Selective inhibition by mepacrine of the release of “rabbit aorta contracting substance” evoked by the administration of bradykinin
Selective inhibition by mepacrine of the release of “rabbit aorta contracting substance” evoked by the administration of bradykinin
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Mepacrine 选择性抑制缓激肽给药引起的“兔主动脉收缩物质”的释放
DOI：
10.1111/j.2042-7158.1972.tb08953.x
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发表时间：
1972
影响因子：
3.3
通讯作者：
N. D. Hai
中科院分区：
文献类型：
--
作者：
B. Vargaftig;N. D. Hai
动脉内注射缓激肽或花生四烯酸至豚鼠离体肺，流出液中出现“兔主动脉收缩物质”（RCS）。RCS的形成可被非甾体酸性抗氧化剂药物（Piper & Vane，1969; Vargaftig & Dao Hai，1971）和各种巯基和抗氧化剂（Vargaftig & Dao Hai，1972）阻断。RCS与前列腺素（PG）F，a和E，a不同，间接证据表明它们的环过氧化物前体与RCS的活性有关（Gryglewski & Vane，1971）。酰基水解酶的活化是触发最终导致PG合成的事件链的必要条件，除非直接提供脂肪酸前体如花生四烯酸，从而缩短反应。触发酶是磷脂酶A（磷脂酰基水解酶，EC 3.1）的证据。1.4.）Kunze &沃格特（1970）对此进行了总结。我们已经验证了这样的假设，即缓激肽和花生四烯酸作用于最终导致RCS形成的反应链的不同临界点：有证据表明抗炎和抗疟疾剂米帕林阻断缓激肽释放RCS，但当使用花生四烯酸时无效，如前所述测试RCS从分离的灌注豚鼠肺的释放（Vargaftig & Dao Hai，1971）通过修改Piper & Vane（1969）的方法。用含有去甲肾上腺素、5-羟色胺和乙酰胆碱拮抗剂（酚苄明，lo-1;麦角新碱和阿托品，g升-1）的Krebs溶液以10 ml/min的流速灌注豚鼠肺。流出物灌注一系列离体器官：兔主动脉和肺动脉，以检测RCS，以及大鼠胃条，以检测胰头素。器官收缩和支气管压力通过Grass No.7多导生理记录仪上的适当传感器记录。使用了以下药物：花生四烯酸（Mann Research Labs）;缓激肽和麦角新碱（Sandoz）;苯氧苄明（Smith Kline & French）和PGF，ct（由Dr. A.货车Dorp，Unilever，荷兰）;二盐酸米帕林（Rhone Poulenc）。通过肺动脉将花生四烯酸（10-20 μ g）注射到5只离体豚鼠肺中。随后在灌注液中出现RCS活性，其不受用含有米帕林（20 μ g/ml）的Krebs溶液灌注肺10分钟的影响，而将10 μ g缓激肽注射到5只豚鼠肺中后的RCS活性被完全阻断。用不含米帕林的Krebs溶液灌注30分钟导致缓激肽释放RCS完全恢复（图1）。为了确定作用部位，将米帕林直接灌注在器官级联上，绕过肺。在这种情况下，由缓激肽释放的RCS明显不受影响，表明阻滞发生在肺水平。由缓激肽引起的RCS释放时，而不是由花生四烯酸引起时，由米帕林的抑制是迄今为止报道的这种选择性抑制的第一个例子。RCS是一种前列腺素前体，可能是环状过氧化物（Gryglewski & Vane，1971），需要激活酰基水解酶（如磷脂酶A）才能释放（Kunze &沃格特，1970）。花生四烯酸的施用缩短了酶的活化，直接提供了PGF α和PGE α形成的识别底物（Anggard & Samuelsson，1965）。美克灵显示器
Intra-arterial injection of bradykinin or of arachidonic acid to guinea-pig isolated lungs is followed by the appearance in the effluent of “rabbit aorta contracting substance”(RCS). Formation of RCS is blocked by nonsteroidal acidic antiinflammatory drugs (Piper & Vane, 1969; Vargaftig & Dao Hai, 1971) and by various sulfhydryl and antioxidant agents (Vargaftig & Dao Hai, 1972). RCS has been distinguished from prostaglandin (PG) F, a and E,, and indirect evidence suggests that their cyclic peroxide precursor is related with the activity of RCS (Gryglewski & Vane, 1971). Activation of an acylhydrolase is a necessary requirement for the triggering of the chain of events that ultimately leads to PG synthesis, except when the fatty acid precursor, as arachidonic acid, is directly provided, thus shortcutting the reaction. Evidence that the triggering enzyme is phospholipase A (phosphatide acylhydrolase, EC 3.1. 1.4.) has been summarized by Kunze & Vogt (1970). We have tested the hypothesis that bradykinin and arachidonic acid act at different critical points of the chain of reactions leading ultimately to RCS formation: evidence that the anti-inflammatory and antimalarial agent mepacrine blocks the release of RCS by bradykinin, but is ineffective when arachidonic acid is used, is provided as follows.Release of RCS from isolated perfused guinea-pig lungs was tested as previously described (Vargaftig & Dao Hai, 1971) by a modification of the method of Piper & Vane (1969). Guinea-pig lungs were perfused with Krebs solution containing antagonists to noradrenaline, 5-hydroxytryptamine and acetylcholine (phenoxybenzamine, lo-’; methysergide and atropine, g litre-l), at a flow of 10 ml/min. The effluent superfused a cascade of isolated organs: rabbit aorta and pulmonary artery, to detect RCS, and a strip of rat stomach, to detect prostaglandins. Organ contractions and bronchial pressure were recorded through appropriate transducers on a Grass No. 7 Polygraph. The following drugs were used: arachidonic acid (Mann Research Labs); bradykinin and methysergide (Sandoz); phenoxybenzamine (Smith Kline & French) and PGF, ct (provided by Dr. A. van Dorp, Unilever, The Netherlands); mepacrine dihydrochloride (Rhone Poulenc). Arachidonic acid (10-20 pg) was injected through the pulmonary artery into five isolated guinea-pig lungs. This was followed by the appearance in the perfusate of RCS activity, which was unaffected by a 10 min perfusion of the lung with Krebs solution containing mepacrine (20 pg/ml), whereas the RCS activity which followed the injection of 10 pg of bradykinin into five guinea-pig lungs was completely blocked. A thirty min perfusion with mepacrine-free Krebs solution resulted in complete recovery for the release of RCS by bradykinin (Fig. 1). To ascertain the site of action, mepacrine was directly superfused upon the organ cascade, by-passing the lungs. Under such conditions, RCS released by bradykinin was clearly unaffected, showing that blockade occurs at the pulmonary level. Suppression by mepacrine of the release of RCS when evoked by bradykinin but not when evoked by arachidonic acid is the first example of such a selective inhibition reported up to now. RCS is a prostaglandin precursor, probably the cyclic peroxide (Gryglewski & Vane, 1971) which requires the activation of an acylhydrolase, as phospholipase A, to be set free (Kunze & Vogt, 1970). Administration of arachidonic acid shortcuts the enzyme activation, directly providing the recognized substrate for PGF, a and for PGE, formation (Anggard & Samuelsson, 1965). Mepacrine displays