Pabla R, Curtis M J
Department of Pharmacology, King's College, University of London, UK.
J Mol Cell Cardiol. 1996 Oct;28(10):2097-110. doi: 10.1006/jmcc.1996.0202.
Nitric oxide (NO) is an endogenous protectant against reperfusion-induced ventricular fibrillation (VF) in the rat isolated heart. Here, the following were investigated: (1) the tissue source of cardioprotective NO using a novel inhibitor (7-nitro indazole; 7-NI) of the neuronal form of NO synthase (NOS) and direct detection of coronary effluent NO by chemiluminescence; and (2) the species dependence by comparing rat and rabbit hearts. Perfusion with modified Krebs solution was followed by 60 min left regional ischemia and 10 min reperfusion. 7-NI (1 microM) increased the incidence of VF from 0% to 60% in rat hearts (n = 10; P < 0.05). Co-perfusion with L-arginine (1 mM) reduced VF incidence to 20% (P:N.S. v controls). The inactive analog of 7-NI (6-amino indazole: 6-AI) had no pro-fibrillatory activity. Neither 7-NI nor 6-AI affected coronary flow or recovery of flow during reperfusion. 7-NI reduced basal coronary effluent NO levels to below the limit of detection (< 1 pmol), but a massive increase in NO levels occurred when L-arginine was co-perfused with 7-NI. Although 7-NI had no effect on basal coronary flow and, by implication, resting NO release, it was found, in separate studies, to antagonise substance P-induced vasodilatation and NO release, suggesting that its neuronal selectivity is lost in the presence of an exogenously administered activator of endothelial NOS in rat hearts. In rabbit hearts, in contrast, 7-NI had no effect on VF or NO levels. However, in rabbit hearts the isozyme non-selective NO synthase blocker, NG-nitro-L-arginine methyl ester (L-NAME; 100 microM), increased VF incidence from 0 to 50% (P < 0.05) and, during the first minute of reperfusion, reduced NO levels from 4929 +/- 893 to 2505 +/- 483 pmol/min/g (P < 0.05) and recovery of coronary flow by 22% (P < 0.05). Each of these effects were prevented by L-arginine co-perfusion. These data indicate a role for basally released NO as an endogenous antifibrillatory cardioprotectant in rat and rabbit isolated heart and indicate that the tissue source (neuronal in rat but not in rabbit heart) is species-dependent.
一氧化氮（NO）是大鼠离体心脏中对抗再灌注诱导的心室颤动（VF）的内源性保护剂。在此，研究了以下内容：（1）使用新型神经元型一氧化氮合酶（NOS）抑制剂（7-硝基吲唑；7-NI）和通过化学发光直接检测冠状动脉流出液中的NO，来确定具有心脏保护作用的NO的组织来源；（2）通过比较大鼠和兔心脏来研究物种依赖性。用改良的 Krebs 溶液灌注后，进行 60 分钟的左区域缺血和 10 分钟的再灌注。7-NI（1 microM）使大鼠心脏中VF的发生率从0%增加到60%（n = 10；P < 0.05）。与L-精氨酸（1 mM）共同灌注可将VF发生率降低至20%（与对照组相比，P：无统计学意义）。7-NI的无活性类似物（6-氨基吲唑：6-AI）没有促纤颤活性。7-NI和6-AI均不影响冠状动脉血流或再灌注期间血流的恢复。7-NI将基础冠状动脉流出液中的NO水平降低至检测限以下（< 1 pmol），但当L-精氨酸与7-NI共同灌注时，NO水平会大幅增加。尽管7-NI对基础冠状动脉血流没有影响，因此对静息状态下的NO释放也没有影响，但在单独的研究中发现，它能拮抗P物质诱导的血管舒张和NO释放，这表明在大鼠心脏中，当存在外源性给予的内皮型NOS激活剂时，其神经元选择性丧失。相比之下，在兔心脏中，7-NI对VF或NO水平没有影响。然而，在兔心脏中，同工酶非选择性的NO合酶阻滞剂NG-硝基-L-精氨酸甲酯（L-NAME；100 microM）使VF发生率从0增加到50%（P < 0.05），并且在再灌注的第一分钟内，将NO水平从4929 +/- 893降低至2505 +/- 483 pmol/分钟/克（P < 0.05），并使冠状动脉血流恢复降低22%（P < 0.05）。L-精氨酸共同灌注可防止所有这些效应。这些数据表明基础释放的NO在大鼠和兔离体心脏中作为内源性抗纤颤心脏保护剂发挥作用，并表明组织来源（大鼠心脏中为神经元来源，兔心脏中不是）具有物种依赖性。
