Baker Kathryn E, Curtis Michael J
Cardiovascular Research, Rayne Institute, St. Thomas' Hospital, London SE17EH, UK.
Br J Pharmacol. 2004 May;142(2):352-66. doi: 10.1038/sj.bjp.0705767. Epub 2004 Apr 5.
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 (3)H-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 microm), 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 microm) 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 microm norepinephrine evoked arrhythmias of a severity similar to arrhythmias evoked by PAF alone, without adding to or diminishing the arrhythmogenic effects of PAF. (3)H-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.
人们已经提出了多种用于抑制缺血性室颤（VF）的假定药物靶点，但在抑制心脏性猝死（SCD）方面的治疗效果却不尽人意。血小板活化因子（PAF）是缺血环境中一种已知的成分。我们使用无缺血的体外心脏生物测定法和一种特异性PAF拮抗剂（BN - 50739），研究了其致心律失常活性及其与另外两种假定介质去甲肾上腺素和K⁺的相互作用。使用专门设计的导管将PAF（0.1 - 100 nmol）选择性地注入大鼠离体心脏的左冠状动脉床。在一些心脏中，在同时用去甲肾上腺素和/或K⁺进行区域灌注时，将PAF注入左冠状动脉床。在单独的研究中，使用³H - PAF评估灌注心脏组织中PAF的蓄积情况。PAF浓度依赖性地诱发室性心律失常（P < 0.05）。它还使QT间期延长，并选择性地减少PAF暴露的左冠状动脉床的冠状动脉血流（两者P < 0.05）。心脏需要两次暴露于PAF才能引发QT和节律效应。PAF拮抗剂BN - 50739（10 μmol）部分抑制了PAF诱导的心律失常和冠状动脉收缩，尽管BN - 50739本身会使QT间期延长。K⁺（8和15 mmol）出人意料地拮抗了PAF的致心律失常作用，而其本身不会引发心律失常（P < 0.05）。去甲肾上腺素（0.1 μmol）对PAF的作用几乎没有影响，同时其本身也不会诱发心律失常。然而，15 mmol K⁺和0.1 μmol去甲肾上腺素的组合诱发的心律失常严重程度与单独PAF诱发的心律失常相似，既不增强也不减弱PAF的致心律失常作用。³H - PAF在心脏组织中蓄积，推注给药5分钟后仍有43±5%存在，这解释了心脏需要两次暴露于PAF才能诱发心律失常。因此，通过激活心室中的特异性受体，PAF有望在缺血期间促进心律失常的发生。然而，它与缺血环境中其他成分的相互作用很复杂，仅选择性阻断其在缺血环境中的作用（或其蓄积）不太可能降低VF/SCD。
