BackgroundCardiac reperfusion initiates release of inositol 1,4,5-triphosphate [Ins(1,4,5)P3] and arrhythmogenesis via norepinephrine stimulation of alpha1-adrenergic receptors. The present study examines arrhythmogenic effects of thrombin-stimulated Ins(1,4,5)P3release under these conditions.Methods and Results[sup 3 H]Ins(1,4,5)P3release was measured in [sup 3 H]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 [sup 3 H]Ins(1,4,5)P3from 1123 plus/minus 77 to 2238 plus/minus 44 cpm/mg tissue. No increase was observed in catecholamine-depleted hearts (755 plus/minus 89 cpm/mg). The addition of thrombin (5 IU/mL) or thrombin receptor agonist peptide (TRAP1-6, 50 micro mol/L) restored the reperfusion Ins(1,4,5)P3response (thrombin, 1518 plus/minus 68 cpm/mg and TRAP1-6, 1755 plus/minus 128 cpm/mg). Ins(1,4,5)P3release initiated by norepinephrine or thrombin was inhibited by gentamicin (150 micro mol/L; 986 plus/minus 52 and 868 plus/minus 125 cpm/mg, respectively). The thrombin response was inhibited by the phospholipase C inhibitor U-73122 (5 micro mol/L; 394 plus/minus 59 cpm/mg) but not by its inactive isomer U-73343. The norepinephrine response was not inhibited by U-73122 (2126 plus/minus 74 cpm/mg). Ventricular tachycardia and ventricular fibrillation were observed in intact hearts but not in hearts from catecholamine-depleted rats (ventricular fibrillation duration, 110 plus/minus 19 versus 0 plus/minus 0 seconds). The addition of thrombin or TRAP1-6 increased arrhythmias in catecholamine-depleted hearts (112 plus/minus 32 and 89 plus/minus 28 seconds, respectively). Gentamicin and U-73122 but not U-73343 prevented thrombin-induced arrhythmias. Gentamicin inhibited norepinephrine-initiated arrhythmias, but U-73122 was ineffective.ConclusionsThis study demonstrates that the development of reperfusion arrhythmias under these conditions depends on the release of Ins(1,4,5)P3. (Circulation. 1996;93:23-26.)Key Wordsarrhythmia, enzymes, receptors, adrenergic, alpha, thrombin, inositol phosphates.