Background: The blockade of cardiac transmembrane potassium channels, which is commonly seen with vanous antiarrhythmic drugs, plays an important role in their mechanism of action. We studied and compared the less-explored effects of three Class IA antiarrhythmics on the transient outward current (It.) and on the inward rectifier (Ikl), ATP sensitive (I), and delayed rectifier (IK) potassium currents in rabbit ventricular myocytes.
Methods and Results: Transmembrane currents were measured by applying the whole-cell configuration of the patch-clamp technique at 37°C in myocytes enzymatically isolated from rabbit ventricular preparations. Quinidine (10,uM), disopyramide (10 itM), and procainamide (50,uM) were studied at concentrations close to or exceeding the therapeutic plasma level. All studied drugs significantly decreased the amplitude of I”, (activated by 50,uM pinacidil) and IK currents. None of them influenced significantly Lk. The amplitude of I, was decreased by quinidine and disopyramide but was not considerably altered by procainamide. The fast inactivation of I,o was not changed by procainamide and was significantly accelerated by quinidine and disopyramide.
Conclusion: Although quinidine, disopyramide, and procainamide are all classified as Class IA antiarrhythmics, these drugs had different effects on various potassium currents, which may partially explain their distinct effect on repolarization in various cardiac tissues and on cardiac arrhythmias in clinical settings.
1. The CAST Investigators. Preliminary report: Effect of encainide and flecainide on mortality in randomized trial arrhythmia suppression after myocardial infarction. N Engl J Med321:406-412, 1989
2.
2. The CAST II Investigators: Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med327:227-233, 1992
3.
3. Waldo AL, Camm AJ, de Ruyter H, et al, for the SWORD Investigators: Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet348:7-12, 1966
4.
4. Stanton MS. Class I antiarrhythmic drugs: Quinidine, procainamide, disopyramide, lidocaine, mexiletine, tocainide, phenytoin, moricizine, flecainide, propafenone. In Zipes DEp, Jalif J (eds): Cardiac Electrophysiology, from Cell to Bedside. 2nd edn.WB Saunders Co, pp 1296-1317, 1995
5.
5. Johnson EA, McKinnon MG. The differential effect of quinidine and pyrilamine on the myocardial action potential at various rates of stimulation. J Pharmacol Exp Ther117:237-244, 1956
6.
6. Morady F, DiCarlo LA Jr, Baerman JM, Krol RB. Ratedependent effects of intravenous lidocaine, procainamide and amiodarone on intraventricular conduction. J Am Coll Cardiol6:179-185, 1985
7.
7. Sunami A, Fan Z, Nitta J, Hiraoka M. Two components of use-dependent block of Na+ current by disopyramide and lidocaine in guinea-pig ventricular myocytes. Circ Res68:653-661, 1991
8.
8. Whalley DW, Wendt DJ, Grant AO. Basic concepts in cellular cardiac electrophysiology: Part I: Ion channels, membrane currents and action potential. PACE18:1556-1574, 1995
9.
9. Buggisch D, Isenberg G, Ravens U, Scholtysik G. The role of sodium channels in the effects of the cardiotonic compound DPI 201-106 on contractility and membrane potentials in isolated mammalian heart preparations. Eur J Pharmacol118:303-311, 1985
10.
10. Coraboeuf E, Carmeliet E. Existence of two transient outward currents in sheep cardiac Purkinje fibers. Pfluigers Arch392:352-359, 1982
11.
11. Escande D, Coulombe A, Faivre JF, Deroubaix E, Coraboeuf E. Two types of transient outward currents in adult human atrial cells. Am J Physiol252:H142-H148, 1987
12.
12. Hiraoka M, Kawano S. Calcium-sensitive and insensitive transient outward current in rabbit ventricular myocytes. J Physiol410:187-212, 1989
13.
13. Zygmunt AC, Gibbons WR. Calcium-activated chloride current in rabbit ventricular myocytes. Circ Res68:424-437, 1991
14.
