Chi L, Black S C, Kuo P I, Fagbemi S O, Lucchesi B R
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0626.
J Cardiovasc Pharmacol. 1993 Feb;21(2):179-90. doi: 10.1097/00005344-199302000-00001.
We investigated the effects of the ATP-dependent K+ channel antagonist glyburide and the ATP-dependent K+ channel agonist pinacidil in a Langendorff-perfused rabbit isolated heart subjected to a period of global hypoxia. A class III antiarrhythmic drug, E-4031, also was studied in this model. These studies aimed to define the mechanism of action of putative profibrillatory actions of pinacidil and the mechanism for the antifibrillatory effect of the class III antiarrhythmic drug, E-4031, in the hypoxic heart. After stabilization and determination of baseline functional parameters under normoxic perfusion conditions (95% O2/5% CO2), hearts were subjected to global hypoxia by switching to a 95% N2/5% CO2 saturated perfusion medium for a period of 12 min. After the hypoxic period, normoxia was re-established by switching to the oxygen-carbon dioxide saturated buffer medium for a period of 40 min. The oxygen tension of the perfusion buffer was reduced from approximately 400 mm Hg to below 50 mm Hg during the hypoxic period. All hearts subjected to hypoxia had reduced function: the left ventricular developed pressure and +/- dP/dt were reduced significantly. Myocardial tissue ATP concentrations were reduced (> 50%) in hearts subjected to hypoxia. Under conditions of hypoxic/reoxygenation and in the presence of a low (2.5 mM) potassium concentration ([K+]0), pinacidil (1.25 microM) facilitated the induction of ventricular fibrillation (80% fibrillation in the presence of pinacidil vs. 20% in the absence of pinacidil). Glyburide (10 microM) and E-4031 (1 and 10 microM) significantly reduced the incidence of ventricular fibrillation associated with pinacidil (20% fibrillation in the presence of hypoxia, pinacidil, and glyburide or 10 microM E-4031). Opening of the ATP-dependent K+ channel by pinacidil under normoxia and low K+ also facilitated the induction of ventricular fibrillation (60% ventricular fibrillation). Pinacidil failed to induce ventricular fibrillation under either normoxic or conditions of hypoxic/reoxygenation when the [K+]0 was increased to 5.1 mM. The results of this study demonstrate that K+ channel activators facilitate the induction of ventricular fibrillation under both normoxic conditions and conditions of hypoxic/reoxygenation when the perfusion buffer K+ concentration is reduced.
我们研究了ATP依赖性钾通道拮抗剂格列本脲和ATP依赖性钾通道激动剂吡那地尔对离体兔心脏Langendorff灌注模型在经历一段整体缺氧时的影响。还在该模型中研究了Ⅲ类抗心律失常药物E - 4031。这些研究旨在确定吡那地尔可能的促心律失常作用机制以及Ⅲ类抗心律失常药物E - 4031在缺氧心脏中的抗心律失常作用机制。在常氧灌注条件（95% O₂/5% CO₂）下稳定并测定基线功能参数后，通过切换至95% N₂/5% CO₂饱和灌注培养基12分钟使心脏经历整体缺氧。缺氧期过后，通过切换至氧 - 二氧化碳饱和缓冲培养基40分钟重新建立常氧状态。在缺氧期，灌注缓冲液的氧张力从约400 mmHg降至50 mmHg以下。所有经历缺氧的心脏功能均降低：左心室舒张末压以及±dP/dt显著降低。经历缺氧的心脏中，心肌组织ATP浓度降低（>50%）。在缺氧/复氧条件下且钾浓度（[K⁺]₀）较低（2.5 mM）时，吡那地尔（浓度为1.25 μM）促进室颤的诱发（存在吡那地尔时80%发生室颤，不存在吡那地尔时为20%）。格列本脲（10 μM）和E - 4031（1 μM和10 μM）显著降低与吡那地尔相关的室颤发生率（存在缺氧、吡那地尔以及格列本脲或10 μM E - 4031时20%发生室颤）。在常氧和低钾条件下，吡那地尔使ATP依赖性钾通道开放也促进室颤的诱发（60%发生室颤）。当[K⁺]₀增加至5.1 mM时，吡那地尔在常氧或缺氧/复氧条件下均未能诱发室颤。本研究结果表明，当灌注缓冲液中钾浓度降低时，钾通道激活剂在常氧条件以及缺氧/复氧条件下均促进室颤的诱发。
