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Uniqueness of Pilsicainide in Class Ic Antiarrhythmics Takeshi

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Uniqueness of Pilsicainide in Class Ic Antiarrhythmics Takeshi Uniqueness of Pilsicainide in Class Ic Antiarrhythmics Takeshi YAMASHITA, MD, Yuji MURAKAWA, MD, Kazunori SEZAKI, MD, Noriyuki HAYAMI, MD, Masashi INOUE, MD, Ei-ichi FUKUI, MD, and Masao OMATA, MD SUMMARY Pilsicainide, a class Ic agent, is known to be an effective drug particularly for treating atrial tachyarrhythmias. However, its electrophysiological effects on the atrium have not been well studied. To characterize the electrophysiologic effects of pilsicainide on atrial myocytes in class Ic drugs, we examined the effects of this drug on membrane currents in single rabbit atrial myocytes using the tight-seal whole cell voltage-clamp technique. Under the current-clamp condition, pilsicainide did not affect the action potential duration at therapeutic ranges (3ƒÊM) and slightly shortened it at higher concentrations (10ƒÊM). These observations were quite different from those with other class Ic agents including flecainide and propafenone which prolong the atrial action potential duration. The drug did not affect the resting membrane potential. Under the voltage-clamp condition, pilsicainide inhibited the transient outward current (Ito) that is more prominent in the atrium than in the ventricle in a concentra- tion-dependent manner. However, in contrast to other class Ic agents, the inhibition of Ito by pilsicainide was observed only at much higher concentra- tions (IC50-300ƒÊM) and did not affect the inactivation time-course of Ito. Moreover, the drug (10ƒÊM) did not significantly affect the Ca2+, delayed rec- tifier K+, inward rectifying K+, acetylcholine-induced K+ or ATP-sensitive K+ currents. From these results, pilsicainide could be differentiated as a pure Na+ channel blocker from other class Ic agents with diverse effects on membrane currents and should be recognized accordingly in clinical situations. (Jpn Heart J 1998; 39: 389-397) Key words: Pilsicainide, Potassium channel, Antiarrhythmics, Electrophysi- ology, Atrium ILSICAINIDE, a class Ic agent according to the Vaughan Williams classification,1,2) is known to be an effective antiarrhythmic drug, particu- larly for atrial tachyarrhythmia.3,4) Clinically, a single oral dose of 150mg From the Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan. Address for correspondence: Takeshi Yamashita, MD, The Second Department of Internal Medicine, Fac- ulty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. Received for publication February 3, 1998. Accepted March 25, 1998. 389 Jpn Heart J 390 YAMASHITAET AL May 1998 pilsicainide has been reported to be effective in terminating paroxysmal atrial fibrillation in approximately half of the patients.3) Class Ic drugs including pilsicainide, flecainide, and propafenone which are clinically used in Japan are characterized by their potent inhibitory effect on the conduction of excitation, which is ascribed to the use-dependent blocking action on Na+ inward current with slow onset and offset kinetics.5) However, class Ic drugs have been shown to have many other significant effects on membrane currents, thereby exerting their antiarrhythmic action.6-12) Actually, flecainide and propafenone are shown to prolong the atrial (but not ventricular) action potential duration .6,12) This effect can result from their inhibitory effect on the Ca2+-independent transient outward current (Ito) that is more prominent in the atrium than in the ventricle.6,12) In addition, both drugs are also reported to inhibit Ca2+ and delayed rectifier K+ currents .6,7,11) These additional effects might lead to their antiarrhythmic action, but at the same time could result in their adverse effects (proarrhythmic and negative inotropic action). Although pilsicainide is classified in the same group as these class Ic agents,1,2) the effects of this drug on other membrane currents have not been studied. Because this drug is frequently used in treating atrial tachyarrhythmia, its effects on Ito, which is important in determining the atrial action potential, should be clarified. The present study was undertaken to exam- ine whether pilsicainide has any effects on atrial myocyte membrane currents other than Na+ current with special reference to Ito. METHODS Preparations: New Zealand White rabbits weighing about 1.0kg were anes- thetized with pentobarbital (-50mg, i.v.) and the hearts were rapidly removed and mounted on a Langendorff apparatus. Single atrial cells were enzymatically isolated as reported previously.13) Briefly, the heart was perfused for about 10 min with nominally Ca2+-free bathing solution containing 0.6mg/ml type II collag- enase (Worthington, Lakewood, USA) at a perfusion pressure of 80cmH2O. Thereafter, the