Inhibition of the reverse mode of the Na+/Ca2+ exchange by KB-R7943 augments arrhythmogenicity in the canine heart during rapid heart rates.
To test the hypothesis that the reverse mode of the Na+/Ca2+ exchange augmented by a rapid heart rate has an antiarrhythmic effect by shortening the action potential duration, we examined the effects of KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl] isothiourea methanesulfonate), a selective inhibitor of the reverse mode of the Na+/Ca2+ exchange, to attenuate this effect. We recorded the electrocardiogram, monophasic action potential (MAP), and left ventricular pressure in canine beating hearts. In comparison to the control, KB-R7943 significantly increased the QTc value and MAP duration. MAP alternans and left ventricular pressure alternans were observed after changing the cycle length to 300 milliseconds in the control studies. KB-R7943 magnified both types of alternans and produced spatially discordant alternans between right and left ventricles. Early after-depolarizations and nonsustained ventricular tachycardia occurred in the presence of KB-R7943. Our data suggest that the reverse mode of the Na+/Ca2+ exchange may contribute to suppression of arrhythmias by abbreviating action potential duration under pathophysiological conditions. This conclusion is based on further confirmation by future studies of the specificity of KB-R7943 for block of the reverse mode of the Na+/Ca2+ exchange.
The First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
Takuro
T
Shinada
Yoshiyuki
Y
Hirayama
Mitsunori
M
Maruyama
Toshihiko
T
Ohara
Masaaki
M
Yashima
Yoshinori
Y
Kobayashi
Hirotsugu
H
Atarashi
Teruo
T
Takano
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control*; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D017180:Tachycardia, Ventricular / Q000517:prevention & control; D013890:Thiourea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018879:Ventricular Premature Complexes / Q000517:prevention & control; D017725:Ventricular Pressure / Q000187:drug effects
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D019831:Sodium-Calcium Exchanger; D013890:Thiourea