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右美托咪定在腹腔镜手术中的应用【摘要】目的：分析右美托咪定在腹腔镜手术中应用的安全性和可能获益。
方法：随机将80例腹腔镜胆囊切除术患者分为对照组（不预注右美托咪定组）和实验组（术毕前静脉预注右美托咪定组），观察并记录手术完毕时（to）、气管拔管后lmin（t1）、6 min （t2）、11 min（t3）时的sbp、dbp和hr。
记录手术时间和手术结束后至气管导管拔出时的间隔时间（拔管时间）。
结果：与实验组比较，t1～t3时对照组sbp、dbp明显升高，hr明显增快（p<o.05），且明显高/快于实验组（p<0.05）。
结论：右美托咪定在腹腔镜手术中应用可明显减轻气管拔管时应激反应，保持患者生命体征平稳性。
【关键词】右美托咪定；腹腔镜手术腹腔镜手术时间较短，术后要求尽快苏醒，多采用气管插管全身麻醉。
术后苏醒期间麻醉减浅，吸痰、拔管等引起的心血管不良反应，对患者安全性能造成影响。
右美托咪定具有抑制交感神经活性、镇痛、维持手术期心血管系统稳定性作用[1]。
可明显减轻气管插管及外科手术刺激引起的血流动力学改变等不良反应【2】。
本文观察国产右美托咪定对腹腔镜手术后应激反应的影响，探讨小剂量右美托咪定在全麻苏醒期间的临床使用价值。
1 资料与方法1.1 一般资料：择期行腹腔镜胆囊切除术患者80例，asaⅰ～ⅱ，男48例，女32例，年龄：18～69岁，无严重心脑血管、呼吸系统疾病；无糖尿病、长期服用镇静药、精神神经病病史。
随机均分为实验组（术毕前静脉预注右美托咪定组d组）和对照组（生理盐水组c组）。
1.2 方法：麻醉前肌注阿托品0.5 mg、苯巴比妥钠0.1g。
入室后经上肢静脉滴注复方氯化钠10ml/kg/h。
采用多功能监测仪检测sbp、dbp、hr。
麻醉诱导采用咪达唑仑0.03 mg/kg、芬太尼2～3μg/kg、丙泊酚1.5～2.0 mg/kg、阿曲库铵0.5～1 mg/kg静注，3min后行气管插管，机械通气，麻醉维持采用静脉输注丙泊酚4～8 mg/kg/h、瑞芬太尼15～30μg/kg/h，必要时间断吸人七氟醚。
妇科炎症原因分析及预防措施的探讨作者：刘慧群来源：《中国实用医药》2013年第26期【摘要】妇科炎症为女性常见疾病，主要症状为月经不调，经期疼痛，尿频尿急，白带异常及性交疼痛等。
引起妇科炎症主要原因有物理损伤，化学刺激，生理因素及生物源性污染等。
预防妇科炎症主要措施有，建立预防措施，在意生活中细节及防止医源性感染等。
本文也为妇女健康运动起到一定推动作用。
【关键词】妇科炎症；原因分析；预防措施妇科炎症为女性常见疾病，主要包括急性炎症与慢性炎症。
具体有外阴及阴道炎症，宫颈炎症，盆腔炎性疾病（主要包括子宫内膜炎、输卵管炎、输卵管卵巢脓肿、盆腔腹膜炎）。
据统计，约75%女性受这五种疾病困扰[1]。
本文对女性妇科炎症发病原因进行了分析并探讨了对此病的预防措施。
1 妇科炎症症状妇科炎症的表现形式为生殖器官炎症。
由于女性生殖器官生理结构特殊，暴露在外，与肛门、尿道紧挨，使得生殖器官易被尿液、大便污染，较难清洁，较少干燥。
这为各类细菌的大量增殖提供了良好条件，从而使女性发生妇科炎症。
根据不同发病原因，妇科炎症有多种症状，一般为月经不调、经期疼痛、尿频尿急、白带异常、性交疼痛、外阴瘙痒和下腹坠胀等。
月经异常：当女性发生妇科炎症时，容易损害卵巢功能及导致女性盆腔充血，最终导致月经失调。
腹痛：腹痛是妇科炎症主要症状，小腹剧烈疼痛为急性炎症的主要症状，而慢性症状特征为腰酸背痛及小腹产生坠胀[2]。
阴道瘙痒：阴道瘙痒也为妇科炎症一主要症状，患者多数表现为阴道瘙痒及阴部有灼热感。
2 妇科炎症发病原因妇科炎症发病原因有多种，任何细节均可导致炎症的发生。
总的来说引发炎症的因素主要有四种，物理损伤、化学刺激、生理因素及生物源性污染。
2. 1 物理损伤女性生殖器官生理结构特殊，常暴露在外，易受到衣裤挤压。
而且当女性剧烈运动或性生活频繁时，容易使生殖器官充血和受到损伤，继而引发细菌感染。
2. 2 化学刺激当女性在治疗妇科炎症过程中，有些药物会对生殖器官产生较大刺激。
Chinese Journal of Tissue Engineering Research ｜Vol 25｜No.21｜July 2021｜3395第2骶椎骶髂螺钉固定骶骨骨盆的优势及意义刘 钢，杨 强，郝永宏，邓树才文题释义：第2骶椎骶髂螺钉：是由KEBAISH 和SPONSELL 开发的，以避免髂骨螺钉技术的许多缺点。
入钉点的中点与脊柱椎弓根螺钉的尾帽结构处于同一条线，不需要放置连接器、单独的切口及广泛的髂棘旁肌肉剥离。
骶骨骨盆固定：通过相应的内固定装置，达到骶骨与骨盆的坚强固定，消除其相对运动。
摘要背景：在脊柱畸形、肿瘤等的外科治疗中，实现腰骶交界处牢固稳定的固定是手术中的重要操作，且具有相对较大的挑战，术后并发症(如假关节、内固定失败和松动)的发生率较高。
骶骨中骨组织的机械强度低，腰椎和骨盆中的较大负荷导致内固定拔出的风险增高，进一步导致内固定松动。
虽然存在一些较为有效的手术方案，但技术的复杂性经常导致不满意的临床结果。
目的：概述关于骶骨骨盆固定技术以及第2骶椎(S 2)骶髂螺钉临床应用的最新研究进展，为临床治疗提供参考。
