© 1995 American Heart Association, Inc.
Articles |
Effects of Delayed Rectifier Current Blockade by E-4031 on Impulse Generation in Single Sinoatrial Nodal Myocytes of the Rabbit
From the Department of Physiology, University of Amsterdam (Netherlands), Academic Medical Centre.
Correspondence to E. Etienne Verheijck, Department of Physiology, University of Amsterdam, Academic Medical Centre, Meibergdreef 15, 1105 AZ Amsterdam, Netherlands.
Abstract The role of the delayed rectifier current (IK) in impulse generation was studied in single sinoatrial nodal myocytes of the rabbit. We used the class III antiarrhythmic drug E-4031, which blocks IK in rabbit ventricular myocytes. In single sinoatrial nodal cells, E-4031 (0.1 µmol/L) significantly prolonged cycle length and action potential duration, depolarized maximum diastolic potential, and reduced both the upstroke velocity of the action potential and the diastolic depolarization rate. Half of the cells were arrested completely. At higher concentrations (1 and 10 µmol/L), spontaneous activity ceased in all cells. Three ionic currents fundamental for pacemaking, ie, IK, the long-lasting inward calcium current (ICa,L), and the hyperpolarization-activated current (If), were studied by using the whole-cell and amphotericin–perforated patch technique. E-4031 blocked part of the outward current during depolarizing steps as well as the tail current upon subsequent repolarization (ITD) in a dose-dependent manner. E-4031 (10 µmol/L) depressed ITD (88±4%) (n=6), reduced peak ICa,L at 0 mV (29±15%) (n=4), but did not affect If. Lower concentrations did not affect ICa,L. Additional use of 5 µmol/L nifedipine demonstrated that ITD is carried in part by a calcium-sensitive current. Interestingly, complete blockade of IK and ICa,L unmasked the presence of a background current component with a reversal potential of -32±5.4 mV (n=8) and a conductance of 39.5±5.6 pS/pF, which therefore can contribute both to the initial part of repolarization and to full diastolic depolarization. In conclusion, IK in conjunction with an inward background current plays an essential role in maintaining normal automaticity.
Key Words: sinoatrial nodal cells • class III antiarrhythmic agent E-4031 • delayed rectifier current • impulse generation • background current
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