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

Abstract

Aim: The augmentation of late sodium current (I Na.L ) not only causes intracellular Na + accumulation, which results in intracellular Ca 2+ overload via the reverse mode of the Na + /Ca 2+ 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 IC 50 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 I Na.L . In contrast, much high concentrations of Tol was needed to inhibit the transient sodium current (I Na.T ) with an IC 50 value of 183.03 μmol/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 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 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.

Molecular Determinants for the High-Affinity Blockade of Human Ether-à-go-go-Related Gene K+ Channel by Tolterodine

“…Among the cardiac ion channels found to be targets of tolterodine, hERG channel exhibited the highest sensitivity (IC 50 of 17 or 9.6 nM when overexpressed in mammalian cells) compared with Na + channel (no effect at 1 μM in overexpression system; IC 50 of 32.08 nM for late Na + current in rabbit ventricular myocytes) and L-type Ca 2+ channel (IC 50 of 143 and 1084 nM in guinea pig ventricular myocytes). 18,19,43 In clinical practice, tachycardia and palpitations have been observed after use of tolterodine. 44 Because the inhibitory potency of tolterodine on hERG channel is similar to that on muscarinic receptors, 1 both pharmacological mechanisms may contribute to its potential to increase heart rate.…”

Modification of distinct ion channels differentially modulates Ca2+ dynamics in primary cultured rat ventricular cardiomyocytes

“…It has been demonstrated that veratridine prolongs AP duration in rabbit ventricular myocytes47. Although inactive on hERG channels, alfuzosin produces LQT syndrome in the clinic due to its ability to increase the peak current of Nav1.548.…”

Barbaloin inhibits ventricular arrhythmias in rabbits by modulating voltage-gated ion channels

“…We also noted an APD reverserate dependence (RRD) in these experiments ( Figure 1D and 1C). However, 100 and 200 μmol/L barbaloin decreased the APD 90 at the frequencies of 0.5, 1 and 2 Hz by 15.1%±3.4%, 12.9%±3.2% (n=8, P>0.05 vs 0.5 Hz), and 9.6%±2.5% (n=8, Effects of barbaloin on ATX II-induced APD prolongation and EADs, as well as Ca 2+ -induced DADs It has been reported that enhanced I Na.L causes APD prolongation and EADs in various pathological conditions [15,16] . ATX II, an I Na.L opener, significantly enhanced I Na.L and thus significantly increased the incidence of APD prolongation and EADs in the ventricular myocytes (Figure 2A and 2C).…”

“…Effects of barbaloin and TTX on I Na.L I Na.L is generally known as a TTX-sensitive current that is almost completely blocked by 4 μmol/L TTX [16] . The amplitude of the current enhanced by 10 nmol/L ATX II was decreased to almost zero after the administration of 4 μmol/L TTX ( Figure 5A).…”