左旋千金藤立定对大鼠纹状体缺血性损伤的拮抗作用

AIM: To elucidate the protection of l-stepholidine (SPD) on neuronal morphology and function against the striatal ischemic injury in rat. METHODS: The forebrain ishemia to Sprague Dawley rats was induced with four-vessel occlusion. Histological examination was performed on the dorsolateral striatum with cresylviolet stain. In striatal slices of rat as an in vitro ischemic model, the activity of calcium/calmodulin-dependent protein kinase II (CCDPK) and lactate dehydrogenase (LDH) was examined by the method of 32P-incorporation and colorimetry, respectively. RESULTS: In the SPD-treated groups, most of the neurons in the striatum kept the normal morphological appearance after 30-min ischemia followed by 6-h or 12-h reperfusion. The number of neurons was much more in SPD groups than that in vehicle group. The sparse and abnormal neurons were observed in the vehicle group. SPD attenuated the ischemic effect on the CCDPK activity in striatal slices. In addition, SPD inhibited the leakage of LDH from neurons induced by ischemia in incubated striatal slices. CONCLUSION: SPD protected striatal neurons against ischemic injury and antagonized the inhibitory action on CCDPK activity induced by ischemia. SPD reduced the leakage of LDH from striatal neurons induced by ischemia.     

左旋千金藤立定对大鼠阻力动脉的松弛作用

应用离体阻力动脉技术,研究了左旋千金藤立定(l-stepholidine,l-SPD)对离体阻力动脉的松弛作用。l-SPD对KCl(125mmol·L^-1)引起的心、肾、脑、肠系膜的阻力动脉收缩均有松弛作用,其中以脑阻力动脉的松弛作用为最弱,-Log EC₅₀值为4.25±0.22;对肠系膜阻力动脉的松弛作用为最强,-Log EC₅₀值为4.76±0.15。上述结果提示,l-SPD直接松弛内脏阻力动脉、降低外周阻力,可能是其产生降压作用的一个机制。     

左旋千金藤立定对大鼠血清中催乳素水平的影响

目的：观察左旋千金藤立定（ＳＰＤ）对血清催乳素（ＰＲＬ）水平的影响，研究ＳＰＤ的药理作用，方法：成熟♀鼠ｉｐ多巴胺受体激动剂，拮抗剂或ＳＰＤ后断头取血，然后用放射免疫法测定血清中的催乳素水平。结果：ＳＰＤ引起血清ＰＲＬ水平迅速而显著的增增加，效应持续效约１ｈ，具有剂量依赖性，ＳＰＤ的半数有效剂量为３．７ｍｇ．ｋｇ＾－１（９５％可信限为２．６－４．３ｍｇ．ｋｇ＾－１）剂量为２０ｍｇ．ｋｇ＾－１时产生     

慢性给予左旋千金藤立定对纹状体多巴胺D1和D2受体密度和更新…

目的：观察慢性给予左旋千金藤立定（ＳＰＤ）对纹状体多巴胺（ＤＡ）受体密度和更新率的影响，推论ＳＰＤ的药理性质。方法：应用ＥＥＤＱ失活ＤＡ受体，用放射受体结合分析法测定受体的密度，计算有关的动力学参数。结果：慢性给予ＳＰＤ２１ｄ便纹状体Ｄ１与Ｄ２受体密度分别增加４１．５％和４３．７％。并且慢性给予ＳＰＤ改变ＤＡ受体的更新率，使Ｄ１受体的生成速度由对照组的１．７７ｐｍｏｌ·ｈ＾－１／ｇ ｐｒｏｔｅｉｎ     

左旋千金藤立定对大鼠血清中催乳素水平的影响(英文)

目的:观察左旋千金藤立定(SPD)对血清催乳素(PRL)水平的影响,研究SPD的药理作用。方法:成熟♀鼠ip多巴胺受体激动剂、拮抗剂或SPD后断头取血,然后用放射免疫法测定血清中的催乳素水平。结果:SPD引起血清PRL水平迅速而显著的增加,效应持续约1h,具有剂量依赖性。SPD的半数有效剂量为3.7mg·kg~(-1)(95％可信限为2.6—4.3mg·kg~(-1))。剂量为20mg·kg~(-1)时产 生最大效应,使血清PRL水平达到448±64μg·L~(-1),0.2mg·kg~(-1)则无效。对于多巴胺受体激动剂培高利特(pergolide)引起的PRL水平低下,SPD5mg·kg~(-1)有部分对抗作用,10mg·kg~(-1)能够完全对抗。结论:SPD是D_2多巴胺受体拮抗剂。     

Effects of （-）-stepholidine on NMDA receptors： comparison with haloperidol and clozapine

