Dofetilide enhances the contractility of rat ventricular myocytes via augmentation of Na+-Ca 2+ exchange.
OBJECTIVE
Dofetilide (DOF), a novel Class III antiarrhythmic drug, prolongs the action potential duration (APD) and shows a positive inotropic effect in guinea pig papillary muscle. The present experiments were designed to study the positive inotropic effect of DOF on rat ventricle and explore its possible mechanism(s).


METHODS
Hearts from male Wistar rats (260-320 g) were divided into five groups and perfused in Langendorff mode. Ventricular myocytes were enzymatically isolated from male Wistar rats. Whole-cell voltage-clamping technique was used to test the Na(+)-Ca(2+) exchange (NCE) current (I(NCX)); Calcium transients and cell shortening provoked by field stimulation or using calcium current command waveform were observed synchronously with an ionic imaging system.


RESULTS
DOF (0.03-1.0 microM) increased left ventricular function in isolated rat hearts in a concentration-dependent manner. DOF (0.03-1.0 microM) also concentration-dependently increased both inward and outward I (NCX) in isolated rat ventricular cells. The EC(50) values of DOF were 0.149 microM for the inward I(NCX) and 0.249 microM for outward I(NCX), respectively. DOF 0.2 microM significantly enhanced Ca(2+) transient and cell shortening in single rat ventricular myocytes driven by field electric stimulation. When the patch clamp system was connected to the ionic imaging system, Ca(2+) current (I(Ca)), Ca(2+) transient and cell shortening amplitude in a same cell were recorded synchronously. Application of DOF 0.2 microM had no effect on I(Ca), but significantly increased Ca(2+) transient and cell shortening. NCX inhibitor KB-R7943 0.6 microM significantly depressed the effects of DOF on Ca(2+) transient and cell shortening.


CONCLUSIONS
We conclude that DOF enhanced contractility of rat ventricular myocytes. The enhancement of NCE may be involved in the positive inotropic action of DOF.
Zhang
Xuan-Ping
XP
Department of Pharmacology, Shanxi Medical University, Shanxi, People's Republic of China.
Wu
Bo-Wei
BW
Yang
Cai-Hong
CH
Wang
Jie
J
Niu
Shuan-Cheng
SC
Zhang
Ming-Sheng
MS
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019831:Sodium-Calcium Exchanger / Q000819:agonists* / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects*
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D019831:Sodium-Calcium Exchanger; D013449:Sulfonamides; D013890:Thiourea; C063533:dofetilide