Electromechanical and atrial and ventricular antiarrhythmic actions of CIJ-3-2F, a novel benzyl-furoquinoline vasodilator in rat heart.

Abstract

BACKGROUND AND PURPOSE:

This study was designed to examine the antiarrhythmic efficacy and the underlying mechanisms of the benzyl-furoquinoline vasodilator, CIJ-3-2F, in rat cardiac preparations.

EXPERIMENTAL APPROACH:

Conduction electrograms and left ventricular pressure were determined in Langendorff-perfused hearts. Action potentials were assessed with microelectrode techniques, calcium transients by fura-2 fluorescence and ionic currents by whole-cell patch-clamp techniques.

KEY RESULTS:

In isolated hearts, CIJ-3-2F prolonged sinus cycle length, QT interval, Wenckebach cycle length, atrio-His bundle and His bundle-ventricular conduction intervals, refractory periods in atrium, AV node, His-Purkinje system and ventricle, and also increased left ventricular pressure. CIJ-3-2F reduced the incidences of both ischaemic and reperfusion-induced ventricular arrhythmias and prevented the induction of atrial tachyarrhythmias. In both atrial and papillary muscles, CIJ-3-2F decreased upstroke velocity and prolonged duration of the action potential. In ventricular myocytes, CIJ-3-2F moderately increased the amplitude of [Ca(2+)]i transients and cell shortening. CIJ-3-2F inhibited the transient outward K(+) current (Ito ) (IC₅₀ = 4.4 μM) with accelerated inactivation, a slower rate of recovery from inactivation and use-dependency. CIJ-3-2F also suppressed the steady-state outward K(+) current (Iss , IC₅₀ = 3.6 μM, maximum inhibition = 65.7%) and both the inward Na(+) current (INa , IC₅₀ = 2.8 μM) and L-type Ca(2+) current (ICa,L , IC₅₀ = 4.9 μM, maximum inhibition = 69.4%).

CONCLUSIONS AND IMPLICATIONS:

CIJ-3-2F blocked Na(+) and Ito channels and, to some extent, also blocked Ca(2+) and Iss channels, modifying cardiac electromechanical function. These effects are likely to underlie its antiarrhythmic properties.

• Authors: Gwo-Jyh Chang, Yung-Hsin Yeh, Tsung-Pin Lin, Chi-Jen Chang, Wei-Jan Chen
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 171 Issue 16 Pg. 3918-37 (Aug 2014) ISSN: 1476-5381 [Electronic] England
• PMID: 24820856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• Anti-Arrhythmia Agents
• N-(2-fluoro-benzyl)-7-bromo-2,3,4,9-tetrahydrofuro(2,3-b)quinoline-3,4-dione
• Quinolines
• Vasodilator Agents
• Calcium

Topics

• Action Potentials (drug effects)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Calcium (physiology)
• Female
• Heart (drug effects, physiology)
• In Vitro Techniques
• Male
• Muscle Contraction (drug effects)
• Myocardial Reperfusion Injury (physiopathology)
• Quinolines (pharmacology)
• Rats, Sprague-Dawley
• Vasodilator Agents (pharmacology)