Background and Aims: Carvedilol ((+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol), a β-adrenoceptor-blocker, has multi-channel blocking and vasodilator properties. This agent dose-dependently improves left ventricular function and reduces mortality in patients with arrhythmia and chronic heart failure. However, the effect of carvedilol on the cardiac Na+/Ca2+ exchanger (NCX1) has not been investigated. Methods and Results: We examined the effects of carvedilol and metoprolol, 2 β-blockers, on Na+/Ca2+ exchange current (INCX) in guinea-pig cardiac ventricular cells and fibroblasts expressing dog cardiac NCX1. Carvedilol suppressed INCX in a concentration-dependent manner but metoprolol did not. IC50 values for the Ca2+ influx (outward) and efflux (inward) components of INCX were 69.7 and 61.5 µmol/l, respectively. Carvedilol at 100 μmol/l inhibited INCX in CCL39 cells expressing wild type NCX1 similar to mutant NCX1 without the intracellular regulatory loop. Carvedilol at 30 µmol/l abolished ouabain-induced delayed afterdepolarizations. Conclusion: Carvedilol inhibited cardiac NCX in a concentration-dependent manner in isolated cardiac ventricles, but metoprolol did not. We conclude that carvedilol inhibits NCX1 at supratherapeutic concentrations.

1.
Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene A; Carvedilol OR Metoprolol European Trial Investigations: Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the carvedilol or metoprolol European trial (COMET): randomized controlled trial. Lancet 2003;362:7-13.
2.
EL-Sherif N, Turitto G: Electrophysiologic effects of carvedilol: is carvedilol an antiarrhythmic agent? Pacing Clin Electrophysiol 2005;28:985-990.
3.
Deng C, Yu X, Kuang S, Zhang W, Zhou Z, Zhang K, Qian W, Shan Z, Yang M, Wu S, Lin S: Effects of carvedilol on transient outward and ultra-rapid delayed rectifier potassium currents in human atrial myocytes. Life Sci 2007;80:665-671.
4.
Ferrer T, Ponce-Balbuena D, López-Izquierdo A, Aréchiga-Figueroa IA, de Boer TP, van der Heyden MA, Sánchez-Chapula JA: Carvedilol inhibits Kir2.3 channels by interference with PIP2-channel interaction. Eur J Pharmacol 2011;668:72-77.
5.
Cheng J, Niwa R, Kamiya K, Toyama J, Kodama I: Carvedilol blocks the repolarizing K+ currents and the L-type Ca2+ current in rabbit ventricular myocytes. Eur J Pharmacol 1999;376:189-201.
6.
Barrington PL, Ten Eick RE: Characterization of the electrophysiological effects of metoprolol on isolated feline ventricular myocytes. J Pharmacol Exp Ther 1990;252:1043-1052.
7.
DiNicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O'Keefe JH: Meta-analysis of carvedilol versus beta 1 selective beta-blockers (atenolol, bisoprolol, metoprolol, and nebivolol). Am J Cardiol 2013;111:765-769.
8.
Naccarelli GV, Lukas MA: Carvedilol's antiarrhythmic properties: therapeutic implications in patients with left ventricular dysfunction. Clin Cardiol 2005;28:165-173.
9.
Maruyama M, Xiao J, Zhou Q, Vembaiyan K, Chua SK, Rubart-von der Lohe M, Lin SF, Back TG, Chen SR, Chen PS: Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations. Heart Rhythm 2013;10:101-107.
10.
Yao A, Kohmoto O, Oyama T, Sugishita Y, Shimizu T, Harada K, Matsui H, Komuro I, Nagai R, Matsuo H, Serizawa T, Maruyama T, Takahashi T: Characteristic effects of alpha1-beta1,2-adrenergic blocking agent, carvedilol, on [Ca2+]i in ventricular myocytes compared with those of timolol and atenolol. Circ J 2003;67:83-90.
11.
Watanabe Y, Koide Y, Kimura J: Topics on the Na+/Ca2+ exchanger: pharmacological characterization of Na+/Ca2+ exchanger inhibitors. J Pharmacol Sci 2006;102:7-16.
12.