方法：利用计算机检索中国知网、万方数据库、PubMed 中2005至2020年的相关文章，检索词为“骶髂螺钉，S 2AI ，髂骨螺钉，骶骨骨盆固定，S 2 alar iliac screw ，Iliac screw ，sacropelvic fixation ，alar iliac screw ”。
查阅相关文章，最终共纳入43篇文献进行分析。
结果与结论：①在脊柱长节段固定的下端增加了骶骨骨盆固定，如髂骨和S 2骶髂螺钉，以解决上述相关并发症；②S 2骶髂螺钉置入技术在稳定骶髂关节方面发挥重要作用，因其独特的置钉方式，可避免螺钉脱位，减轻术后骶髂关节疼痛，降低了再次手术的风险；③S 2骶髂螺钉作为脊柱骨盆固定的新兴技术，有着多方面的优势及临床意义，但由于骶髂关节复杂多样的结构及患者个体差异，使S 2骶髂螺钉的临床应用仍存在着相关问题。
盐酸右美托咪啶在ICU的应用昆明医学院附属二院SICU 黄青青镇静镇痛是重症治疗病房尤其是机械通气患者的基本治疗措施，理想和适度的镇静镇痛可缩短机械通气时间、ICU居住时间和住院时间[1,2]。
在ICU达到满意的镇静镇痛可以选择多种药物，包括阿片类、苯二氮卓类、巴比托类、丙泊酚和抗精神病类。
右美托咪定(Dexmededomidine Dex)是一种新的ICU镇静镇痛药物，它不是阿片类，也不是苯二氮卓类，美国食品与药品监督管理局于1999年批准用于ICU机械通气患者最初24小时镇静。
最近国内才开展临床Ⅱ期研究。
1 右美托咪啶的药理学Dex是一种新研制的高选择性a2肾上腺素受体(a2一AR)激动药，为咪哇类衍生物。
与同属a2肾上腺素受体激动药可乐定相比，其a2受体的选择性(a2/ a1为1620：1)远高于可乐定(a2/ a1为220：1)，而Dex在体内的活性强于可乐定(3:1)[3,4]。
蓝斑核是α2受体密度最高区域之一，是大脑中最主要的去甲肾上腺素能神经核团，负责许多重要的脑功能的调控（觉醒、睡眠、焦虑及伤害性神经传导等）。
蓝斑核是右美托咪啶产生镇静、催眠和抗焦虑作用的关键部位。
其主要作用机制为抑制中枢神经突触前与突触后去甲肾上腺素(NE)释放，降低突触后膜的兴奋性。
Dex的镇痛作用理论上是通过激动α2c受体亚型与阿片类药产生协同作用和可能激动脊髓后角a2受体，抑制感觉神经递质(如P物质)的释放，并与胆碱能、嘌吟及五羟色胺疼痛系统相互作用有关。
Dex的起效时间大约15分钟，持续输注1小时达到峰浓度。
具有双相半衰期，分布半衰期约6分钟，消除半衰期约2小时。
右美托咪定具有高蛋白结合力（94%）和较大的分布容积（1.33L/kg）[5]。
其主要代谢途径为咪啶环上直接发生糖苷化，细胞色素P450酶系负责氧化和还原。
大部分由肝脏代谢，在轻、中、重度肝损伤的患者中，其平均清除率为74%、64%和53%，因此，对肝损伤的患者需适当减量。
锌alpha2糖蛋白通过法尼酯X受体改善肝脏脂肪沉积的研究摘要目的：探讨锌alpha2糖蛋白(Zinc-α2-glycoprotein,ZAG)是否通过法尼酯X受体(Farnesoid X receptor,FXR)改善肝脏脂肪沉积。
方法：用胶原酶灌注法分离8周龄C57BL/6野生型（WT）和同窝出生FXR敲除杂合子( WT/KO)雄性小鼠原代肝细胞，原代肝细胞均用棕榈酸处理造成肝细胞脂质沉积，棕榈酸干预24小时后用Ad-ZAG 转染细胞，并分为 4 组，即:①野生型组(WT);②野生型加过表达ZAG 组(WT+Ad-ZAG); ③FXR敲除杂合子组（WT/KO）;④FXR敲除杂合子加过表达ZAG组（WT/KO+Ad-ZAG），其中WT+Ad-ZAG及WT/KO+ZAG两组行Ad-ZAG转染。
细胞转染48小时后用油红 O 染色观察原代肝细胞内脂滴，酶法检测细胞内甘油三酯的水平，通过Western blot检测ZAG、代谢性核受体固醇调节元件结合蛋白（Sterol regulatory element binding protein-1c，SREBP-1c）及脂肪酸合成酶（Fatty acid synthase，FAS）蛋白表达水平。
结果：1.在棕榈酸干预下，油红O染色显示与WT组比较，WT+Ad-ZAG组的原代肝细胞内橘红色脂滴明显减少；与WT/KO组相比，WT/KO+Ad-ZAG组原代肝细胞内橘红色脂滴无明显改变。
细胞内甘油三酯测定显示，与WT组比较，WT+Ad-ZAG组的原代肝细胞内甘油三酯含量减少(P<0.01)；与WT/KO组相比，WT/KO+Ad-ZAG 组原代肝细胞内甘油三酯无明显改变(P>0.05)。
I2.与WT组相比，WT+Ad-ZAG组 ZAG蛋白表达增加（P<0.01），SREBP-1c、FAS蛋白表达降低（P<0.05）;与WT/KO 组相比，WT/KO+Ad-ZAG组ZAG蛋白表达增加（P<0.01），而SREBP-1c、FAS蛋白表达无明显改变（P>0.05）。
任研究发现在右美托咪陡脑保护作用的研究进展长和△（综述），欧册华※（审校）（洲州医学院附属医院麻醉科，四 洲州646000）中日分类号：R971.3 文献标识码：A 文童编号：1006⁃2084（2012）05⁃0721⁃03 摘要：右美托咪嚏（DEX ）是α2肾上腺素受体激动剂美托咪嚏的右旋异构体，高选择性激动α2肾上腺素受体，抑制交感神经兴奋，产生镇静、镇痛和抗焦虑作用，无呼吸抑制和不于扰脑电生理活动，不良反应少。
因此，DEX 被广泛应用于临床。
研究发现，DEX 对心脏、大脑、肝脏、肾脏、肺等器官具有一定的保护作用。
