Effects of a Na+/Ca2+ exchanger inhibitor on pulmonary vein electrical activity and ouabain-induced arrhythmogenicity.
OBJECTIVE
Pulmonary veins (PVs) are the most important focus for generation of atrial fibrillation. The Na(+)/Ca(2+) exchange (NCX) current is important in PV electrical activity and cardiac glycosides-induced arrhythmias. The purpose of this study was to investigate whether KB-R7943, a NCX current blocker with preferential inhibition of the Ca(2+) influx, may alter PV electrophysiological characteristics and reduce glycoside-induced arrhythmogenicity.


METHODS
Conventional microelectrodes were used to record the effects of KB-R7943 on action potentials and contractility in isolated rabbit PV tissue specimens with and without administration of ouabain. The ionic currents and intracellular calcium were studied in isolated single cardiomyocytes before and after KB-R7943 by the whole-cell patch clamp and indo-1 fluorimetric ratio techniques.


RESULTS
KB-R7943 (0, 3, 10, 30 microM) concentration-dependently prolonged APD(50) and APD(90) and decreased the PV firing rates (2.3 +/- 1.2 Hz, 2.1 +/- 1.2 Hz, 1.9 +/- 0.9 Hz, 1.7 +/- 1.1 Hz, n = 7, p < 0.05) and incidences of delayed afterdepolarizations (DADs). KB-R7943 (3, 30 microM) decreased transient inward currents, Ca(2+) transient and sarcoplasmic reticulum Ca(2+) content. Ouabain (0, 0.1, 1 microM) concentration-dependently increased the PV firing rates and DADs in PVs with spontaneous activity (n = 7) and induced nonsustained spontaneous activity (1 microM) in the PVs without spontaneous activity (n = 14). However, in the presence of KB-R7943 (30 microM), ouabain (1 microM) did not increase the PV firing rates or induce spontaneous activity in the PVs without spontaneous activity (n = 7).


CONCLUSIONS
KB-R7943 reduces the PV arrhythmogenic activity and prevents the ouabain-induced arrhythmogenicity. Our findings support the role of the NCX current in the PV electrical activity.
National Yang-Ming University, School of Medicine, Division of Cardiology, Veterans General Hospital-Taipei, Taiwan.
Wanwarang
W
Wongcharoen
Yao-Chang
YC
Chen
Yi-Jen
YJ
Chen
Che-Ming
CM
Chang
Hung-I
HI
Yeh
Cheng-I
CI
Lin
Shih-Ann
SA
Chen
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes; D005470:Fluorometry; D007211:Indoles; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010042:Ouabain; D018408:Patch-Clamp Techniques; D011667:Pulmonary Veins / Q000187:drug effects / Q000503:physiopathology*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000627:therapeutic use
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D005456:Fluorescent Dyes; D007211:Indoles; D019831:Sodium-Calcium Exchanger; D010042:Ouabain; D013890:Thiourea; C048960:indo-1; D002118:Calcium