Antoons G, Willems R, Sipido KR: Alternative strategies in arrhythmia therapy: evaluation of Na/Ca exchange as an anti-arrhythmic target. Pharmacol Ther 2012;134:26-42.
13.
Reeves JP, Bailey CA, Hale CC: Redox modification of sodium-calcium exchange activity in cardiac sarcolemmal vesicles. J Biol Chem 1986;261:4948-4955.
14.
Goldhaber JI: Free radicals enhance Na+/Ca2+ exchange in ventricular myocytes. Am J Physiol 1996;271(3 pt 2):H823-H833.
15.
Eigel BN, Gursahani H, Hadley RW: ROS are required for rapid reactivation of Na+/Ca2+ exchanger in hypoxic reoxygenated guinea pig ventricular myocytes. Am J Physiol Heart Circ Physiol 2004;286:H955-H963.
16.
Hinata M, Matsuoka I, Iwamoto T, Watanabe Y, Kimura J: Mechanism of Na+/Ca2+ exchanger activation by hydrogen peroxide in guinea-pig ventricular myocytes. J Pharmacol Sci 2007;103:283-292.
17.
Watanabe Y, Kimura J: Inhibitory effect of amiodarone on Na+/Ca2+ exchange current in guinea-pig cardiac myocytes. Br J Pharmacol 2000;131:80-84.
18.
Yue TL, Cheng HY, Lysko PG, McKenna PJ, Feuerstein R, Gu JL, Lysko KA, Davis LL, Feuerstein G: Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther 1992;263:92-98.
19.
Ide T, Tsutsui H, Kinugawa S, Utsumi H, Takeshita A: Amiodarone protects cardiac myocytes against oxidative injury by its free radical scavenging action. Circulation 1999;100:690-692.
20.
Watanabe Y, Kimura J: Acute inhibitory effect of dronedarone, a noniodinated benzofuran analogue of amiodarone, on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes. Naunyn Schmiedebergs Arch Pharmacol 2008;377:371-376.
21.
Watanabe Y, Iwamoto T, Shigekawa M, Kimura J: Inhibitory effect of aprindine on Na+/Ca2+ exchange current in guinea-pig cardiac ventricular myocytes. Br J Pharmacol 2002;136:361-366.
22.
Watanabe Y, Iwamoto T, Matsuoka I, Ono T, Shigekawa M, Kimura J: Effects of amiodarone on mutant Na+/Ca2+ exchangers expressed in CCL 39 cells. Eur J Pharmacol 2004;496:49-54.
23.
Yamakawa T, Watanabe Y, Watanabe H, Kimura J: Inhibitory effect of cibenzoline on Na+/Ca2+ exchange current in guinea-pig cardiac ventricular myocytes. J Pharmacol Sci 2012;120:59-62.
24.
Zima AV, Blatter LA: Redox regulation of cardiac calcium channels and transporters. Cardiovasc Res 2006;71:310-321.
25.
Wagner S, Rokita AG, Anderson ME, Maier LS: Redox regulation of sodium and calcium handling. Antioxid Redox Signal 2013;18:1063-1077.
26.
Kimura J: Effects of various calmodulin antagonists on Na/Ca exchange current of single ventricular cells of guinea-pig. Pflugers Arch 1993;424:523-528.
27.
Watanabe Y, Iwamoto T, Matsuoka I, Ohkubo S, Ono T, Watano T, Shigekawa M, Kimura J: Inhibitory effect of 2,3-butanedione monoxime (BDM) on Na(+)/Ca(2+) exchange current in guinea-pig cardiac ventricular myocytes. Br J Pharmacol 2001;132:1317-1325.
28.
Homma N, Amran MS, Nagasawa Y, Hashimoto K: Topics on the Na+/Ca2+ exchanger: involvement of Na+/Ca2+ exchange system in cardiac triggered activity. J Pharmacol Sci 2006;102:17-21.
29.
Shryock JC, Song Y, Rajamani S, Antzelevitch C, Belardinelli L: The arrhythmogenic consequences of increasing late INa in the cardiomyocyte. Cardiovasc Res 2013;99:600-611.
30.
Pezhouman A, Madahian S, Stepanyan H, Ghukasyan H, Qu Z, Belardinelli L, Karagueuzian HS: Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts. Heart Rhythm 2014;11:492-501.
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