Beta-cardiotoxin, a funny current inhibitor, and its effect on ion channels involved in heart rate regulation and on calcium transient profile in mouse sinoatrial node cells

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Beta-cardiotoxin (β-CTX) from the king cobra venom possesses a negative chronotropic effect on rat hearts. However, the mechanism of β-CTX-induced bradycardia remains unknown. Therefore, this study aimed to elucidate its role on ion channels and intracellular calcium transients involved in heart rate regulation in mouse sinoatrial node (SAN) cells. Patch-clamp and fluorescence imaging techniques were employed to measure the spontaneous activity and current densities of funny ( I f ) channels, delayed rectifier potassium currents ( I Kr ), L -type calcium currents ( I CaL ), and intracellular calcium transient profiles in isolated mouse SAN cells. β-CTX (0.3 µM) significantly decreased the spontaneous activity of SAN cells by 26%. β-CTX caused a further decrease in the maximum diastolic potential of approximately 2 mV and a shallower slope of diastolic depolarization of 0.009 mV/ms. β-CTX also reduced I f current by 43% and completely blocked I Kr . However, it did not alter the I CaL at the same concentration. Additionally, β-CTX significantly reduced the frequency of calcium transients in SAN cells by 32%. The negative chronotropic effect of β-CTX results from the inhibition of both I f and I Kr , without affecting I CaL . The negative chronotropic mechanism of β-CTX was revealed. β-CTX attenuated I f and I Kr activities. These characteristics of β-CTX would support the further development of a novel heart rate–reducing agent for the treatment of tachyarrhythmia or diastolic dysfunction. • The novel mechanism of bradycardia by β-CTX was revealed. • β-CTX, the first three-finger toxin, inhibits HCN channels and decreases heart rate. • β-CTX also inhibits I kr without altering action potential duration. • In contrast, β-CTX did not alter the intracellular Ca 2 + transients in SAN cells. • Due to its unique properties, β-CTX will help to treat diastolic dysfunction.

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