Z Wang1, B Fermini, S Nattel. 1. Department of Medicine, Montreal Heart Institute, Quebec, Canada.
Abstract
OBJECTIVE: Previous studies in guinea pig heart cells have shown pharmacologically and kinetically distinct components of the classical delayed rectifier current (IK), generally referred to as IKr (rapid IK) and IKs (slow IK). This study was designed to determine whether the human heart contains corresponding components. METHODS: The whole cell voltage clamp technique was used to study IK in single myocytes isolated from human right atrial appendages removed at the time of aortocoronary artery bypass surgery. RESULTS: The activation of IK was best fitted by a biexponential relation, with time constants averaging 204(SEM 20) and 1080(197) ms at +10 mV. IK was inhibited by the specific IKr blocker E-4031 (5 microM), with the drug sensitive and drug resistant components having markedly different kinetic properties. The E-4031 sensitive current activated rapidly, while the drug resistant component activated more slowly, and the activation time courses of E-4031 sensitive and resistant currents paralleled the rapid and slow components of IK between -20 and +50 mV. The E-4031 sensitive component showed strong inward rectification, a half activation voltage (V 1/2) of -14.0(3.3) mV and a slope factor (k) of 6.5(1.5) mV, while the E-4031 resistant current had a linear current-voltage relationship, and values of +19.9(4.2) mV and 12.7(2.5) mV for V 1/2 and k respectively. The envelope of tails analysis showed a time dependent change in IKtail/IKstep under control conditions, and E-4031 strongly reduced the time dependent variation, suggesting that the E-4031 resistant current consisted of one dominant component. CONCLUSIONS: (1) IK in human atrium shows kinetically distinguishable rapid and slow components. (2) These components correspond to E-4031 sensitive and resistant currents. (3) The kinetics and voltage dependence of the rapid (E-4031 sensitive) and slow (E-4031 resistant) components correspond to properties previously described in guinea pig myocytes. These findings have important potential implications for understanding the mechanisms of human atrial repolarisation and its regulation by the autonomic nervous system and antiarrhythmic drugs.
OBJECTIVE: Previous studies in guinea pig heart cells have shown pharmacologically and kinetically distinct components of the classical delayed rectifier current (IK), generally referred to as IKr (rapid IK) and IKs (slow IK). This study was designed to determine whether the human heart contains corresponding components. METHODS: The whole cell voltage clamp technique was used to study IK in single myocytes isolated from human right atrial appendages removed at the time of aortocoronary artery bypass surgery. RESULTS: The activation of IK was best fitted by a biexponential relation, with time constants averaging 204(SEM 20) and 1080(197) ms at +10 mV. IK was inhibited by the specific IKr blocker E-4031 (5 microM), with the drug sensitive and drug resistant components having markedly different kinetic properties. The E-4031 sensitive current activated rapidly, while the drug resistant component activated more slowly, and the activation time courses of E-4031 sensitive and resistant currents paralleled the rapid and slow components of IK between -20 and +50 mV. The E-4031 sensitive component showed strong inward rectification, a half activation voltage (V 1/2) of -14.0(3.3) mV and a slope factor (k) of 6.5(1.5) mV, while the E-4031 resistant current had a linear current-voltage relationship, and values of +19.9(4.2) mV and 12.7(2.5) mV for V 1/2 and k respectively. The envelope of tails analysis showed a time dependent change in IKtail/IKstep under control conditions, and E-4031 strongly reduced the time dependent variation, suggesting that the E-4031 resistant current consisted of one dominant component. CONCLUSIONS: (1) IK in human atrium shows kinetically distinguishable rapid and slow components. (2) These components correspond to E-4031 sensitive and resistant currents. (3) The kinetics and voltage dependence of the rapid (E-4031 sensitive) and slow (E-4031 resistant) components correspond to properties previously described in guinea pig myocytes. These findings have important potential implications for understanding the mechanisms of human atrial repolarisation and its regulation by the autonomic nervous system and antiarrhythmic drugs.
Authors: Bjorn C Knollmann; Syevda Sirenko; Qi Rong; Alexander N Katchman; Mathew Casimiro; Karl Pfeifer; Steven N Ebert Journal: Biochem Biophys Res Commun Date: 2007-06-15 Impact factor: 3.575