat preparations (1.6%), whereas it elicited marked prolongation in other species (9.0–47.7%), especially being pronounced in human preparations (60.3%). I_Ks inhibition elicited similar but minor APD prolongation (0.3–11.4%) in all species. Inhibition of I_to moderately lengthened APD in dog (22.3%) and rabbit (17.5%) preparations but elicited no change of APD in human preparations. In contrast, block of I_to caused marked APD prolongation in rat preparations (33.2%). Our findings suggest that the specific inhibition of various ion channels elicits fundamentally different effects in rodent ventricular action potential when compared with those of other species, including human. Therefore, from a translational standpoint, rodent models in cardiac electrophysiological and arrhythmia research should be used with great caution.