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

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 [Ca²⁺]_i transients and cell shortening. CIJ-3-2F inhibited the transient outward K⁺ current (I_to) (IC ₅₀ = 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 (I_ss, IC₅₀ = 3.6-μM, maximum inhibition = 65.7%) and both the inward Na⁺ current (I_Na, IC₅₀ = 2.8-μM) and L-type Ca²⁺ current (I_Ca,L, IC₅₀ = 4.9-μM, maximum inhibition = 69.4%). Conclusions and Implications CIJ-3-2F blocked Na⁺ and I _to channels and, to some extent, also blocked Ca²⁺ and I_ss channels, modifying cardiac electromechanical function. These effects are likely to underlie its antiarrhythmic properties.