关键词：右美托咪嚏；脑保护；作用机制Research Progress of Brain Protective Effect of Dexmedetomidine REN Chang⁃he ，OU Ce⁃hua.（De⁃partment of Anesthesiology ，the First Affiliated Hospital of Luzhou Medical College ，Luzhou 646000，China ）Abstract ：Dexmedetomidine （DEX ）is a dextroisomer of the α2⁃adrenergic receptor agonist.It is a highly selective α2⁃adrenergic agonist ，inhibiting sympatholytic excitement ，producingsedation ，analgesiaia ，antianxiety function without respiratory depression or interference of the cerebral electrophysiologic activi⁃ties ，with less adverse effects.So ，it′s widely used in clinic.The studies have found that DEX has a certain protective effects for organs including heart ，brain ，livers ，kidneys ，and lungs etc..Key words ：Dexmedetomidine ；Brain protection ；Mechanism 盐酸右美托咪陡（dexmedetomidine ，DEX ）是一种韶型的高选择性α2肾k腺素受体激动剂，是美托咪陡的右旋异构体，选择性地与α2∶α1肾k腺素受体结合的比例为1620∶1；与α2肾k腺素受体的亲和力为可乐定的8倍［1］，并巨其半衰期也较可乐定短，分布半衰期约为6min ，消除半衰期约为2h ，在药动学方面的可预测性更强。
右美托咪定和地左辛联合术后自控静脉镇痛研究【摘要】目的评估不同剂量右美托咪定联合地佐辛术后患者静脉自控镇痛（pcia）的有效性和安全性。
方法 240例行择期手术，asaⅰ-ⅲ级， 18-65岁的患者，随机分为4组：舒芬太尼组（s 组）、低剂量右美托咪定+地佐辛组（dd1组）、中剂量右美托咪定+地佐辛组（dd2组）、高剂量右美托咪定+地佐辛组（dd3组），每组各60例。
s组镇痛泵为舒芬太尼1.5 μg /kg+昂丹司琼8mg+0.9%氯化钠注射液。
其它3组为右美托咪定+地左辛1mg/kg+昂丹司琼8 mg+0.9%氯化钠注射液， dd1组、dd2组和dd3组右美托咪定剂量分别为2.5 μg/kg、5 μg/kg和7.5μg/kg。
镇痛泵容量100 ml，持续输注量2 ml/h， pca量0.5 ml，锁定时间15 min。
采用vas 评分和ramsy镇静评级评估术后2 h、4 h、8 h、12 h、24 h和48 h的疼痛程度和镇静情况，同时记录不良反应发生情况，并于术后4 h、12 h、24 h、48 h时测定血浆皮质醇浓度。
结果 vas评分，s组、dd2组、dd3组3组间比较差异无统计学意义（p>0.05）， dd1组显著高于其它3组（p0.05）。
2. 2 疼痛视觉模拟评分（vas）和ramsy镇静评级在同时点的vas， s组、dd2组、dd3组3组间无显著差异（p>0.05）， dd1组显著高于其它3组（p0.05）， dd3组和dd2组显著高于s组和dd1组（p0.05），见表4。
2. 5 不良反应 dd1组和dd2组的不良反应发生率显著低于s组和dd3组（p地佐辛是苯吗啡烷类衍生物，是κ受体激动剂，也是μ受体拮抗剂，是兼备阿片类激动剂和拮抗剂的药物，是一种新型的阿片类镇痛药，其镇痛作用比吗啡更强，不良反应更少。
地佐辛已应用于术后疼痛的治疗。
我们前期研究发现地左辛可用于术后pcia，镇痛效果满意，且不良反应显著少于传统阿片类药物芬太尼和舒芬太尼[2， 3]。
The Maillard reaction and its control during food processing.The potential of emerging technologiesLa re´action de Maillard et son controˆle pendant la fabrication des aliments.Le potentiel des nouvelles technologiesH.Jaeger*,A.Janositz,D.KnorrDepartment of Food Biotechnology and Food Process Engineering,Berlin University of Technology,Koenigin-Luise-Str.22,14195Berlin,GermanyPathologie Biologie58(2010)207–213A R T I C L E I N F OArticle history:Received13July2009Accepted14September2009Available