Abdel-Latif A A, Smith J P, Akhtar R A
Biochem Pharmacol. 1983 Dec 15;32(24):3815-21. doi: 10.1016/0006-2952(83)90154-5.
We have investigated the effects and mechanism of action of propranolol and mepacrine, two drugs with local anesthetic-like properties, on phospholipid metabolism in rabbit iris and iris microsomal and soluble fractions. In the iris, propranolol, like mepacrine [A. A. Abdel-Latif and J. P. Smith, Biochim, biophys. Acta 711, 478 (1982)], stimulated the incorporation of [14C]arachidonic acid ( [14C]AA) into phosphatidic acid (PA), CDP-diacylglycerol (CDP-DG), phosphatidylinositol (PI), the polyphosphoinositides (poly PI) and DG, and it inhibited that of phosphatidylcholine (PC), phosphatidylethanolamine (PE), triacylglycerol (TG) and the prostaglandins. Similarly, mepacrine, like propranolol [A. A. Abdel-Latif and J. P. Smith, Biochem. Pharmac. 25, 1697 (1976)], altered the incorporation of [14C]oleic acid, [3H]glycerol, 32Pi and [14C]choline into glycerolipids of the iris. Time-course studies in iris muscle prelabeled with [14C]AA showed an initial decrease in the production of DG and a corresponding increase in that of PA by the drugs, followed by an increase in accumulation of DG at longer time intervals (60-90 min). The above findings are in accord with the hypothesis that these drugs redirect glycerolipid synthesis by inhibiting PA phosphohydrolase. Propranolol and mepacrine stimulated the activities of DG kinase and phosphoinositide kinases and inhibited that of DG cholinephosphotransferase. The drugs had little effect on the activity of DG acyltransferase. It is concluded that propranolol and mepacrine redirect glycerolipid metabolism in the iris by exerting multiple effects on the enzymes involved in phospholipid biosynthesis. We suggest that these drugs could exert their local anesthetic-like effects by effecting an increase in the synthesis of the acidic phospholipids (PA, PI and the poly PI) and subsequently the binding of Ca2+- to the cell plasma membrane.
我们研究了普萘洛尔和米帕林这两种具有局部麻醉样特性的药物对兔虹膜、虹膜微粒体及可溶性组分中磷脂代谢的影响及其作用机制。在虹膜中，普萘洛尔与米帕林一样 [A. A. 阿卜杜勒 - 拉蒂夫和J. P. 史密斯，《生物化学与生物物理学学报》711, 478 (1982)]，刺激了[14C]花生四烯酸([14C]AA)掺入磷脂酸(PA)、CDP - 二酰甘油(CDP - DG)、磷脂酰肌醇(PI)、多磷酸肌醇(poly PI)和二酰甘油(DG)，并抑制了其掺入磷脂酰胆碱(PC)、磷脂酰乙醇胺(PE)、三酰甘油(TG)和前列腺素。同样，米帕林与普萘洛尔一样 [A. A. 阿卜杜勒 - 拉蒂夫和J. P. 史密斯，《生物化学药理学》25, 1697 (1976)]，改变了[14C]油酸、[3H]甘油、32Pi和[14C]胆碱掺入虹膜甘油脂质的情况。对预先用[14C]AA标记的虹膜肌肉进行的时间进程研究表明，这些药物最初使DG的生成减少，同时PA的生成相应增加，随后在较长时间间隔(60 - 90分钟)时DG的积累增加。上述发现符合这些药物通过抑制PA磷酸水解酶来重新引导甘油脂质合成的假说。普萘洛尔和米帕林刺激了DG激酶和磷酸肌醇激酶的活性，并抑制了DG胆碱磷酸转移酶的活性。这些药物对DG酰基转移酶的活性影响很小。得出的结论是，普萘洛尔和米帕林通过对参与磷脂生物合成的酶产生多种作用来重新引导虹膜中的甘油脂质代谢。我们认为，这些药物可能通过增加酸性磷脂(PA、PI和poly PI)的合成，随后使Ca2 +与细胞质膜结合，从而发挥其局部麻醉样作用。
