Effect of verapamil on tachycardia-induced early cellular electrical remodeling in rabbit atrium

Laszlo, Roman; Winkler, Christoph; Wöhrl, Stefan; Wessel, Ralf E.; Laszlo, Sara; Busch, Mathias; Schreieck, Jürgen; Bosch, Ralph F.

doi:10.1007/s00210-007-0188-0

Cited by 5 publications

(4 citation statements)

References 59 publications

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“…Jones et al ( 2000 ) reported a reduction of I K1 current in guinea pig ventricular cardiomyocytes, whereas Waldegger et al ( 1999 ) reported a significant reduction of current produced by Kir2.1 subunits expressed in Xenopus laevis oocytes where other cardiac potassium channels were coexpressed including the potassium channels Kv1.1, Kv1.5, Kir2.1, and HERG, and the IsK subunit of the I Ks -channel complex. Contrary to these findings in a rabbit atrium tachycardia pacing model, no effect of verapamil pretreatment on I K1 was reported by Laszlo et al ( 2007 ). We therefore oriented our study towards the effects of verapamil on all the Kir channel subunits that constitute the cardiac I K1 current (Kir2.1, 2.2, and 2.3).…”

Section: Discussioncontrasting

confidence: 79%

Verapamil inhibits Kir2.3 channels by binding to the pore and interfering with PIP2 binding

Xynogalos

Rahm

Fried

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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The inwardly rectifying potassium current of the cardiomyocyte (IK1) is the main determinant of the resting potential. Ion channels Kir2.1, Kir2.2, and Kir2.3 form tetramers and are the molecular correlate of macroscopic IK1 current. Verapamil is an antiarrhythmic drug used to suppress atrial and ventricular arrhythmias. Its primary mechanism of action is via blocking calcium channels. In addition, it has been demonstrated to block IK1 current and the Kir2.1 subunit. Its effect on other subunits that contribute to IK1 current has not been studied to date. We therefore analyzed the effect of verapamil on the Kir channels 2.1, 2.2, and 2.3 in the Xenopus oocyte expression system. Kir2.1, Kir2.2, and Kir2.3 channels were heterologously expressed in Xenopus oocytes. Respective currents were measured with the voltage clamp technique and the effect of verapamil on the current was measured. At a concentration of 300 µM, verapamil inhibited Kir2.1 channels by 41.36% ± 2.7 of the initial current, Kir2.2 channels by 16.51 ± 3.6%, and Kir2.3 by 69.98 ± 4.2%. As a verapamil effect on kir2.3 was a previously unknown finding, we analyzed this effect further. At wash in with 300 µM verapamil, the maximal effect was seen within 20 min of the infusion. After washing out with control solution, there was only a partial current recovery. The current reduction from verapamil was the same at − 120 mV (73.2 ± 3.7%), − 40 mV (85.5 ± 6.5%), and 0 mV (61.5 ± 10.6%) implying no voltage dependency of the block. Using site directed mutations in putative binding sites, we demonstrated a decrease of effect with pore mutant E291A and absence of verapamil effect for D251A. With mutant I214L, which shows a stronger affinity for PIP2 binding, we observed a normalized current reduction to 61.9 ± 0.06% of the control current, which was significantly less pronounced compared to wild type channels. Verapamil blocks Kir2.1, Kir2.2, and Kir2.3 subunits. In Kir2.3, blockade is dependent on sites E291 and D251 and interferes with activation of the channel via PIP2. Interference with these sites and with PIP2 binding has also been described for other Kir channels blocking drugs. As Kir2.3 is preferentially expressed in atrium, a selective Kir2.3 blocking agent would constitute an interesting antiarrhythmic concept.

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Section: Discussioncontrasting

confidence: 79%

Verapamil inhibits Kir2.3 channels by binding to the pore and interfering with PIP2 binding

Xynogalos

Rahm

Fried

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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“…As another molecular basis of Ito, Kv4.2 50 shows a stretch-induced downregulation in cultured atrial neonatal myocytes of rats, 51 positive haemodynamic effects of EPT and consequent lowered wall-stress during RAP cannot be excluded as another mechanism for prevention of Ito downregulation by RAP after EPT. Similar to our experiments with verapamil 52 the observation that downregulation of one channel (enalapril: Ito, verapamil: ICa,L) due to RAP can be prevented by medicamental pre-treatment whereas downregulation of the other (enalapril: ICa,L, verapamil: Ito) is not affected, points to different pathways of ICa,L respectively Ito downregulation due to RAP. As the tachypacinginduced downregulation of Ito has complex but relatively small effects on human and canine atrial APD in a mathematical model of an atrial myocyte, 53,54 the functional importance of the prevention of Ito downregulation by EPT cannot be stated at the moment, but insights from these models also showed that absolute impact of Ito on APD in comparison is much more pronounced in the early phases of AF (more 'sinus rhythm-like' action potential) as in chronic AF ('remodelled' action potential), which is in accordance with the already mentioned potential Ang II independence (or indirectly independence of EPT) of AERP-shortening after longer pacing intervals.…”

Section: Transient Outward Potassium Currentsupporting

confidence: 89%

Inhibition of the renin-angiotensin system: effects on tachycardia-induced early electrical remodelling in rabbit atrium

Laszlo

Eick

Rueb

et al. 2008

J Renin Angiotensin Aldosterone Syst

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I In nt tr ro od du uc ct ti io on n. . Tachycardia-induced atrial remodelling (as an equivalent to atrial fibrillation) can be influenced by the renin-angiotensin system. Effects of a seven-day enalapril pre-treatment (EPT, 0.16 mg/kg body weight subcutaneously every 24 h) on ionic currents underlying tachycardia-induced early electrical remodelling after 24 h rapid atrial pacing (RAP, 600 beats/min) in rabbit atrium were studied. M Ma at te er ri ia al ls s a an nd d m me et th ho od ds s. . Animals were divided into four groups (n=4 each): control; paced only; enalapril only; and enalapril and paced, respectively. Using patch-clamp technique in whole-cell mode, current densities were measured in isolated atrial myocytes. R Re es su ul lt ts s. . EPT nearly doubled L-type calcium current (ICa,L, −7.7±0.6 pA/pF [control] vs.

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“…Animals were instrumented as previously described in detail (Laszlo et al 2007). Adult female New Zealand white rabbits (weight 2.5 to 3 kg) were anesthetized with ketamine 75 mg/kg and xylazine 5.8 mg/kg with additional doses applied as needed.…”

Section: Instrumentation Of Animalsmentioning

confidence: 99%

Atorvastatin treatment affects atrial ion currents and their tachycardia-induced remodeling in rabbits

et al. 2010

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Effect of verapamil on tachycardia-induced early cellular electrical remodeling in rabbit atrium

Cited by 5 publications

References 59 publications

Verapamil inhibits Kir2.3 channels by binding to the pore and interfering with PIP2 binding

Verapamil inhibits Kir2.3 channels by binding to the pore and interfering with PIP2 binding

Inhibition of the renin-angiotensin system: effects on tachycardia-induced early electrical remodelling in rabbit atrium

Atorvastatin treatment affects atrial ion currents and their tachycardia-induced remodeling in rabbits

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