Abstract

Sarcoplasmic reticulum generated local subsarcolemmal Ca2+ releases (LCRs) in SANC appear during diastolic depolarization and activate an inward Na+-Ca2+ exchange current accelerating the diastolic depolarization rate and thus increasing spontaneous SANC firing. Sorafenib, multitargeted tyrosine kinase inhibitor treating renal, liver and thyroid malignances, inhibits VEGFR, platelet-derived growth factor-receptor and rapidly accelerated fibrosarcoma (RAF) kinases. Sorafenib treatment is associated with myocardial infarction and increased incidence of atrial fibrillation that could be linked to suppression of cardiac pacemaker function. The goal of the present study is to determine whether sorafenib affects spontaneous firing of SANC and, if so, define specific downstream targets effected by sorafenib. Expression of VEGFR1, VEGFR2 and PLCγ (assessed by RT-qPCR) in rabbit sinoatrial node was comparable to that of β1-adrenergic receptors. Sorafenib: (1) markedly decreased the LCR size and number (confocal microscopy, Ca2+ indicator Fluo-3); (2) prolonged the LCR period (interval between action potential-induced Ca2+ transient and subsequent LCR); (3) in a time-dependent manner decreased and then abrogated spontaneous firing of single isolated SANC. A selective pan-inhibitor of VEGFR1/2/3 (PTK787/ZK222584) also decreased spontaneous SANC beating rate by ∼50%, suggesting that VEGFR1/2 could be one of major targets of sorafenib. The selective VEGFR2 inhibitor ZM-323881, however, suppressed spontaneous firing in only ∼18% of SANC suggesting that VEGFR1, but not VEGFR2 signaling, is linked to SANC automaticity. Phosphoinositide-3-kinase (PI3K) and phospholipase C (PLC) are downstream targets of VEGFR. While selective PI3K inhibitor PI-103 was lacking effects, PLC inhibitor U-73122 markedly decreased the LCR size, number, extended the LCR period and prolonged the spontaneous SANC cycle length. Our results strongly suggest that activation of VEGFR1-PLC pathway is involved in regulation of normal automaticity of cardiac pacemaker cells.

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