Is there a functional correlate of Kv1.5 in the ventricle of canine heart and what would it mean for the use of I_Kur blockers?

Abstract

The cardiac ultrarapid outward current I_Kur, encoded by KCNA5, is of special pharmacological interest, because it is considered to be atrium-specific. I_Kur has therefore become a target in the therapy of atrial tachyarrhythmias. However, the concept of atrium specificity is only valid if a functional I_Kur current is in fact absent from the ventricle. However, new work has detected a I_Kur-like current in canine ventricular myocytes, sensitive to 4-aminopyridine and suppressed by the I_Kur blocker DPO-1, findings that support the existence of a functional ventricular I_Kur. These indications are, however, indirect and more effort is needed to clarify unequivocally the putative role of an expectedly small I_Kur component in the ventricle.

The cardiac ultrarapid potassium outward current I_Kur encoded by Kv1.5 (KCNA5), which is the gene for the pore-forming α-subunit of I_Kur, has gained considerable interest during the last years. Since I_Kur is a prominent current in atrial myocytes of the mammalian heart including man, but not in ventricular tissue, it was regarded as a putative ‘atrial selective' target for treatment of atrial fibrillation (Ehrlich et al., 2007) and several I_Kur blockers have been synthesized during the past 10 years (Lagrutta et al., 2006). The idea was that block of I_Kur should prolong atrial action potential duration and effective refractory period without pro-arrhythmic effects on the ventricle. Several of these drugs, for instance AVE0118 (I_Kur-blocker(2′-{[2-(4-methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide) (Blaauw et al., 2004) and DPO-1 (I_Kur-blocker 2-isopropyl-5-methylcyclohexyl)diphenylphosphine oxide) (Stump et al., 2005), have been shown to inhibit effectively I_Kur, to prolong action potential duration and to convert atrial fibrillation (goat, pig) or flutter (dog). This concept of regional drug specificity is only valid if I_Kur is definitely absent in ventricle. In most mammals I_Kur-like outward currents have not been detected in ventricular myocytes with exception of small rodents that exhibit a well-defined current component attributed to I_Kur (Nerbonne, 2000). More than 15 years ago, Tamkun et al. (1991) and Mays et al. (1995) detected the Kv1.5 both as messenger RNA and protein, although at much lower level than in atrial tissue; these findings have been confirmed in healthy human (Gaborit et al., 2007) and dog heart (Fedida et al., 2003). However, no functional correlate has been identified until now, and Fedida et al. (2003) commented that ‘the electrophysiological role of Kv1.5 expressed in the ventricle remains to be clarified'. Therefore, the question arises whether any non-identified functional I_Kur channels exist in the human ventricle. If so, do we have to revise the concept of an atrium-specific pharmacotherapy based on I_Kur blockade?

It is difficult unequivocally to separate I_Kur from total membrane outward currents even in myocytes with a large I_Kur as in human atrial myocytes (Amos et al., 1996). Because of its ultrarapid activation, I_Kur contributes during the very early phase of atrial repolarization, where the other major player, the transient outward current I_to, is also active. In addition, I_Kur is not the ‘sustained' outward current it was initially taken for (Amos et al., 1996; Wettwer et al., 2004), since, especially at physiological temperature, I_Kur displays extensive inactivation. In addition, there are no truly specific drugs available. 4-Aminopyridine, in low concentrations, discriminates fairly well between I_Kur (IC₅₀∼10 μM) and I_to (IC₅₀∼1 mM) (Amos et al., 1996). Further complications arise from interactions of the Kv1.5 channel with Kvβ subunits that modulate current kinetics from slow to fast inactivation (Uebele et al., 1998). Two current components that activate and inactivate with overlapping time courses can be separated by several methods. Specific knock-out with siRNA would be ideal but is yet not feasible in human native myocytes. Another approach utilizes the 4-aminopyridine selectivity of I_Kur as reported by Sridhar et al. (2007, this issue). With low concentrations of 4-aminopyridine (50 and 100 μM), the authors demonstrate a reversible prolongation of action potential duration in isolated canine ventricular myocytes without effects on the rapid potassium outward current (I_Kr) and I_to. In addition, action potential prolonging effects can also be elicited with DPO-1, a selective I_Kur blocker (Stump et al., 2005). The 4-aminopyridine sensitive current (IC₅₀=24 μM) was, however, very small, the current density at +50 mV was 0.5 pA pF⁻¹ compared to 10 pA pF⁻¹ of total outward current in human atrial myocytes (Amos et al., 1996). It should be kept in mind, however, that it is the relative magnitude of I_Kur current with respect to other components that determines the influence on the action potential plateau and action potential duration. In his pioneering cardiac electrophysiological experiments, Weidmann (1951) described the very low conductance during the plateau of the action potential and therefore only small currents are necessary for regulation of plateau duration. Model simulations performed by Sridhar et al. (2007) support the action potential prolonging effects by blocking the small 4-aminopyridine sensitive current component denoted ‘I_Kur-like'. These results could have implications for the therapeutic use of I_Kur blockers and may require more caution concerning possible arrhythmogenic effects of I_Kur blockers in the ventricle. Action potential- and QT-prolonging effects have not been detected so far for AVE0118 (Schotten et al., 2007) or DPO-1 (Lagrutta et al., 2006). Knock-down experiments with antisense oligonucleotides directed against Kv1.5 did not uncover any sensitive current component in human ventricular myocytes (Feng et al., 1997). Nevertheless, there are indications that I_Kur may indeed contribute to the ventricular action potential plateau. Lagrutta et al., 2006 (figure 8) show elevation of the action potential plateau in the presence of DPO-1. In addition, it is possible that the I_Kur channels, largely localized in the intercalated disk (Mays et al., 1995), are redistributed under pathological conditions due to highly dynamic trafficking (McEwen et al., 2007). This could result in an increased surface expression and function. In a recent study (Oros et al., 2006) of the pro- and anti-arrhythmic effects of AVE0118 in anaesthetized dogs, 3 out of 5 animals died unexpectedly within 24 h after slow infusion with AVE0118 followed by a challenge with dofetilide to provoke torsade de pointe arrhythmias. It is quite possible that torsade de pointe arrhythmias was promoted due to block of ventricular I_Kur. In addition, under conditions of increased sympathetic tone, I_Kur could have an larger impact on ventricular repolarization (Yue et al., 1999). In conclusion, the presence or absence of I_Kur in ventricular tissue needs further experimental investigation, especially in human myocardium. Irrespective of the results, they will have major implications for the development of new anti-arrhythmic drugs.

Abbreviations

AVE0118

I_Kur-blocker (2′-{[2-(4-methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide)

DPO-1

I_Kur-blocker 2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide

Conflict of interest

The author states no conflict of interest.