Arrhythmogenic Action of Thrombin During Myocardial Reperfusion via Release of Inositol 1,4,5-Triphosphate

Background Cardiac reperfusion initiates release of inositol 1,4,5-triphosphate [Ins(1,4,5)P3] and arrhythmogenesis via norepinephrine stimulation of α1-adrenergic receptors. The present study examines arrhythmogenic effects of thrombin-stimulated Ins(1,4,5)P3 release under these conditions. Methods and Results [3H]Ins(1,4,5)P3 release was measured in [3H]inositol-labeled rat hearts by high-performance liquid chromatography. Arrhythmia studies were performed in buffer-perfused rat hearts. Two-minute reperfusion after 20 minutes of global ischemia increased [3H]Ins(1,4,5)P3 from 1123±77 to 2238±44 cpm/mg tissue. No increase was observed in catecholamine-depleted hearts (755±89 cpm/mg). The addition of thrombin (5 IU/mL) or thrombin receptor agonist peptide (TRAP1-6, 50 μmol/L) restored the reperfusion Ins(1,4,5)P3 response (thrombin, 1518±68 cpm/mg and TRAP1-6, 1755±128 cpm/mg). Ins(1,4,5)P3 release initiated by norepinephrine or thrombin was inhibited by gentamicin (150 μmol/L; 986±52 and 868±125 cpm/mg, ...