Tolterodine reduces veratridine-augmented late INa, reverse-INCX and early afterdepolarizations in isolated rabbit ventricular myocytes

作者：Wang, Chao; Wang, Lei-lei; Zhang, Chi; Cao, Zhen-zhen; Luo, An-tao; Zhang, Pei-hua; Fan, Xin-rong; Ma, Ji-hua^*

来源：Acta Pharmacologica Sinica, 2016, 37(11): 1432-1441.

DOI：10.1038/aps.2016.76

• tolterodine
• veratridine
• ventricular myocytes
• late sodium current
• reverse-Na+/Ca2+ exchange current
• early afterdepolarization
• arrhythmia
• cardioprotection

Aim: The augmentation of late sodium current (I-Na.L) not only causes intracellular Na+ accumulation, which results in intracellular Ca2+ overload via the reverse mode of the Na+/Ca2+ exchange current (reverse-I-NCX), but also prolongs APD and induces early afterdepolarizations (EAD), which can lead to arrhythmia and cardiac dysfunction. Thus, the inhibition of I-Na.L is considered to be a potential way for therapeutic intervention in ischemia and heart failure. In this study we investigated the effects of tolterodine (Tol), a competitive muscarinic receptor antagonist, on normal and veratridine (Ver)-augmented I-Na.L, reverse-I-NCX and APD in isolated rabbit ventricular myocytes, which might contribute to its cardioprotective activity. @@@ Methods: Rabbit ventricular myocytes were prepared. The I-Na.L and reverse-I-NCX were recorded in voltage clamp mode, whereas action potentials and Ver-induced early afterdepolarizations (EADs) were recorded in current clamp mode. Drugs were applied via superfusion. @@@ Results: Tol (3-120 nmol/L) concentration-dependently inhibited the normal and Ver-augmented I-Na.L with IC50 values of 32.08 nmol/L and 42.47 nmol/L, respectively. Atropine (100 mu mol/L) did not affect the inhibitory effects of Tol (30 nmol/L) on Ver-augmented I-Na.L. In contrast, much high concentrations of Tol was needed to inhibit the transient sodium current (I-Na.T) with an IC50 value of 183.03 mu mol/L. In addition, Tol (30 nmol/L) significantly shifted the inactivation curve of I-Na.T toward a more depolarizing membrane potential without affecting its activation characteristics. Moreover, Tol (30 nmol/L) significantly decreased Ver-augmented reverse-I-NCX. Tol (30 nmol/L) increased the action potential duration (APD) by 16% under the basal conditions. Ver (20 mu mol/L) considerably extended the APD and evoked EADs in 18/24 cells (75%). In the presence of Ver, Tol (30 nmol/L) markedly decreased the APD and eliminated EADs (0/24 cells). @@@ Conclusion: Tol inhibits normal and Ver-augmented I-NaL and decreases Ver-augmented reverse-I-NCX. In addition, Tol reverses the prolongation of the APD and eliminates the EADs induced by Ver, thus prevents Ver-induced arrhythmia.

• 出版日期2016-11
• 单位武汉科技大学