Aim： To examine whether （-）-stepholidine （SPD） has a direct effect on the N- methyl-D-aspartic acid receptors （NMDAR） containing the NMDA receptor subunits NR2A or NR2B and to compare its effect with those of haloperidol （Hal） and clozapine （Cloz）. Methods： NMDAR was transiently expressed in human embryonic kidney 293 （HEK293） cells. Changes in intracellular calcium concentration （[Ca^2＋]i） induced by NMDAR activation were monitored with Fura-2 ratio imaging techniques. Results： SPD had no significant effects on either subunit of NMDAR at a concentration of less than 100 μmol/L. Hal selectively inhibited NMDAR containing the NR2B subunit, whereas Cloz inhibited both subunits of NMDAR. Although both Hal and Cloz inhibited NRI a/NR2B receptor-mediated Ca^2＋ influx, their effects were different. Hal was more potent and had a faster peak effect than Cloz. Conclusion： Both Hal and Cloz inhibit NMDAR-mediated function, whereas SPD produced only a little inhibition at a high concentration. Based on our other studies, the modulation of SPD on NMDAR function may be via D1 receptor action underlying an indirect mechanism.     

左旋千金藤立定加强尾核脑片多巴胺释放(英文)

观察左旋千金藤立定((-)-stepholidine,SPD)对家兔尾核脑片多巴胺(DA)释放的影响.方法:以[~3H]DA预孵脑片,测定DA放射性.结果:选择性D_2受体激动剂LY171555以剂量依赖方式抑制电诱发的兔尾核脑片[~3H]DA释放.SPD可翻转LY 171555对[~3H]DA释放的抑制作用,并以剂量依赖方式加强[~3H]DA释放,在无电刺激条件下,SPD诱发大鼠尾核[~3H]DA释放被蛋白激酶C(protein kinase C,PKC)激活剂咐波酯所加强.结论:SPD对突触前D_2自身受体是阻滞剂.     

Pharmacokinetic evaluation of (-)-6-aminocarbovir as a prodrug for (-)-carbovir in rats.

The recently synthesized carbocyclic 2',3'-didehydro-2',3'-dideoxy-6-deoxy-6-amino-guanosine [(-)6AC] was evaluated as a prodrug for carbovir, carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine [(-)CBV] in seven male Sprague-Dawley rats. A randomized three-way cross-over design was used. Rats were assigned to receive the following treatments: a 20 mg/kg (-)6AC infusion, 40 mg/kg (-)6AC orally, and a 20 mg/kg (-)CBV infusion. Blood samples were collected over 480 min, and urine was collected for up to 48 hr. A 2- to 3-day washout period was observed between treatments. Following i.v. infusion, (-)6AC concentrations in the blood declined rapidly in a monoexponential pattern with an elimination half-life of 11.3 +/- 3.3 min (mean +/- SD, n = 7). The time-averaged total body clearance was 115.7 +/- 32.6 ml/min/kg. The fraction of the dose excreted unchanged in urine was 0.28 +/- 0.06. The fraction of the (-)6AC dose metabolized to (-)CBV was 0.48 +/- 0.14. Following oral administration of (-)6AC, the bioavailability of (-)CBV was 46.2 +/- 9.9% (n = 6) in comparison with the bioavailability of approximately 20% previously obtained after an oral dose of (-)CBV. The Cmax of (-)CBV after a 40 mg/kg oral dose of (-)6AC was 1.65 +/- 0.7 micrograms/ml as compared with the previously reported Cmax of 1.00 microgram/ml obtained after a 60 mg/kg oral dose of (-)CBV. (-)6AC has considerable potential for the improvement of the extent of absorption of (-)CBV from oral dosing.     

Pharmacokinetics of dopamine-2 agonists in rats and dogs

The absorption, protein binding, blood-to-plasma ratio, renal excretion, and pharmacokinetics of the dopamine-2 agonists (D2-agonists) 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone (1), N-(2'-hydroxy-5'-[N,N-di-n-propylaminoethylphenyl])methanesulfonamide (2), and 4-(2-di-n-propylaminoethyl)-2-(3H)-indolone (3) were examined in dogs and rats. On the basis of relative cumulative urinary recoveries of radiolabeled drug, all three compounds are well absorbed in rats and dogs. In dogs, the free fractions in plasma of unchanged 1, 2, and 3, determined by in vitro studies, were 74, 86, and 63%, respectively, and the protein binding was constant with increasing concentration. The blood-to-plasma partition ratios of the respective compounds were 1.22, 1.14, and 1.16 in dogs, and the ratios were constant with increasing concentration. Large differences between species (dogs, rats, and humans) in protein binding and blood-to-plasma ratios were not seen. The clearances (blood or plasma) of 1 and 2 in dogs were significantly greater than the clearance of 3. The clearance of 3 was almost exclusively nonrenal, whereas 13% of 1 and 2 were recovered unchanged in urine. The steady-state volumes of distribution and the distribution and elimination half-lives of the three compounds were not significantly different. Importantly, the mean residence time of 3 (147 min) in dogs was significantly longer than those of 1 (90 min) and 2 (96 min). The results of analogous studies in rats indicate that 1 and 2 are more rapidly metabolized than 3.