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摘要
Background Cardiac reperfusion initiates release of inositol 1,4,5-triphosphate [Ins(1,4,5)P-3] and arrhythmogenesis via norepinephrine stimulation of alpha(1)-adrenergic receptors. The present study examines arrhythmogenic effects of thrombin-stimu lated Ins(1,3,5)P-3 release under these conditions.
Methods and Results [H-3]Ins(1,4,5)P-3 release was measured in [H-3]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 [H-3]Ins(1,4,5)P-3 from 1123+/-77 to 2238+/-44 cpm/mg tissue. No increase was observed in catecholamine-depleted hearts (755+/-59 cpm/mg). The addition of thrombin (5 IU/mL) or thrombin receptor agonist peptide (TRAP(1.6), 50 mu mol/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; release initiated by norepinephrine or thrombin was inhibited by gentamicin (150 mu mol/L; 986+/-52 and 868+/-125 cpm/mg, respectively). The thrombin response was inhibited by the phospholipase C inhibitor U-73122 (5 mu mol/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.
- 出版日期1996-1-1
