Endogenous adenosine reduces the occurrence of ischemia-induced ventricular fibrillation in rat heart.
Endogenous adenosine reduces the occurrence of ischemia-induced ventricular fibrillation in rat heart.
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内源性腺苷可减少大鼠心脏缺血引起的心室颤动的发生。
DOI：
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发表时间：
1999
影响因子：
5
通讯作者：
G. Richardt
中科院分区：
文献类型：
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作者：
J. Schreieck;G. Richardt
本研究的目的是确定内源性腺苷是否对缺血诱发的室性快速性心律失常有抗心律失常的作用。因此，我们使用四种不同的方法来调节内源性腺苷在离体鼠心脏中的作用。首先，用ehna(红血球-9-(2-羟基-3-nonly)腺嘌呤)或艾司汀[5-氨基-1-β-D-咪唑-4-甲酰胺]代谢抑制使间质腺苷升高。第二，腺苷A1受体的心脏效应被PD81,723(2-amino-4，5-dimethyl-3-thienyl)[3-(trifluoromethyl)phenyl]-methanone变构增强。3.S(4-硝基苄基)-6-硫代肌苷(NBMPR)抑制内源性腺苷释放；4.不同选择性拮抗剂阻断腺苷受体亚型。冠状动脉结扎诱发的局部缺血在30min的观察期内，在低钙(0.80 mmoL/L CaCl2)和高钙(1.85 mmoL/L)的灌流介质中，约20%的未处理心脏和约75%的心脏引起可重复性的室颤。在高钙条件下，茶碱(1、10微克/L)和艾司汀(500微克/L)分别抑制室颤的发生率，从对照组的68%降至47%、33%和38%。反之，PD81,723(10微克/L)不影响室颤的发生。在低钙条件下，NBMPR(0.1和1微摩尔/L)可使室颤发生率从对照组的13%分别增加到40%和57%，且呈浓度依赖性。腺苷受体拮抗剂茶碱(100微克/L)、XAC(黄嘌呤类化合物；1微克/L)和8-PT(8-苯基茶碱；1微克/L)使室颤的发生率分别从对照组的25%、15%和18%增加到57%、39%和44%；选择性A2a受体拮抗剂Csc(8-(3-氯苯乙基)咖啡因；5微摩尔/L)使室颤的发生率从20%增加到56%。相反，选择性A1受体阻断剂DPCPX(8-环戊基-1，3-二丙基-黄嘌呤；1微克/L)无效。NBMPR或eHNA分别以浓度依赖的方式抑制或增加缺血诱导的腺苷溢出，而腺苷受体拮抗剂不影响腺苷溢出。我们的结论是，内源性腺苷是一种抗心律失常的介质，在急性缺血心肌中积聚到一定水平，通过激活A2腺苷受体有效地减少离体大鼠心脏室颤的发生。
The aim of this study was to determine whether endogenous adenosine has antiarrhythmic effects on ischemia-induced ventricular tachyarrhythmias. We therefore modulated the effect of endogenous adenosine in isolated rat hearts using four different approaches. First, interstitial adenosine was elevated by metabolic inhibition with either EHNA (erythro-9-(2-hydroxy-3-nonly)adenine) or acadesine [5-amino-1-beta-D-imidazole-4-carboxamide). Second, cardiac effects of A1 adenosine receptors were allosterically enhanced with PD81,723 (2-amino-4,5-dimethyl-3-thienyl)[3-(trifluoromethyl)phenyl]-methanone . Third, endogenous adenosine release was suppressed with NBMPR (S-(4-nitrobenzyl)-6-thioinosine), and fourth, adenosine receptor subtypes were blocked with antagonists of different selectivity. Regional ischemia, induced by coronary artery ligation, caused ventricular fibrillation of a reproducible kind in about 20% of untreated hearts with a low calcium concentration in the perfusion medium (0.80 mmol/l CaCl2) and in about 75% with high calcium (1.85 mmol/l) within an observation period of 30 min. At high calcium, EHNA (1 and 10 micromol/l) and acadesine (500 micromol/l) suppressed the occurrence of ventricular fibrillation from 68% (controls) to 47%, 33% and 38%, respectively. Conversely, PD81,723 (10 micromol/l) did not influence the occurrence of ventricular fibrillation. At low calcium, NBMPR (0.1 and 1 micromol/l) resulted in a concentration-dependent rise of ventricular fibrillation from 13% (controls) to 40% and 57%, respectively. The adenosine receptor antagonists theophylline (100 micromol/l), XAC (Xanthine Amine Congener; 1 micromol/l) and 8-PT (8-phenyltheophylline; 1 micromol/l) caused a rise in the occurrence of ventricular fibrillation from 25%, 15% and 18% (controls) to 57%, 39% and 44%, respectively, and the selective A2a receptors antagonist CSC (8-(3-chlorostyryl)caffeine; 5 micromol/l) from 20% to 56%. Conversely, the selective A1 receptor blocker DPCPX (8-cyclopentyl-1,3-dipropyl-xanthine; 1 micromol/l) was ineffective. NBMPR or EHNA concentration-dependent suppressed or increased ischemia-induced adenosine overflow, respectively, in a concentration-dependent manner, whereas the adenosine receptor antagonists did not influence adenosine overflow. We conclude that endogenous adenosine is an antiarrhythmic mediator accumulating in acute ischemic myocardium to a level which effectively decreases the occurrence of ventricular fibrillation by an A2 adenosine receptor activation in the isolated rat heart.