Arrhythmogenic action of thrombin during myocardial reperfusion via release of inositol 1,4,5-triphosphate
Arrhythmogenic action of thrombin during myocardial reperfusion via release of inositol 1,4,5-triphosphate
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DOI：
10.1161/01.cir.93.1.23
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发表时间：
1996-01-01
期刊：
影响因子：
37.8
通讯作者：
Woodcock, EA
中科院分区：
文献类型：
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作者：
Jacobsen, AN;Du, XJ;Woodcock, EA
背景：心脏再灌注通过去甲肾上腺素刺激α(1)-肾上腺素能受体，启动肌醇1，4，5-三磷酸[INS(1，4，5)P-3]的释放和心律失常的发生。本研究观察了凝血酶刺激的Ins(1，3，5)P-3在上述条件下的致心律失常作用。方法和结果用高效液相色谱法测定[H-3]Ins(1，4，5)P-3在[H-3]肌醇标记的大鼠心脏中的释放。在缓冲液灌流的大鼠心脏中进行了心律失常研究。全脑缺血20分钟再灌流2分钟，[H-3]Ins(1，4，5)P-3由1123+/-77升至2238+/-44cpm/mg组织。在儿茶酚胺耗竭的心脏(755+/-59cpm/mg)中没有观察到增加。加入凝血酶(5IU/mL)或凝血酶受体激动肽(TRAP，1.6，50MU/L)可恢复INS(1，4，5)P-3反应(凝血酶，1518+/-68cpm/mg和TRAP(1.6)，1755+/-128cpm/mg)。庆大霉素可抑制去甲肾上腺素或凝血酶引起的INS(1，4，5)P释放(分别为150 mU/L，986+/-52和868+/-125cpm/mg)。磷脂酶C抑制剂U-73122(5umol/L；394cpm/mg)可抑制凝血酶反应，但其失活异构体U-73343不能抑制凝血酶反应。U-73122(2126+/-74cpm/mg)不抑制去甲肾上腺素的反应。在完整心脏中观察到室性心动过速和室颤，但在儿茶酚胺耗竭大鼠的心脏中未观察到室速和室颤(室颤持续时间，110+/-19秒对0+/-0秒)。添加凝血酶或TRAP(1.6)会增加儿茶酚胺耗竭心脏的心律失常(分别为112+/-32秒和89+/-28秒)。庆大霉素和U-73122而不是U-73343可预防凝血酶引起的心律失常。庆大霉素可抑制去甲肾上腺素诱发的心律失常，但U-73122无此作用。结论在此条件下再灌注性心律失常的发生依赖于INS(1，4，5)P-3的释放。
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.