Clonidine inhibits the isoproterenol-induced desensitization of the beta noradrenergic activated adenylate cyclase system in astrocytes

Studies were conducted to determine if alpha agonists could influence the desensitization of the beta-noradrenergic receptor activated adenylate cyclase system. Pretreatment of astrocyte cultures with isoproterenol results in a rapid decrease in the cyclic AMP response to subsequent re-exposure to this agonist. The cyclic AMP response to isoproterenol in astrocytes pre-exposed for 2 h to isoproterenol plus clonidine was 2–3 times higher than in cells pre-exposed to isoproterenol alone. The response in astrocytes pretreated with phenylephrine plus isoproterenol was not different from that in cells pretreated with isoproterenol alone. Cyclic AMP may be involved in the effects elicited by clonidine, since this agonist can inhibit the accumulation of cyclic AMP in these cells. Also pretreatment with isobutylmethylxanthine decreases the cyclic AMP response to isoproterenol. The results suggest that clonidine can effect the desensitization of the noradrenergic receptor coupled adenylate cyclase system independent of effects on neurotransmitter release.     

可乐定镇痛与中枢Ca~(2+)的关系

用大鼠甩尾法和放射配基结合实验,探讨了可乐定镇痛与中枢Ca~(2+)的关系。CaCl_2(1μmol/rat,icv)和EGTA(0.2μmol/rat,icv)分别拮抗和增强可乐定(1mg/kg,sc)的镇痛。戊脉安(0.1μmol/rat,icy)对可乐定(1 mg/kg,sc)镇痛无明显影响,但可部分翻转CaCl_2对可乐定镇痛的拮抗。CaCl_2(1×10~(-3)mol)对[~3H]-可乐定结合无明显抑制。结果表明可乐定镇痛与脑室周围组织中Ca~(2+)浓度变化密切相关,Ca~(2+)至少部分需经对戊脉安敏感的钙通道进入细胞内方可拮抗可乐定镇痛。推沦:可乐定镇痛与神经元内Ca~(2+)有关。     

Effects of shock intensity on observed tolerance to decreased avoidance responding by clonidine

Interruption of a photobeam by rats was maintained under a Sidman avoidance schedule, and moderate response rates were maintained at low frequencies of electrical stimulation. After acute injections of clonidine, responding decreased, and frequency of electric stimulation increased, in a dose-dependent manner. At a lower intensity of electric stimulation, response-suppressive effects of clonidine did not diminish for up to 40 sessions with daily administration of clonidine. At a higher stimulus intensity, however, response-suppressive effects of clonidine diminished within 15 sessions, and stimulus frequency was at control level after 40 sessions with daily administration of clonidine. Behavioral consequences altered the effects of chronic clonidine so that tolerance was observed at a higher, but not a lower, intensity of electric stimulation.     

Effect of prolonged clonidine treatment and its withdrawal on noradrenaline turnover in the cerebral cortex and medulla oblongata of the spontaneously hypertensive rat

Summary We have investigated the effect of prolonged treatment with clonidine (delivered intravenously via osmotic minipumps, 0.5 mg-kg^–1 · 24 h^–1 for 10 days) and of withdrawal of this treatment on ingestive behaviour and on the cerebral turnover of noradrenaline in the adult spontaneously hypertensive rat (SHR). Clonidine amplified the fall in food and water intakes induced by minipump implantation. Ingestive behaviour returned to normal by the 4th to the 5th day in controls and by the 7th to the 8th day in clonidinetreated SHR. Clonidine withdrawal produced an increase in water intake above pre-implantation values. Body weight fell during clonidine treatment, then recovered slightly during withdrawal. After 5 days' treatment total DOPEG levels (an index of noradrenaline turnover) were reduced in cerebral cortex and medulla oblongata. The noradrenaline metabolite levels increased following withdrawal of drug treatment, the increase being more marked and faster in onset in cerebral cortex than in medulla oblongata. Thus prolonged treatment with clonidine decreases noradrenaline turnover and withdrawal of such treatment increases turnover. Send offprint requests to J. Atkinson at the above address     

盐酸可乐定透皮贴剂家兔体外法预测其吸收率

中枢性作用的抗高血压药盐酸可乐定、其透皮吸收制剂称为乐百事膏,用家兔体外剩余法预测其吸收率,贴药后3小时透皮吸收累计约18%、12小时约39.7%、24小时约52.79%,贴药3天后累积吸收约60.7%。由于可乐定用药量小,有效血药浓度极低,须用较精密的分析手段才能准确测出血药浓度,应用体外剩余法可间接了解透皮吸收情况。经实验证明不失为一简单而有效的方法,具有一定的参考价值。     

Comparative study between intravenous dexmedetomidine and clonidine as premedication in pediatric patients undergoing spinal anesthesia

Title

Comparative study between intravenous dexmedetomidine and clonidine as premedication in pediatric patients undergoing spinal anesthesia.

