JTV-519 (K201) has been shown to be anti-arrhythmic in the ischemic/reperfusion setting. The mechanism is unknown.
Purpose:
To investigate the effects of JTV-519(K201) (Aetas Pharm Co.) in Purkinje cells dispersed from the subendocardium of the 48hr infarcted canine heart (IZPCs). IZPCs are the source of the triggered ventricular arrhythmias that occur at this time post coronary artery occlusion.
Methods:
Ca
2+
release events (elevations of basal [Ca
2+
] equivalent to F/F
0
3.4 SD over F
0
) in both intact and permeabilized single IZPCs were imaged using 2DCM with Fluo-4 and analyzed using a custom IDL program.
Results:
In intact IZPCs, the Ca
2+
release event (ev) rate was increased in the Subsarcolemmal region (SSL, a layer of ∼ 5μm thickness below the membrane; 0.0161±0.0031 ev/μm
2
/sec, n=cells=30, 1198 ev) but not in the Core region, when compared to normal Purkinje cells (NZPCs; SSL, 0.0089±0.0018 ev/μm
2
/sec, n=34, 747 ev, p<0.05). SR Ca
2+
ontent as estimated by rapid caffeine (20mM) application was comparable between NZPCs and IZPCs in both subcellular regions. Superfusion of JTV-519(K201) (1μM) normalized the SSL Ca
2+
event rate in intact IZPCs (to 0.0086±0.0016 ev/μm
2
/sec, n=17, 510ev, p<0.05 vs untreated IZPC value) without a change in SR Ca
2+
content. The incidence of spontaneous Ca
2+
waves is increased in intact IZPCs (0.0016/μm
2
/sec*1000, n=57) and was also normalized by JTV-519(K201)(0.0004/ μm
2
/sec*1000, n=30). In saponin-treated IZPCs ([Ca
2+
]
cyto=
100nM), JTV-519(K201) normalized the enhanced Ca
2+
event rate (from 0.0246±0.0030 ev/μm
2
/sec, n=28 to 0.0110±0.0023 ev/μm
2
/sec, n=7, P<0.05).
Conclusion:
In Purkinje cells that survive in the infarcted heart, the enhanced subcellular Ca
2+
event rate is due to enhanced Ca
2+
induced Ca
2+
release. This leads to cell wide Ca
2+
waves and arrhythmias. By normalizing Ca
2+
sensitivity of Ca
2+
release channels of IZPCs, JTV519(K201) reduces the spontaneous Ca
2+
event rate, the incidence of Ca
2+
waves and thus the likelihood of infarct Purkinje cell induced triggered arrhythmias.
Targeting late ICaL to close the window to ventricular arrhythmias
