Phosphodiesterase 10A Inhibitor Modulates Right Ventricular Outflow Tract Electrophysiological Activities and Calcium Homeostasis via the cGMP/PKG Pathway.

Phosphodiesterase inhibitors regulate intracellular Ca of cardiomyocytes through enhancing second messenger signalling. This study aimed to investigate whether TP-10, a selective phosphodiesterase10A inhibitor, modulates Ca cycling, attenuating arrhythmogenesis in the right ventricular outflow tract (RVOT). Right ventricular tissues from New Zealand white rabbits were harvested, and electromechanical analyses of ventricular tissues were conducted. Intracellular Ca was monitored using Fluo-3, and ionic current was recorded using patch-clamp in isolated cardiomyocytes. Tissues from RVOT exhibited a reduction in action potential duration at both 50% and 90% repolarisation following treatment with TP-10. This treatment also inhibited burst firing induced by isoproterenol (ISO) in RVOT tissues, an effect that was nullified by thapsigargin. The protein kinase G inhibitor KT5823, whether used alone or in conjunction with TP-10, also suppressed ISO-induced burst firing in these tissues. Compared to the control group, RVOT cardiomyocytes treated with TP-10 demonstrated enhanced amplitudes of Ca transients and increased stores of Ca in the sarcoplasmic reticulum. Although the L-type Ca current was diminished in TP-10-treated cardiomyocytes, the current from the Na-Ca exchanger was elevated. Furthermore, the density of late Na current was significantly reduced in these treated cardiomyocytes. TP-10 administration also resulted in increased levels of calcium regulatory proteins, specifically phosphorylated phospholamban at Thr17 and sarcoplasmic/endoplasmic reticulum Ca ATPase 2a. Our findings indicate that TP-10 attenuates ISO-induced arrhythmic events in RVOT tissues via cGMP-mediated modulation of intracellular Ca regulation.