微量盐酸可乐定含量测定

目的：建立高效液相色谱法测定微量盐酸可乐定的含量的方法。方法：色谱柱：C18柱，流动相：0．22％辛烷磺酸钠-甲醇-磷酸（500：500：1），用2mol／L氨水溶液调节pH至3.0；检测波长：220nm．外标法。结果：该方法的线性范围是101μg／ml～50μg/ml，R=0．9999；平均回收率为99．7％。RSD（％）=0．13％。结论：该方法测定样品效果佳，灵敏度高，结果准确可靠。     

Differential Central NOS‐NO Signaling Underlies Clonidine Exacerbation of Ethanol‐Evoked Behavioral Impairment

Background: The molecular mechanisms that underlie clonidine exacerbation of behavioral impairment caused by ethanol are not fully known. We tested the hypothesis that nitric oxide synthase (NOS)‐derived nitric oxide (NO) signaling in the locus coeruleus (LC) is implicated in this phenomenon. Methods: Male Sprague–Dawley rats with intracisternal (i.c.) and jugular vein cannulae implanted 6 days earlier were tested for drug‐induced behavioral impairment. The latter was assessed as the duration of loss of righting reflex (LORR) and rotorod performance every 15 minutes until the rat recovered to the baseline walk criterion (180 seconds). In a separate cohort, we measured p‐neuronal NOS (nNOS), p‐endothelial NOS (eNOS), and p‐ERK1/2 in the LC following drug treatment, vehicle, or NOS inhibitor. Results: Rats that received clonidine [60 Ig/kg, i.v. (intravenous)] followed by ethanol (1 or 1.5 g/kg, i.v.) exhibited synergistic impairment of rotorod performance. Intracisternal pretreatment with nonselective NOS inhibitor N^ω‐nitro‐l ‐arginine methyl ester (l ‐NAME, 0.5 mg) or selective nNOS inhibitor N‐propyl‐l ‐arginine (1 μg) exacerbated the impairment of rotorod performance caused by clonidine–ethanol combination. Exacerbation of behavioral impairment was caused by l ‐NAME enhancement of the effect of ethanol, not clonidine. l ‐NAME did not influence blood ethanol levels; thus, the interaction was pharmacodynamic. LORR caused by clonidine (60 μg/kg, i.v.)–ethanol (1 g/kg, i.v.) combination was abolished by selective inhibition of central eNOS (l ‐NIO, 10 μg i.c.) but not by nNOS inhibition under the same conditions. Western blot analyses complemented the pharmacological evidence by demonstrating that clonidine–ethanol combination inhibits phosphorylation (activation) of nNOS (p‐nNOS) and increases the level of phosphorylated eNOS (p‐eNOS) in the LC; the change in p‐nNOS was paralleled by similar change in LC p‐ERK1/2. NOS inhibitors alone did not affect the level of nitrate/nitrite, p‐nNOS, p‐eNOS, or p‐ERK1/2 in the LC. Conclusions: Alterations in NOS‐derived NO in the LC underlie clonidine–ethanol induced behavioral impairment. A decrease in nNOS activity, due at least partly to a reduction in nNOS phosphorylation, mediates rotorod impairment, while enhanced eNOS activity contributes to LORR, elicited by clonidine–ethanol combination.     

珍菊降压片含量及均匀度测定方法研究

目的:建立一种高效液相色谱法测定珍菊降压片中盐酸可乐定的含量及均匀度。方法:采用Diamonsil(钻石)C18(200×4.6mm,5μm)色谱柱;0.05mol/L磷酸二氢钾-乙腈(80:20)为流动相;柱温35℃;流速1.0ml·min-1;检测波长210nm。结果:盐酸可乐定在1.041μg·ml-1～8.328μg·ml-1浓度范围内具有良好的线性关系,R=1.00000;平均回收率为99.99%,RSD(%)=0.68%。结论:该方法准确,可靠,重复性好,可作为珍菊降压片质量控制方法。     

可乐定对慢性神经病理性痛大鼠背根神经节GAP-43 mRNA表达的影响

目的 探讨可乐定对慢性神经病理性痛大鼠生长相关蛋白(GAP-43)mRNA表达的影响.方法 雄性成年SD大鼠36只,体重180～220 g,随机分为假手术组(S组)、慢性压迫性损伤组(CCI组)和可乐定组(CL组),每组12只.采用结扎坐骨神经法制备慢性压迫性损伤模型,S组仅暴露坐骨神经,不结扎.CL组于坐骨神经结扎术后3～14 d每天腹腔注射可乐定1 mg/kg.S组和CCI组腹腔注射生理盐水1 ml.于术前、术后3、7、14 d时测定机械痛阈和热痛阈,术后3、7、14 d测定痛阈后随机取4只大鼠断头处死,取腰段脊髓(L_(4～6))及背根神经节,采用RT-PCR法检测GAP-43 mRNA的表达水平.结果 与S组比较,CCI组和CL组术后机械痛阈和热痛阈降低,背根神经节GAP-43 mRNA表达上调(P<0.05);与CCI组比较,CL组术后7、14 d时机械痛阈和热痛阈升高,背根神经节GAP-43 mRNA表达下调(P<0.05).结论 坐骨神经结扎术后3～14 d每天腹腔注射可乐定1 mg/kg可有效减轻大鼠慢性神经病理性痛,其机制可能与其抑制背根神经节GAP-43 mRNA表达上调有关.