Background: Carvedilol and its analogues suppress delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardias by direct action on the cardiac ryanodine receptor type 2 (RyR2).
Objective: To test a hypothesis that carvedilol analogue may also prevent triggered activities (TAs) through the suppression of early afterdepolarizations (EADs).
Methods: Intracellular Ca(2+) and membrane voltage were simultaneously recorded by using optical mapping technique in Langendorff-perfused mouse and rabbit hearts to study the effect of carvedilol analogue VK-II-36, which does not have significant beta-blocking effects.
Results: Spontaneous intracellular Ca(2+) elevations (SCaEs) during diastole were induced by rapid ventricular pacing and isoproterenol infusion in intact rabbit ventricles. Systolic and diastolic SCaEs were simultaneously noted in Langendorff-perfused RyR2 R4496(+/-) mouse hearts after creating atrioventricular block. VK-II-36 effectively suppressed SCaEs and eliminated TAs observed in both mouse and rabbit ventricles. We tested the effect of VK-II-36 on EADs by using a rabbit model of acquired long QT syndrome, in which phase 2 and phase 3 EADs were observed in association with systolic SCaEs. VK-II-36 abolished the systolic SCaEs and phase 2 EADs, and greatly decreased the dispersion of repolarization and the amplitude of phase 3 EADs. VK-II-36 completely prevented EAD-mediated TAs in all ventricles studied.
Conclusions: A carvedilol analogue, VK-II-36, inhibits ventricular tachyarrhythmias in intact mouse and rabbit ventricles by the suppression of SCaEs, independent of beta-blocking activity. The RyR2 may be a potential target for treating focal ventricular arrhythmias triggered by either EADs or DADs.[1]

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VK-II-36 suppresses DAD-mediated arrhythmias
That diastolic SCaEs can be induced by a prolonged rapid ventricular pacing (cycle length 200 ms for 200 beats) under isoproterenol infusion (0.01 to 0.3 μM) in the rabbit ventricle. Since diastolic SCaEs represent the sum of the Ca2+ waves at the tissue level, this rabbit model was used to determine whether VK-II-36 prevents DAD-mediated ventricular arrhythmias (n = 12). Optical mapping of Cai revealed that diastolic SCaEs were observed following prolonged rapid ventricular pacing under isoproterenol infusion in all 12 hearts studied . VK-II-36 (30 μM) suppressed the diastolic SCaE (0.139 ± 0.017 AU to 0.007 ± 0.004 AU, P < 0.001), and DAD (0.035 ± 0.011 AU to 0.00 ± 0.00 AU, P = 0.008). Ventricular arrhythmias were reproducibly induced in 7 of 12 hearts (single TAs in 2 hearts, VTs in 5 hearts). VK-II-36 (30 μM) abolished all episodes of the ventricular arrhythmias . Thus, VK-II-36 effectively prevented DAD-mediated ventricular arrhythmias in intact rabbit hearts.[1]

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VK-II-36 suppresses EAD-mediated arrhythmias and reduces dispersion of repolarization
VK-II-36 (30 μM) consistently eliminated the systolic SCaEs (0.08 ± 0.03 AU to 0.00 ± 0.00 AU, P = 0.04) and phase-2 EADs (0.03 ± 0.01 AU to 0.00 ± 0.00 AU, P = 0.067). Also, VK-II-36 decreased phase-3 EADs (0.23 ± 0.02 AU to 0.05 ± 0.02 AU, P = 0.003). Since phase-2 EADs developed only at sites with a long APD, the elimination of phase-2 EADs shortened the maximal APD70 (458 ± 37 ms to 310 ± 19 AU, P = 0.002), but did not significantly change the minimal APD70 (263 ± 12 ms to 244 ± 10 ms, P = 0.10). As a result, VK-II-36 dramatically reduced the spatial dispersion of repolarization (APD70 dispersion: 195 ± 33 ms to 66 ± 14 ms, P = 0.002; standard deviation of APD70: 48 ± 10 ms to 15 ± 4 ms, P = 0.005). The decrease in the spatial dispersion of repolarization was accompanied by a decrease in Vm gradient during repolarization (0.33 ± 0.02 AU/mm to 0.18 ± 0.03 AU/mm, P = 0.003), which accounts for the suppression of phase-3 EADs since electrotonic depolarization across a high Vm gradient underlies the mechanism of phase-3 EAD.15 With Ikr blockade and 50% reduction in extracellular K+ and Mg2+, both phase-2 and phase-3 EAD developed TAs leading to polymorphic VT . VK-II-36 (30 μM) abolished the TAs and VTs induced by EADs in all hearts studied . Therefore, VK-II-36 directly abolished phase-2 EADs with indirect suppression of phase-3 EADs, which eliminated the EAD-mediated ventricular arrhythmias in a rabbit model of acquired long QT syndrome.[1]

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VK-II-36 suppresses both systolic and diastolic SCaEs
VK-II-36 (10 μM) suppressed both systolic and diastolic SCaEs (0.14 ± 0.03 AU to 0.00 ± 0.00 AU, and 0.23 ± 0.02 AU to 0.11 ± 0.01 AU, respectively, both P < 0.05), indicating that carvedilol analogue has the potential for the treatment of cardiac arrhythmias associated with TA induced by either EADs or DADs.

[1]. Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations. Heart Rhythm. 2013 Jan;10(1):101-7.

C26H26N2O5

446.503

446.184

C, 69.94; H, 5.87; N, 6.27; O, 17.92

955371-66-1

24802973

White to off-white solid powder

1.3±0.1 g/cm3

698.6±55.0 °C at 760 mmHg

376.3±31.5 °C

0.0±2.2 mmHg at 25°C

1.644

4.25

1

5

8

33

648

0

O=C1COC(COC2C3=C(NC4C3=CC=CC=4)C=CC=2)CN1CCOC1C(OC)=CC=CC=1

OPUVSUMPCOUABG-UHFFFAOYSA-N

InChI=1S/C26H26N2O5/c1-30-22-10-4-5-11-23(22)31-14-13-28-15-18(32-17-25(28)29)16-33-24-12-6-9-21-26(24)19-7-2-3-8-20(19)27-21/h2-12,18,27H,13-17H2,1H3

6-[(9H-Carbazol-4-yloxy)methyl]-4-[2-(2-methoxyphenoxy)ethyl]-3-morpholinone

VK-II 36VK-II-36 VK-II36 VKII36 VK II36

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~223.96 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.60 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.60 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)