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

Phosphodiesterase inhibitors regulate intracellular Ca(2+) of cardiomyocytes through enhancing second messenger signalling. This study aimed to investigate whether TP-10, a selective phosphodiesterase10A inhibitor, modulates Ca(2+) 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(2+) 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(2+) transients and increased stores of Ca(2+) in the sarcoplasmic reticulum. Although the L-type Ca(2+) current was diminished in TP-10-treated cardiomyocytes, the current from the Na(+)-Ca(2+) 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(2+) ATPase 2a. Our findings indicate that TP-10 attenuates ISO-induced arrhythmic events in RVOT tissues via cGMP-mediated modulation of intracellular Ca(2+) regulation.