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(Circulation. 1996;93:23-26.)
© 1996 American Heart Association, Inc.

Articles

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

Alexander N. Jacobsen, BSc, MBBS; Xiao-Jun Du, MB, PhD; Kim A. Lambert, BSc; Anthony M. Dart, MRCP, PhD; Elizabeth A. Woodcock, PhD

From the Cellular Biochemistry Laboratory and Alfred and Baker Medical Unit, Baker Medical Research Institute, Melbourne, Australia.

Correspondence to Dr Alexander Jacobsen, Alfred and Baker Medical Unit, Baker Medical Research Institute, Commercial Rd, Prahran (Melbourne), Victoria 3181, Australia.

Background Cardiac reperfusion initiates release of inositol 1,4,5-triphosphate [Ins(1,4,5)P₃] and arrhythmogenesis via norepinephrine stimulation of ₁-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 (TRAP_1-6, 50 µmol/L) restored the reperfusion Ins(1,4,5)P₃ response (thrombin, 1518±68 cpm/mg and TRAP_1-6, 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, 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)P₃.

Key Words: arrhythmia • enzymes • receptors, adrenergic, alpha • thrombin • inositol phosphates

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