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

1996; Lippincott Williams & Wilkins; Volume: 93; Issue: 1 Linguagem: Inglês

10.1161/01.cir.93.1.23

1524-4539

Alexander Jacobsen, Xiao‐Jun Du, Kim A. Lambert, Anthony M. Dart, Elizabeth A. Woodcock,

Cardiac Ischemia and Reperfusion

Background Cardiac reperfusion initiates release of inositol 1,4,5-triphosphate [Ins(1,4,5)P 3 ] and arrhythmogenesis via norepinephrine stimulation of α 1 -adrenergic receptors. The present study examines arrhythmogenic effects of thrombin-stimulated Ins(1,4,5)P 3 release under these conditions. Methods and Results [ 3 H]Ins(1,4,5)P 3 release was measured in [ 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 [ 3 H]Ins(1,4,5)P 3 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 (TRAP 1-6 , 50 μmol/L) restored the reperfusion Ins(1,4,5)P 3 response (thrombin, 1518±68 cpm/mg and TRAP 1-6 , 1755±128 cpm/mg). Ins(1,4,5)P 3 release initiated by norepinephrine or thrombin was inhibited by gentamicin (150 μmol/L; 986±52 and 868±125 cpm/mg, respectively). The thrombin response was inhibited by the phospholipase C inhibitor U-73122 (5 μmol/L; 394±59 cpm/mg) but not by its inactive isomer U-73343. The norepinephrine response was not inhibited by U-73122 (2126±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±19 versus 0±0 seconds). The addition of thrombin or TRAP 1-6 increased arrhythmias in catecholamine-depleted hearts (112±32 and 89±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. Conclusions This study demonstrates that the development of reperfusion arrhythmias under these conditions depends on the release of Ins(1,4,5)P 3 .