Effects of Ik,Ach Channel Inhibitor Tertiapin-Q on Right Atrial Preparations from Patients in Sinus Rhythm and Atrial Fibrillation

Abstract

Background: The acetylcholine-activated inward rectifying current, IK,Ach, has been suggested as a novel atrial-selective putative drug target for the treatment of atrial fibrillation (AF). Here we have studied the effects of a selective IK,ACh channel inhibitor tertiapin-Q in human right atrial preparations from patients in sinus rhythm (SR) and permanent chronic atrial fibrillation (AF, >6 months).Methods: Action potentials (APs) were measured using sharp electrodes in right atrial trabeculae or patch electrodes in cardiomyocytes from patients undergoing open heart surgery (48 in SR and 34 in AF).Results and Conclusion: Tertiapin-Q (300nM) did not affect APs recorded in AF trabeculae (APD90 at 1Hz: control 205.8±9.0ms vs. drug 209.0±9.0ms, n.s.). Consistent with electrical remodelling of IK,ACh channels in AF, 1µM carbachol caused minimal effect on APD in AF trabeculae and no further effect was detected following combined exposure to carbachol and tertiapin-Q (APD90 242.0±16.9ms, 233.0±20.5ms, 234.0±19.1ms, respectively). In SR trabeculae, tertiapin-Q modestly, though not significantly, attenuated the shortening effect of carbachol on APD90: 310.0±7.7ms, 215.0±16.4ms, and 254.0±17.8ms, respectively). In the continuous presence of carbachol and tetrodotoxin (1µM), tertiapin-Q prolonged effective refractory period and APD90. In atrial cardiomyocytes from SR patients, tertiapin-Q fully reversed the carbachol-induced shortening of APD90. At a holding potential of −80mV, tertiapin-Q had no effect on the basal inward current in SR cardiomyocytes (2.0±0.5pA/pF vs. 2.5±0.7pA/pF, n=7), but significantly reduced in AF cardiomyocytes (6.8±1.1pA/pF vs. 5.9±0.8pA/pF, P<0.05, n=12), providing evidence for constitutive activity of IK,ACh in AF cardiomyocytes. From the modest effects of tertiapin-Q in multicellular preparations in comparison to cardiomyocytes, we conclude that access of the IK,ACh channel inhibitor to its target may be limited in intact superfused tissues.