Schreieck J, Richardt G
Deutsches Herzzentrum München, I. Medizinische Klinik, Klinikum rechts der Isar der Technischen Universität München, Germany.
J Mol Cell Cardiol. 1999 Jan;31(1):123-34. doi: 10.1006/jmcc.1998.0858.
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.
本研究的目的是确定内源性腺苷对缺血诱导的室性心律失常是否具有抗心律失常作用。因此，我们使用四种不同方法调节离体大鼠心脏内源性腺苷的作用。第一，用EHNA（赤型-9-(2-羟基-3-壬基)腺嘌呤）或阿卡地新[5-氨基-1-β-D-咪唑-4-甲酰胺]通过代谢抑制来提高间质腺苷水平。第二，用PD81,723（2-氨基-4,5-二甲基-3-噻吩基）[3-(三氟甲基)苯基]甲酮变构增强A1腺苷受体的心脏效应。第三，用NBMPR（S-(4-硝基苄基)-6-硫代肌苷）抑制内源性腺苷释放，第四，用不同选择性的拮抗剂阻断腺苷受体亚型。冠状动脉结扎诱导的局部缺血，在灌注介质中钙浓度低（0.80 mmol/L CaCl2）时，约20%未经处理的心脏在30分钟观察期内会出现可重复性的室颤，而在钙浓度高（1.85 mmol/L）时，约75%会出现室颤。在高钙情况下，EHNA（1和10 μmol/L）和阿卡地新（500 μmol/L）分别将室颤的发生率从68%（对照组）降至47%、33%和38%。相反，PD81,723（10 μmol/L）不影响室颤的发生。在低钙情况下，NBMPR（0.1和1 μmol/L）导致室颤发生率浓度依赖性升高，分别从13%（对照组）升至40%和57%。腺苷受体拮抗剂茶碱（100 μmol/L）、XAC（黄嘌呤胺同类物；1 μmol/L）和8-PT（8-苯基茶碱；1 μmol/L）分别使室颤发生率从25%、（15%和18%（对照组）升至57%、39%和44%，而选择性A2a受体拮抗剂CSC（8-(3-氯苯乙烯基)咖啡因；5 μmol/L）使室颤发生率从20%升至56%。相反，选择性A1受体阻滞剂DPCPX（8-环戊基-1,3-二丙基黄嘌呤；1 μmol/L）无效。NBMPR或EHNA分别以浓度依赖性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。我们得出结论，内源性腺苷是一种抗心律失常介质，在急性缺血心肌中积累到一定水平，通过激活离体大鼠心脏中的A2腺苷受体有效降低室颤的发生率。