14. Yue L, Feng J, Li GR, Nattel S. Transient outward and delayed rectifier currents in canine atrium: Properties and role of isolation methods. Am J Physiol270:H2157-2168, 1996
15.
15. Giles WR, Imaizumi Y. Comparison of potassium currents in rabbit atrial and ventricular cells. J Physiol405:123-145, 1988
16.
16. Josephson IR, Sanchez-Chapula J, Brown AM. A comparison of calcium currents in rat and guinea pig single ventricular cells. Circ Res54:144-156, 1984
17.
17. Wang Z, Feng J, Shi H, Pond A, Nerbonne JM, Nattel S. Potential molecular basis of different physiological properties of the transient outward K+ current in rabbit and human atrial myocytes. Circ Res84:551-561, 1999
18.
18. Liu XK, Wang W, Ebert SN, Franz MR, Katchman A, Woosley RL. Female gender is a risk factor for torsades de pointes in an in vitro animal model. J Cardiovasc Pharmacol34:287-294, 1998
19.
19. Virag L, Varré A, Papp J.Gy. Effect of disopyramide on potassium currents in rabbit ventricular myocytes. N-S Arch Pharmacol357:268-275, 1998
20.
20. Sanchez-Chapula JA. Mechansm of transient outward K+ channel block by disopyramide. J Pharmacol Exp Ther290:515-523, 1999
21.
21. Dixon JE, McKinnon D. Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats. Circ Res75:252-260, 1994
22.
22. Dixon JE, Shi W, Wang HS, et al. Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current. Circ Res79:659-668, 1996
23.
23. Rolf S, Haverkamp W, Borggrefe M, Musshoff U, Eckardt L, Mergenthaler J, Snyders DJ, Pongs O, Speckmann EJ, Breithardt G, Madeja M. Effects of antiarrhythmic drugs on cloned cardiac voltage-gated potassium channels expressed in Xenopus oocytes. N-S Arch Pharmacol362:22-31, 2000
24.
24. Geelen P, O'Hara GE, Roy N, et al. Comparison of propafenone versus procainamide for the acute treatment of atrial fibrillation after cardiac surgery. Am J Cardiol84:345-347, 1999
25.
25. Singh BN, Opie LH, Marcus Fl. Antiarrhythmic agents. In Opie LH (ed), Drugs for the heart, 3rd edn.WB Saunders Company, Philadelphia, pp 180-216, 1991
26.
26. Martin CL, Chinn K. Contribution of delayed rectifier and inward rectifier to repolarization of the action potential: Pharmacologic separation. J Cardiovasc Pharmacol19:830-837, 1992
27.
27. Shimoni Y, Clark RB, Giles WR. Role of an inwardly rectifying potassium current in rabbit ventricular action potential. J Physiol448:709-727, 1992
28.
28. Biliczki P, Virag L, lost N, Papp JGy, Varré A. Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: Role of repolarization reserve. Br J Pharmacol, in press, 2002
29.
29. Salata JJ, Wasserstrom JA. Effects of quinidine on action potentials and ionic currents in isolated canine ventricular myocytes. Circ Res62:324-337, 1988
30.
30. Duan D, Fermini B, Nattel S. Potassium channel blocking properties of propafenone in rabbit atrial myocytes. J Pharmacol Exp Ther264:1113-1123, 1993
31.
31. Martin DK, Nakaya Y, Wyse KR, Campbell TJ. Effects of disopyramide and flecainide on the kinetics of inward rectifier potassium channels in rabbit heart muscle. Br J Pharmacol111:873-879, 1994
32.
32. Varré A, Papp JGy. The impact of single cell voltage clamp on the understanding of the cardiac ventricular action potential. Cardioscience3:131-144, 1992
33.
33. Barry DM, Nerbonne JM. Myocardial potassium channels: Electrophysiological and molecular diversity. Annu Rev Physiol58:363-394, 1996
34.
