Properties of [3H]Prazosin-Labeled α1Adrenergic Receptors in Rat Brain and Porcine Neurointermediate Lobe Tissue

Abstract: [³H]Prazosin binding to α₁ receptors in homogenates of rat prefrontal cortical tissue and porcine pituitary neurointermediate lobe tissue was investigated. Competition curves produced by coincubating adrenergic agonists and antagonists with 0.5 n M [³H]prazosin and tissue revealed some anomalous binding properties. In the brain and pituitary tissue, agonist competition curves produced "shallow" slopes, with Hill coefficients significantly lower than unity. The IC₅₀ of the agonists epinephrine, norepinephrine, and clonidine for inhibition of 0.5 n M [³H]prazosin binding were significantly lower in the porcine pituitary than in the rat brain. Most antagonists, such as prazosin, chlorpromazine, and piperoxan, produced "steep" competition curves with Hill coefficients close to unity, with two notable exceptions. WB-4101 and phentolamine produced competition curves with Hill coefficients significantly less than unity in the rat brain preparation. Ketanserin, an antagonist, displayed a sevenfold higher affinity for the a, sites in the pituitary tissue than in the brain tissue. These anomalies in the binding results may indicate the presence of an endogenous modulatory factor affecting agonist and antagonist affinities for the a, receptor.     

蓝斑复合核区注射L—谷氨酸钠对呼吸的影响

实验在55只乌拉坦麻醉、制动、人工呼吸及切断双侧颈迷走神经的家兔上进行。结果如下:双侧蓝斑复合核(Lc-Sc)区注射胞体兴奋剂L-谷氨酸钠(L-Glu)100μg/μl,使呼吸频率(RF)、膈神经放电频率(PhrD)明显增加(P<0.01及0.05),吸气时程、呼气时程均缩短,动脉血压无明显变化。于双侧孤束核(NTS)区分别预注射哌唑嗪(0.5μg/μl)、育亨宾(4μg/μl)、心得安(2μg/μl)可阻断L-Glu的上述效应。实验结果提示,Lc-Sc区对呼吸具有兴奋作用,其增加RF的效应是通过NTS区的α和β受体实现的,而使PhrD增加的机制则有所不同。     

褪黑素对大鼠下丘脑薄片视交叉上核神经元放电昼夜节律性的调制

先用持续光照和松果腺切除预处理大鼠,然后制成下丘脑薄片,记录其视交叉上核（ＳＣＮ）神经元自发放电,观察其昼夜变化和褪黑素（ＭＥＬ）对它的影响。实验结果表明：⑴在正常光照（光照：黑暗＝１２：１２）条件下,ＳＣＮ神经元自发放电频率呈现昼夜低的节律性。在昼夜时间（ＣＴ）６－８出现放电高峰,频率约为８．３Ｈｚ;在ＣＴ１８－２０出现低谷,频率约为３．８Ｈｚ。松果腺切除后,ＳＣＮ神经元自发放电的昼夜节律性基本     

Study of the effects of the casein derived bitter tastant on the melanophores in milieu with the melatonin receptors

The present study was undertaken to ascertain whether the casein derived bitter tastant Cyclo (Leu-Trp) [CLT] has an affinity or not for the particular receptors of the pineal hormone, melatonin, on the melanophores of a major carp Labeo rohita (Ham.). The bitter tastant CLT, in the dose range of 3.34?×?10^?16 M to 3.34?×?10^?4 M, has induced an aggregatory effect but not in a dose dependent manner. Binding of CLT with the receptors may vary at different concentrations. Denervation of the melanophores has shown a complete inhibition of the CLT mediated aggregation. Prazosin has partially inhibited the aggregatory effect of CLT. Moreover, the bitter tastant’s response is mediated through the α₂ adrenoceptors only at particular dose ranges. The MT₁ and MT₂ melatonin receptor antagonist luzindole and the MT₂ specific antagonist K185 have perfectly blocked the aggregatory effects of CLT. We have found that the CLT mediated aggregatory effect is dependent upon the release of neurotransmitters and the two subtypes of melatonin (MT) receptors (MT₁ and MT₂) possess a perfect affinity towards the bitter tastant CLT. Our study demands a need to further make a clinical research on the effects of bitter tastants on the physiology of the biological rhythm maintaining hormone melatonin.     

X-ray structural studies of quinone reductase 2 nanomolar range inhibitors

Quinone reductase 2 (QR2) is one of two members comprising the mammalian quinone reductase family of enzymes responsible for performing FAD mediated reductions of quinone substrates. In contrast to quinone reductase 1 (QR1) which uses NAD(P)H as its co‐substrate, QR2 utilizes a rare group of hydride donors, N‐methyl or N‐ribosyl nicotinamide. Several studies have linked QR2 to the generation of quinone free radicals, several neuronal degenerative diseases, and cancer. QR2 has been also identified as the third melatonin receptor (MT3) through in cellulo and in vitro inhibition of QR2 by traditional MT3 ligands, and through recent X‐ray structures of human QR2 (hQR2) in complex with melatonin and 2‐iodomelatonin. Several MT3 specific ligands have been developed that exhibit both potent in cellulo inhibition of hQR2 nanomolar, affinity for MT3. The potency of these ligands suggest their use as molecular probes for hQR2. However, no definitive correlation between traditionally obtained MT3 ligand affinity and hQR2 inhibition exists limiting our understanding of how these ligands are accommodated in the hQR2 active site. To obtain a clearer relationship between the structures of developed MT3 ligands and their inhibitory properties, in cellulo and in vitro IC₅₀ values were determined for a representative set of MT3 ligands (MCA‐NAT, 2‐I‐MCANAT, prazosin, S26695, S32797, and S29434). Furthermore, X‐ray structures for each of these ligands in complex with hQR2 were determined allowing for a structural evaluation of the binding modes of these ligands in relation to the potency of MT3 ligands.     

