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

Abstract

AIM:

The augmentation of late sodium current (INa.L) not only causes intracellular Na+ accumulation, which results in intracellular Ca2+ overload via the reverse mode of the Na+/Ca2+ exchange current (reverse-INCX), but also prolongs APD and induces early afterdepolarizations (EAD), which can lead to arrhythmia and cardiac dysfunction. Thus, the inhibition of INa.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 INa.L, reverse-INCX and APD in isolated rabbit ventricular myocytes, which might contribute to its cardioprotective activity.

METHODS:

Rabbit ventricular myocytes were prepared. The INa.L and reverse-INCX 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 INa.L with IC50 values of 32.08 nmol/L and 42.47 nmol/L, respectively. Atropine (100 μmol/L) did not affect the inhibitory effects of Tol (30 nmol/L) on Ver-augmented INa.L. In contrast, much high concentrations of Tol was needed to inhibit the transient sodium current (INa.T) with an IC50 value of 183.03 μmol/L. In addition, Tol (30 nmol/L) significantly shifted the inactivation curve of INa.T toward a more depolarizing membrane potential without affecting its activation characteristics. Moreover, Tol (30 nmol/L) significantly decreased Ver-augmented reverse-INCX. Tol (30 nmol/L) increased the action potential duration (APD) by 16% under the basal conditions. Ver (20 μmol/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 INaL and decreases Ver-augmented reverse-INCX. In addition, Tol reverses the prolongation of the APD and eliminates the EADs induced by Ver, thus prevents Ver-induced arrhythmia.

• Authors: Chao Wang, Lei-Lei Wang, Chi Zhang, Zhen-Zhen Cao, An-Tao Luo, Pei-Hua Zhang, Xin-Rong Fan, Ji-Hua Ma
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 37 Issue 11 Pg. 1432-1441 (Nov 2016) ISSN: 1745-7254 [Electronic] United States
• PMID: 27569391 (Publication Type: Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Muscarinic Antagonists
• Sodium Channel Blockers
• Sodium Channels
• Sodium-Calcium Exchanger
• Tolterodine Tartrate
• Veratridine

Topics

• Action Potentials
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Female
• Heart Ventricles (cytology)
• In Vitro Techniques
• Male
• Muscarinic Antagonists (pharmacology)
• Myocytes, Cardiac (drug effects, physiology)
• Patch-Clamp Techniques
• Rabbits
• Sodium Channel Blockers (pharmacology)
• Sodium Channels (physiology)
• Sodium-Calcium Exchanger (metabolism)
• Tolterodine Tartrate (pharmacology)
• Veratridine (pharmacology)