Dar M S
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27834.
Eur J Pharmacol. 1989 May 19;164(2):303-13. doi: 10.1016/0014-2999(89)90471-8.
Dilazep (i.p.), a coronary vasodilator and an uptake inhibitor of adenosine, dose dependently potentiated acute ethanol-induced motor incoordination in mice. In view of peripheral cardiovascular depressive effects of dilazep, the effect of i.c.v. dilazep (25, 50 and 75 micrograms), and its metabolites, 1,4-bis(3-hydroxypropyl)perhydro-1,4-diazepine (BHPD) (15, 31 and 62 micrograms) and 1-[3-(3,4,5-trimethoxybenzoyloxy)propyl]perhydro-1,4-diazepine (TBPD) (62 and 125 micrograms) on ethanol-induced motor incoordination was studied. Dose-related potentiation of ethanol-induced motor incoordination was noted with dilazep and its metabolites. Whereas dilazep (i.p.) produced no apparent central nervous system (CNS) effects, by i.c.v. route, it caused CNS excitation including tonic-clonic seizures. Adenosine uptake inhibition, Ca2+ entry blockade or direct activation of adenosine receptors was ruled out as the possible mechanism of seizures because dipyridamole, verapamil or N6-(2-phenylisopropyl)-adenosine (R-PIA) administered i.c.v., while potentiating ethanol (i.p.)-induced motor incoordination did not produce seizures. The CNS excitation was minimal with BHPD and none with TBPD. Theophylline pretreatment partially blocked potentiation of ethanol-induced motor incoordination by dilazep and BHPD and not by TBPD. The data suggest dilazep-induced potentiation of ethanol-induced motor incoordination is partially due to central adenosine receptor mechanism and partly due to other yet unknown mechanism(s) and further supported our earlier reports about adenosine involvement in the CNS effects of ethanol. The data also suggest that dilazep (i.c.v.)-induced seizures are due to mechanism(s) other than adenosine uptake inhibition, Ca2+ entry blockade or direct adenosine receptor activation.
双嘧达莫（腹腔注射）是一种冠状血管扩张剂和腺苷摄取抑制剂，它能剂量依赖性地增强急性乙醇诱导的小鼠运动不协调。鉴于双嘧达莫对外周心血管的抑制作用，研究了脑室内注射双嘧达莫（25、50和75微克）及其代谢产物1,4 - 双（3 - 羟丙基）全氢 - 1,4 - 二氮杂卓（BHPD）（15、31和62微克）以及1 - [3 - （3,4,5 - 三甲氧基苯甲酰氧基）丙基]全氢 - 1,4 - 二氮杂卓（TBPD）（62和125微克）对乙醇诱导的运动不协调的影响。观察到双嘧达莫及其代谢产物与乙醇诱导的运动不协调呈剂量相关的增强作用。腹腔注射双嘧达莫未产生明显的中枢神经系统（CNS）效应，但通过脑室内途径给药会引起CNS兴奋，包括强直阵挛性惊厥。由于脑室内注射双嘧达莫、维拉帕米或N6 - （2 - 苯异丙基） - 腺苷（R - PIA）在增强乙醇（腹腔注射）诱导的运动不协调时未引发惊厥，因此排除了腺苷摄取抑制、Ca2 + 内流阻断或腺苷受体直接激活作为惊厥可能机制的可能性。BHPD引起的CNS兴奋最小，而TBPD未引起CNS兴奋。茶碱预处理部分阻断了双嘧达莫和BHPD对乙醇诱导的运动不协调的增强作用，但未阻断TBPD的增强作用。数据表明，双嘧达莫诱导的乙醇诱导运动不协调的增强部分归因于中枢腺苷受体机制，部分归因于其他未知机制，这进一步支持了我们早期关于腺苷参与乙醇中枢神经系统效应的报道。数据还表明，脑室内注射双嘧达莫引起的惊厥是由腺苷摄取抑制、Ca2 + 内流阻断或腺苷受体直接激活以外的机制引起的。
