Electromechanical characterization of cinnamophilin, a natural thromboxane A2 receptor antagonist with anti-arrhythmic activity, in guinea-pig heart

Background and purpose: Cinnamophilin, a thromboxane A(2) receptor antagonist, has been identified as a prominent antiarrhythmic agent in rat heart. This study aimed to determine its electromechanical and anti-arrhythmic effects in guinea-pig hearts. Experimental approach: Microelectrodes were used to study action potentials in ventricular papillary muscles. Fluo-3 fluorimetric ratio and whole-cell voltage-clamp techniques were used to record calcium transients and membrane currents in single ventricular myocytes, respectively. Intracardiac electrocardiograms were obtained and the anti-arrhythmic efficacy was determined from isolated perfused hearts. Key results: In papillary muscles, cinnamophilin decreased the maximal rate of upstroke (V-max) and duration of action potential, and reduced the contractile force. In single ventricular myocytes, cinnamophilin reduced Ca2+ transient amplitude. Cinnamophilin decreased the L-type Ca2+ current (I-Ca,I-L)(IC50=7.5 mu M) with use-dependency, induced a negative shift of the voltage-dependent inactivation and retarded recovery from inactivation. Cinnamophilin also decreased the Na+ current (I-Na) (IC50=2.7 mu M) and to a lesser extent, the delayed outward (I-K), inward rectifier (I-K1), and ATP-sensitive (I-K,I-ATP) K+ currents. In isolated perfused hearts, cinnamophilin prolonged the AV nodal conduction interval and Wenckebach cycle length and the refractory periods of the AV node, His-Purkinje system and ventricle, while shortening the ventricular repolarization time. Additionally, cinnamophilin reduced the occurrence of reperfusion-induced ventricular fibrillation. Conclusions and implications: These results suggest that the promising anti-arrhythmic effect and the changes in the electromechanical function induced by cinnamophilin in guinea-pig heart can be chiefly accounted for by inhibition of I-Ca,I-L and I-Na.