Elliott G R, Braquet P, van Batenburg M, Bonta I L
Biochim Biophys Acta. 1985 Dec 4;837(3):213-21. doi: 10.1016/0005-2760(85)90044-x.
Altering the buffer K+/Na+ ratio ([K+]o/[Na+]o) resulted in a biphasic change in the basal release of prostaglandin E2, 6-ketoprostaglandin F1 alpha (the stable breakdown product of prostaglandin I2) and thromboxane B2 (the stable metabolite of thromboxane A2), from resident rat peritoneal macrophages. Changing the [K+]o (at the expense of [Na+]o) from 15 mM to 0 mM or 75 mM (combined concentration of [K+]o and [Na+]o was maintained at 150 mM) resulted in a stimulation of 6-ketoprostaglandin F1 alpha and thromboxane B2 release. Prostaglandin E2 synthesis was also stimulated when the [K+]o was decreased from 15 mM to 0 mM. When the [K+]o was increased to 45 mM, prostaglandin E2 formation was inhibited but returned to values observed at 15 mM K+ when the [K+]o was further increased to 75 mM. Prostaglandin E2 synthesis at 75 mM K+ was still only 40% of that measured in the absence of K+, however. When cells were incubated in a Ca2+-free medium (+EDTA) eicosanoid release was drastically reduced and the changes in arachidonic acid metabolite release observed on changing the buffer [K+]o/[Na+]o were abolished. Total release of radiolabel ([14C]arachidonic acid and its radiolabelled metabolites) from macrophages prelabelled with [14C]arachidonic acid followed the same pattern as basal eicosanoid release, suggesting that changing [K+]o influenced phospholipase A2 activity, and hence, substrate availability. At all [K+]o values, from 0 mM to 75 mM, cicletanide reduced the release of radioactivity from macrophages prelabelled with [14C]arachidonic acid (by about 15%). In the presence of [K+]o, cicletanide had a stimulatory effect on the metabolism of the free fatty acid which masked the decrease in eicosanoid release expected due to inhibition of arachidonic acid release from phospholipid. In the presence of 5 mM K+, cicletanide inhibited the basal release but enhanced the arachidonic acid-stimulated synthesis of eicosanoids from resident macrophages in a dose-related fashion, confirming the dual action of the drug, i.e., the inhibitory effect on arachidonic acid release and the stimulation of arachidonic acid metabolism. The possible in vivo significance of these results is discussed.
改变缓冲液中钾离子/钠离子比例（[K⁺]ₒ/[Na⁺]ₒ）会导致大鼠腹膜常驻巨噬细胞中前列腺素E₂、6-酮前列腺素F₁α（前列腺素I₂的稳定分解产物）和血栓素B₂（血栓素A₂的稳定代谢产物）的基础释放出现双相变化。将[K⁺]ₒ（以[Na⁺]ₒ为代价）从15 mM改变为0 mM或75 mM（[K⁺]ₒ和[Na⁺]ₒ的总浓度维持在150 mM）会刺激6-酮前列腺素F₁α和血栓素B₂的释放。当[K⁺]ₒ从15 mM降至0 mM时，前列腺素E₂的合成也会受到刺激。当[K⁺]ₒ增加到45 mM时，前列腺素E₂的形成受到抑制，但当[K⁺]ₒ进一步增加到75 mM时，又恢复到在15 mM K⁺时观察到的值。然而，在75 mM K⁺时前列腺素E₂的合成仍仅为无钾时测量值的40%。当细胞在无钙培养基（+EDTA）中孵育时，类花生酸释放急剧减少，并且在改变缓冲液[K⁺]ₒ/[Na⁺]ₒ时观察到的花生四烯酸代谢产物释放的变化也消失了。用[¹⁴C]花生四烯酸预标记的巨噬细胞中放射性标记物（[¹⁴C]花生四烯酸及其放射性标记代谢产物）的总释放与基础类花生酸释放遵循相同模式，表明改变[K⁺]ₒ会影响磷脂酶A₂的活性，从而影响底物的可用性。在所有[K⁺]ₒ值（从0 mM到75 mM）下，环氯噻嗪可减少用[¹⁴C]花生四烯酸预标记的巨噬细胞中放射性的释放（约15%）。在有[K⁺]ₒ存在的情况下，环氯噻嗪对游离脂肪酸的代谢有刺激作用，这掩盖了由于抑制花生四烯酸从磷脂中释放而预期的类花生酸释放减少。在5 mM K⁺存在的情况下，环氯噻嗪抑制基础释放，但以剂量相关的方式增强了花生四烯酸刺激的常驻巨噬细胞中类花生酸的合成，证实了该药物的双重作用，即对花生四烯酸释放的抑制作用和对花生四烯酸代谢的刺激作用。讨论了这些结果可能的体内意义。
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