RAPID AND SLOW COMPONENTS OF DELAYED RECTIFIER CURRENT IN HUMAN ATRIAL MYOCYTES

Objective: Previous studies in guinea pig heart cells have shown pharm acologically and kinetically distinct components of the classical dela yed rectifier current (I-K), generally referred to as I-Kr (rapid I-K) and I-Ks (slow I-K). This study was designed to determine whether the human heart contains corresponding components. Methods: The whole cel l voltage clamp technique was used to study I-K in single myocytes iso lated from human right atrial appendages removed at the time of aortoc oronary artery bypass surgery. Results: The activation of I-K was best fitted by a biexponential relation, with time constants averaging 204 (SEM 20) and 1080(197) ms at +10 mV. I-K was inhibited by the specific I-Kr blocker E-4031 (5 mu M), with the drug sensitive and drug resist ant components having markedly different kinetic properties. The E-403 1 sensitive current activated rapidly, while the drug resistant compon ent activated more slowly, and the activation time courses of E-4031 s ensitive and resistant currents paralleled the rapid and slow componen ts of I-K between -20 and +50 mV. The E-4031 sensitive component showe d strong inward rectification, a half activation voltage (V-1/2) of -1 4.0(3.3) mV and a slope factor (k) of 6.5(1.5) mV, while the E-4031 re sistant 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 en velope of tails analysis showed a time dependent change in I-Ktail/I-K step under control conditions, and E-4031 strongly reduced the time de pendent variation, suggesting that the E-4031 resistant current consis ted of one dominant component. Conclusions: (1) I-K in human atrium sh ows kinetically distinguishable rapid and slow components. (2) These c omponents correspond to E-4031 sensitive and resistant currents. (3) T he kinetics and voltage dependence of the rapid (E-4031 sensitive) and slow (E-4031 resistant) components correspond to properties previousl y described in guinea pig myocytes. These findings have important pote ntial implications for understanding the mechanisms of human atrial re polarisation and its regulation by the autonomic nervous system and an tiarrhythmic drugs.