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- W2912048343 abstract "Spontaneous firing of SANC is regulated by sarcoplasmic reticulum generated local subsarcolemmal Ca2+ releases (LCRs). LCRs appear during diastolic depolarization (DD) and activate an inward Na+-Ca2+exchange current accelerating the rate of DD and spontaneous SANC firing rate. Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have emerged as an effective therapy for treatment of several malignancies but have pronounced cardiac side-effects including arrhythmias. Downstream targets of VEGFR activation include activation of PLCγ and PKC-dependent phosphorylation. We have recently demonstrated that inhibition of basal PLC activity suppresses LCRs and abrogates spontaneous firing of rabbit SANC. Here we measured expression of VEGFR in SANC and effects of VEGFR TKI vatalanib (an inhibitor of VEGFR-(1-3) that is used to treat metastatic colorectal and pancreatic cancers) on rabbit SANC pacemaker function. Expression of VEGFR-1 (RT-qPCR) in rabbit SAN and ventricle was comparable. During vatalanib (10 μmol/L) treatment SANCs became irregular and spontaneous beating rate decreased by ∼50% (perforated patch-clamp technique); both effects were largely reversable upon drug washout. Vatalanib markedly suppressed LCRs in SANC (confocal microscopy, Ca2+indicator Fluo-3); i.e. LCR size and number per each spontaneous cycle were reduced and the LCR period (an interval between AP-induced Ca2+ transient and subsequent LCR) was prolonged. Effect of vatalanib on LCR period predicted the concomitant increase in the spontaneous SANC cycle length. Inhibition of basal PKC activity by GF109203X or calphostin C suppressed LCRs and abrogated spontaneous firing of SANC. We conclude that basal VEGFR activation modulates normal cardiac pacemaker cell automaticity via modulation of basal LCR characteristics possibly via activation of VEGFR-PLC-PKC-dependent pathway. This could be a novel mechanism to regulate normal automaticity of SANC which could be linked to arrhythmogenic side-effects of VEGFR TKIs during cancer therapy." @default.
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- W2912048343 date "2019-02-01" @default.
- W2912048343 modified "2023-09-29" @default.
- W2912048343 title "The Anti-Cancer Drug Vatalanib (Ptk787/Zk222584) Suppresses Normal Spontaneous Firing of Rabbit Sinoatrial Node Cells (SANC)" @default.
- W2912048343 doi "https://doi.org/10.1016/j.bpj.2018.11.2084" @default.
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