Tolterodine reduces veratridine-augmented late INa, reverse-INCX and early afterdepolarizations in isolated rabbit ventricular myocytes.
Acta Pharmacol Sin
; 37(11): 1432-1441, 2016 Nov.
Article
em En
| MEDLINE
| ID: mdl-27569391
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Veratridina
/
Canais de Sódio
/
Antagonistas Muscarínicos
/
Trocador de Sódio e Cálcio
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Bloqueadores dos Canais de Sódio
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Miócitos Cardíacos
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Tartarato de Tolterodina
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Antiarrítmicos
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article