血管活性药物对冷暴露实验动物肢端皮肤温度的调节作用

目的:在冷暴露实验动物模型上,评价盐酸哌唑嗪(Pra)和消旋山莨菪碱(Ani)对大鼠、小鼠肢端皮肤温度的调节作用。方法:将80只大鼠随机分为8组,室温下灌胃给药,60 min后放入指定温度(5℃、18℃)环境中冷暴露,并于给药后180 min和300 min使用红外摄像仪测定实验动物尾部近心端1/3处的皮肤温度,观察皮肤温度的变化,评价药效。结果:单独使用Pra对大鼠肢端皮肤温度无影响,对小鼠肢端皮肤温度提高效果较差;而单独使用Ani对大鼠和小鼠肢端皮肤温度均无提高作用;两药联用后实验动物尾温得到显著提高,且具有一定剂量依赖性。结论:Pra和Ani联用能有效提高冷暴露大鼠、小鼠的肢端皮肤温度,并且不会降低体心温度。     

改善血栓形成新的药物组合物及其分子机制

目的：研究α1受体阻断药与山莨菪碱（Ani）形成的药物组合物改善血栓形成的作用及其分子机制。方法：离体大鼠尾动脉血管模型研究α1受体阻断药及其与山莨菪碱的药物组合物的扩血管效应,角又菜胶诱发小鼠尾部血栓模型研究组合物对抗血栓形成的作用及其机制。结果：α1受体阻断药中哌唑嗪（Pra）对血管环舒张率最大,达（82．6±8．9）％,作用强度最强,Ec50值为O．44μmol/L;山莨菪碱和哌唑嗪分别以不同剂量配伍组成组合物,能使角叉菜胶诱发的鼠尾血栓长度（啪）由24．6±4．6缩短到6．94-2．7,成栓率由86．6％下降到50．0％。上述新药物组合物能显著延长血栓小鼠血浆凝血酶原时间（er）,对活化部分凝血活酶时间（APTT）无影响;能抑制血栓小鼠血浆中组织型纤溶酶原激活剂（t-PA）、6-酮一前列腺素F1a（6．Keto．PGF1α）含量的降低和组织纤溶酶原激活剂抑制物-1（PAI-1）、血栓烷B2（TXB2）的增多;并不在于扩血管作用的进一步增强上。结论：山莨菪碱和哌唑嗪组成的药物组合物具有舒张外周血管和改善血栓形成的作用,其抗血栓形成机制分别与影响外源性凝血途径、抑制血小板的活化功能以及促进纤溶功能有关。     

Effect of Counterion on the Solid State Photodegradation Behavior of Prazosin Salts

The effect of counterion was evaluated on the photodegradation behavior of six prazosin salts, viz., prazosin hydrochloride anhydrous, prazosin hydrochloride polyhydrate, prazosin tosylate anhydrous, prazosin tosylate monohydrate, prazosin oxalate dihydrate, and prazosin camsylate anhydrous. The salts were subjected to UV–Visible irradiation in a photostability test chamber for 10 days. The samples were analyzed for chemical changes by a specific stability-indicating high-performance liquid chromatography method. pH of the microenvironment was determined in 10% w/v aqueous slurry of the salts. The observed order of photostability was: prazosin hydrochloride anhydrous > prazosin camsylate anhydrous ∼ prazosin-free base > prazosin hydrochloride polyhydrate > prazosin tosylate anhydrous > prazosin oxalate dihydrate ∼ prazosin tosylate monohydrate. Multivariate analysis of the photodegradation behavior suggested predominant contribution of the state of hydration and also intrinsic photosensitivity of the counterion. Overall, hydrated salts showed higher photodegradation compared to their anhydrous counterparts. Within the anhydrous salts, aromatic and carbonyl counterion-containing salts showed higher susceptibility to light. The pH of microenvironment furthermore contributed to photodegradation of prazosin salts, especially for drug counterions with inherent higher pH. The study reveals importance of selection of a suitable drug salt form for photosensitive drugs during preformulation stage of drug development.     

Reducing the harm of stress: medications to rescue the prefrontal cortex and overcome bad habits: the science of stress: focus on the brain, breaking bad habits, and chronic disease

Our brain is sensitive to stress. Both acute and chronic stress cause cognitive deficits and induce chronic disorders such as drug addiction. In a June 2011 conference at Yale entitled "The Science of Stress: Focus on the Brain, Breaking Bad Habits, and Chronic Disease," Drs. Amy Arnsten and Sherry Mckee discussed the roles of prefrontal cortex in the treatment of stress impairments and addiction. Medications to strengthen the prefrontal function, such as prazosin and guanfacine, may reduce the harm of stress and help overcome smoking and alcohol abuse.