34. Noble D, Tsien RW. Outward membrane currents activated in the plateau range of potentials in cardiac Purkinje fibres. J Physiol200:205-231, 1969
35.
35. Varré A, Lathrop DA, Hester SB, Nanasi PP, Papp JG. Ionic currents and action potentials in rabbit, rat and guinea pig ventricular myocytes. Basic Res Cardiol88:93-102, 1993
36.
36. Gintant GA. Regional differences in 1K density in canine left ventricle: Role of 1K,S in electrical heterogeneity. Am J Physiol268:H605-H613, 1995
37.
37. Liu DW, Antzelevitch C. Characteristics of the delayed rectifier current (1Kr and IKj) in canine ventricular epicardial, midmyocardial and endocardial myocytes. A weaker 1KS contributes to the longer action potential of the M cell. Circ Res76:351-365, 1995
38.
38. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol96:195-215, 1990
39.
39. Abbott GW, Sesti F, Splawski I, et al. MiRPI forms 1K, potassium channels with HERG and is associated with cardiac arrhythmia. Cell97:175-187, 1999
40.
40. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G. K(V)LQT1 and IsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature384:78-80, 1996
41.
41. Sanguinetti MC, Curran ME, Zou A, et al. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature384:80-83, 1996
42.
42. Daleau P, Khalifa M, Turgeon J. Effects of cadmium and nisoldipine on the delayed rectifier potassium current in guinea pig ventricular myocytes. J Pharmacol Exp Ther281:826-833, 1997
43.
43. lost N, Virag L, Opincariu M, Szecsi J, Varré A, Papp J.Gy. Delayed rectifier potassium current in undiseased human ventricular myocytes. Cardiovasc Res40:508-5151998
45. Carmeliet E. Use-dependent block of the delayed K+ current in rabbit ventricular myocytes. Cardiovasc Drugs Ther (Suppl) 3:599-604, 1993
46.
46. Coyle JD, Carnes CA, Schaal SF, Muir WW 3rd. Electrophysiologic interactions of procainamide and Nacetylprocainamide in isolated canine cardiac Purkinje fibers. J Cardiovasc Pharmacol20:197-205, 1992
47.
47. Surawicz B. Electrophysiologic substrate of Torsade de Pointes: Dispersion of repolarisation or early after depolarisation?J Am Coll Cardiol14:172-184, 1989
48.
48. El-Sherif N. The proarrhythmic mechanism of drugs that prolong repolarization. Role of early afterdepolarisation. New Trends in Arrhythmias8:617-626, 1992
49.
49. Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation82:1106-1116, 1990
50.
50. Moosvi AR, Goldstein S, VanderBrug Medendorp S, et al. Effect of empiric antiarrhythmic therapy in resuscitated out-of-hospital cardiac arrest victims with coronary artery disease. Am J Cardiol65:1192-1197, 1990
51.
51. Stanton MS, Prystowsky EN, Fineberg NS, Miles WM, Zipes DP, Heger JJ. Arrhythmogenic effects of antiarrhythmic drugs: A study of 506 patients treated for ventricular tachycardia or fibrillation. J Am Coll Cardiol14:209-215; 216-217, 1989
52.
52. Minardo JD, Heger JJ, Miles WM, Zipes DP, Prystowsky EN. Clinical characteristics of patients with ventricular fibrillation during antiarrhythmic drug therapy. N Engl J Med319:257-262, 1988
53.
53. Wald RW, Waxman MB, Colman JM. Torsade de pointes ventricular tachycardia. A complication of disopyramide shared with quinidine. J Electrocardiol14:301-307, 1981
54.
54. Roden DM. Taking the “idio” out of “idiosyncratic”: Predicting torsades de pointes. PACE21:1029-1034, 1998
55.
55. Choudhury L, Grais IM, Passman RS. Torsades de pointes due to drug interaction between disopyramide and clarithromycin. Heart Dis1:206-207, 1999
56.
56. Cole WC, Mcpherson CD, Sontag D. ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage. Circ Res69:571-581, 1991
