Background and purpose: Cinnamophilin, a thromboxane A 2 receptor antagonist, has been identified as a prominent anti‐arrhythmic 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 Ca 2+ transient amplitude. Cinnamophilin decreased the L‐type Ca 2+ current ( I Ca,L )(IC 50 =7.5 μM) 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 ) (IC 50 =2.7 μM) and to a lesser extent, the delayed outward ( I K ), inward rectifier ( I K1 ), and ATP‐sensitive ( I K,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,L and I Na . British Journal of Pharmacology (2008) 153 , 110–123; doi: 10.1038/sj.bjp.0707541 ; published online 29 October 2007