Electrophysiologic effects of nicorandil on the guinea pig long QT1 syndrome model.
BACKGROUND
The slow component of the delayed rectifier K+ current IKs modulates repolarization of the cardiac action potential (AP), and the loss of IKs is known to cause long QT1 (LQT1) syndrome by prolonging action potential duration (APD). In this study, we generated a guinea pig LQT1 syndrome model using the IKs blocker chromanol 293B and then assayed the electrophysiologic effects of the ATP-sensitive potassium channel IK,ATP opener nicorandil on this model.


RESULTS
Transmembrane action potentials of perfused right ventricular papillary muscle preparations and both in vitro and in vivo ECGs of guinea pigs were recorded. Blockade of IKs by chromanol 293B (30 microM) prolonged the action potential duration at 90% repolarization (APD90) by 8.5% and QT interval by 16.5% of control values. In addition, proarrhythmic early afterdepolarizations (EADs) and ventricular fibrillation were observed. Venoinjection of chromanol 293B (1 mg/kg) revealed 10.9% QT prolongation. Nicorandil (5-30 microM) dose-dependently shortened APD90 under the control condition, whereas it reversed the AP prolongation effect of chromanol 293B by 7.4% at the 30 microM concentration. Moreover, nicorandil shortened QT intervals both in vitro and in vivo and displayed an inhibitory effect on EADs and ventricular fibrillation.


CONCLUSIONS
The ATP-sensitive potassium channel opener nicorandil may be an effective drug in the therapy of LQT1 syndrome by shortening APD and the QT interval.
Yang
Zhifang
Z
Department of Physiology, Shanghai Second Medical University, Shanghai, China.
Shi
Guozhong
G
Li
Cizheng
C
Wang
Hongwei
H
Liu
Kai
K
Liu
Yuanmou
Y
D000200:Action Potentials; D000818:Animals; D002839:Chromans / Q000494:pharmacology; D004195:Disease Models, Animal; D004562:Electrocardiography; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D020108:Nicorandil / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D002839:Chromans; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D014665:Vasodilator Agents; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D020108:Nicorandil