enzyme-containing solution was flushed with the high-K/low-Cl solution. After the atrium was separated, single atrial cells were obtained by gentle shaking, kept in the high-K/low-Cl solution at 4•Ž for at least 1 hour before use, and dispersed in a recording chamber with the control bathing solu- tion. Electrophysiologic measurements: The patch-clamp technique was used in the whole cell configuration.14) A heat-polished patch pipette, filled with an arti- ficial internal solution, had a tip resistance of 1 to 4Mƒ¶. Membrane currents and potentials were measured through a patch-clamp amplifier (EPC-7, List Electron- ics, Darmstadt, Germany) and monitored with a high-gain oscilloscope. The data Vol 39 No 3 PILSICAINIDEIN CLASSIC ANTIARRHYTHMICS 391 were stored on video tapes using a PCM converter system (VR-10B, Instrutech Corp., New York, USA), reproduced, low-pass-filtered at 1kHz by a filter with Bessel characteristics, sampled at 5kHz and analysed off-line on a personal computer. Results are expressed as means•}SD, and significant differences be- tween values were assessed using a paired t-test. Solutions and drugs: The control bathing solution contained (in mM) NaCl 136.5, KCl 5.4, HEPES 5.5, Na2HPO4 0.33, glucose 5.5, CaCl2 1.8, MgCl2 0.53, pH 7.4. The high-K/low-Cl solution contained (in mM): glutamic acid 70, KCl 25, KH2PO4 10, taurine 10, oxalic acid 10, glucose 11, EGTA 0.5, HEPES 10, pH 7.4. The internal pipette solution contained (in mM) KCl 130, ATPK2 5, HEPES 5, MgCl2 1, EGTA 1, pH 7.2. When measuring Ca2+-independent tran- sient outward current (Ito), the concentration of EGTA in the internal solution was raised to 5mM to block Ca2+-dependent transient outward current, and 0.2 mM Cd2+ was added to the bathing solution to block Ca2+ current. Na+ current was blocked by 10ƒÊM TTX in the bathing solution. Pilsicainide, a gift from Suntory, was used from stock solution (10mM). RESULTS The effects of pilsicainide on the atrial action potential duration: Figure 1 illustrates the effects of pilsicainide (1, 3, 10, 30ƒÊM) on the action potential of isolated rabbit atrial cells. Action potentials were elicited by passing currents through the patch pipette, which caused artifacts at the beginning of each action potential. In contrast to other class Ic drugs (flecainide, propafenone), pilsicainide did not affect the action potential duration significantly at therapeutic ranges (_??_3ƒÊM). At higher concentrations, the drug significantly shortened the atrial Figure 1. A representative example showing atrial action potentials before and after application of pilsicainide (1-30ƒÊM at 0.5Hz). Pilsicainide did not affect the action potential duration at therapeutic ranges (_??_3ƒÊM) but shortened it at higher concentra- tions. Action potentials at control and after application of 1ƒÊM pilsicainide are com- pletely overlapped. Jpn Heart J 392 YAMASHITAET AL May 1998 Table. % Changes in Action Potential Duration by Pilsicainide *p<0 .05 vs before pilsicainide Figure 2. Effects of pilsicainide (3-1000ƒÊM) on Ito. A: Ito was elicited by the com- mand pulses at +40mV for 300ms from the holding potential of -80mV. Na+ current was blocked by 10ƒÊM TTX in the bathing solution. Ca2+ current and Ca2+-dependent transient outward current were blocked by 0.2mM Cd2+ in the bathing solution and 5 mM EGTA in the pipette solution. Pilsicainide (_??_10ƒÊM) depressed the peak outward current in a concentration-dependent manner and also suppressed the steady-state current at a concentration of_??_300ƒÊM. However, in contrast to other class Ic drugs, the inhibition of Ito was observed only at concentrations higher than the therapeutic range (_??_3ƒÊM) and did not accelerate the inactivation time-course of Ito. B: Dose- response relationships of the inhibition of Ito by pilsicainide. Ito was estimated as the difference between the initial peak and steady-state currents. action potential duration in a concentration-dependent manner (Table), and this observation contrasted with those in flecainide and propafenone which prolonged the atrial action potential duration in a concentration-dependent manner.6,2) Pilsicainide did not affect the resting membrane potential, a finding similar to that with flecainide and propafenone.6,12) Vol 39 No 3 PILSICAINIDEIN CLASSIC ANTIARRHYTHMICS 393 Figure 3. Effects of pilsicainide (10ƒÊM) on voltage-dependent Ca2+ current, delayed rectifier K+ current, inward rectifying K+ current, and acetylcholine (Ach)-induced current. A: Pilsicainide (10ƒÊM) did not affect voltage-dependent Ca2+ current, delayed rectifier K+ current, or inward rectifying K+ current. Ito was blocked by 2mM 4- aminopyridine in the bathing solution. Currents elicited by command pulses at -100, 0, and +40mV from a holding potential of -40mV are shown. Zero current level is shown by the bold bar.
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