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首页> 美国卫生研究院文献>British Journal of Pharmacology and Chemotherapy >Left regional cardiac perfusion in vitro with platelet-activating factor norepinephrine and K+ reveals that ischaemic arrhythmias are caused by independent effects of endogenous ‘mediators facilitated by interactions and moderated by paradoxical antagonism
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Left regional cardiac perfusion in vitro with platelet-activating factor norepinephrine and K+ reveals that ischaemic arrhythmias are caused by independent effects of endogenous ‘mediators facilitated by interactions and moderated by paradoxical antagonism

机译：体外用血小板活化因子去甲肾上腺素和K +进行的左区心脏灌注显示缺血性心律不齐是由内源性介体的独立作用引起的这种介导作用是通过相互作用促进的并由矛盾的拮抗作用减轻

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class="enumerated" style="list-style-type:decimal">Various putative drug targets for suppression of ischaemia-induced ventricular fibrillation (VF) have been proposed, but therapeutic success in the suppression of sudden cardiac death (SCD) has been disappointing. Platelet-activating factor (PAF) is a known component of the ischaemic milieu. We examined its arrhythmogenic activity, and its interaction with two other putative mediators, norepinephrine and K+, using an ischaemia-free in vitro heart bioassay, and a specific PAF antagonist (BN-50739).PAF (0.1–100 nmol) was administered selectively to the left coronary bed of rat isolated hearts using a specially designed catheter. In some hearts, PAF was administered to the left coronary bed during concomitant regional perfusion with norepinephrine and/or K+. In separate studies, PAF accumulation in the perfused cardiac tissue was evaluated using 3H-PAF.PAF evoked ventricular arrhythmias concentration-dependently (P<0.05). It also widened QT interval and reduced coronary flow selectively in the PAF-exposed left coronary bed (both P<0.05). Two exposures of hearts to PAF were necessary to evoke the QT and rhythm effects.The PAF-induced arrhythmias and coronary vasoconstriction were partially suppressed by the PAF antagonist BN-50739 (10 μM), although BN-50739 itself widened QT interval.K+ (8 and 15 mM) unexpectedly antagonised the arrhythmogenic effects of PAF without itself eliciting arrhythmias (P<0.05). Norepinephrine (0.1 μM) had little or no effect on the actions of PAF, while failing to evoke arrhythmias itself. Nevertheless, the combination of 15 mM K+ and 0.1 μM norepinephrine evoked arrhythmias of a severity similar to arrhythmias evoked by PAF alone, without adding to or diminishing the arrhythmogenic effects of PAF.3H-PAF accumulated in the cardiac tissue, with 43±5% still present 5 min after bolus administration, accounting for the need for two exposures of the heart to PAF for evocation of arrhythmias.Thus, PAF, by activating specific receptors in the ventricle, can be expected to contribute to arrhythmogenesis during ischaemia. However, its interaction with other components of the ischaemic milieu is complex, and selective block of its actions (or its accumulation) in the ischaemic milieu is alone unlikely to reduce VF/SCD.
机译：class =“ enumerated” style =“ list-style-type：decimal”> <！-list-behavior =枚举前缀-word = mark-type = decimal max-label-size = 0-> 已经提出了多种用于抑制局部缺血引起的心室纤颤（VF）的假定药物靶标，但是在抑制突发性心脏死亡（SCD）方面的治疗成功令人失望。血小板活化因子（PAF）是缺血环境的已知成分。我们使用无局部缺血的体外心脏生物测定法和一种特定的PAF拮抗剂（BN-50739）检查了它的心律失常活性，以及​​与其他两种假定的介导物去甲肾上腺素和K + 的相互作用。使用专门设计的导管，将li> PAF（0.1– 100 nmol）选择性给药于大鼠离体心脏的左冠状动脉。在一些心脏中，在同时进行去甲肾上腺素和/或K + 的区域灌注时，将PAF施用至左冠状动脉床。在单独的研究中，使用 3 H-PAF评估灌注的心脏组织中的PAF积累。PAF引起的室性心律失常浓度依赖性（P <0.05）。它也扩大了QT间期并选择性地减少了暴露于PAF的左冠状动脉冠状动脉血流（两者均P <0.05）。心脏需要两次暴露于PAF才能引起QT和节律作用。 PAF拮抗剂BN-50739（10μM）可以部分抑制PAF引起的心律不齐和冠状动脉收缩，尽管BN-50739 K + （8和15 mM）意外地拮抗了PAF的心律失常作用，而没有引起心律不齐（P <0.05）。去甲肾上腺素（0.1μM）对PAF的作用影响很小或没有作用，而没有引起心律不齐本身。尽管如此，15 mM K + 和0.1μM去甲肾上腺素的组合引起的心律失常的严重程度与仅由PAF引起的心律失常相似，而不会增加或减少PAF的心律失常作用。
  • 3 H-PAF累积在心脏组织中，大剂量给药5分钟后仍存在43±5％，这说明需要两次将心脏暴露于PAF才能诱发心律不齐。

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