online5November2009Keywords:Maillard reactionFood industryThermal unit operationsNon-thermal pasteurisationHigh hydrostatic pressurePulsed electricfieldsMots cle´s:Re´action de MaillardL’industrie agro-alimentaireProce´de´s de traitement thermiquePasteurisation a`froidHaute pressionChamps e´lectriques pulse´sA B S T R A C TThe Maillard reaction between reducing sugars and amino acids is a common reaction in foods whichundergo thermal processing.Desired consequences like the formation offlavor and brown color of somecooked foods but also the destruction of essential amino acids and the production of anti-nutritivecompounds require the consideration of the Maillard reaction and relevant mechanisms for its control.This paper aims to exemplify the recent advances in food processing with regard to the controllability ofheat-induced changes in the food quality.Firstly,improved thermal technologies,such as ohmic heating,which allows direct heating of the product and overcoming the heat transfer limitations of conventionalthermal processing are presented in terms of their applicability to reduce the thermal exposure duringfood preservation.Secondly,non-thermal technologies such as high hydrostatic pressure and pulsedelectricfields and their ability to extend the shelf life of food products without the application of heat,thus also preserving the quality attributes of the food,will be discussed.Finally,an innovative methodfor the removal of Maillard reaction substrates in food raw materials by the application of pulsed electricfield cell disintegration and extraction as well as enzymatic conversion is presented in order todemonstrate the potential of the combination of processes to control the occurrence of the Maillardreaction in food processing.ß2009Elsevier Masson SAS.All rights reserved.R E´S U M E´La re´action de Maillard entre des sucres re´ducteurs et des acides amine´s a lieu dans les aliments lors d’untraitement thermique.Des conse´quences de´sirables comme la formation de certains aroˆmes et de couleurbrune,mais aussi des conse´quences inde´sirables comme la destruction d’acides amine´s essentiels et laformation de substances non nutritives,ne´cessitent la prise en conside´ration de la re´action de Maillard et deses me´canismes.Ce travail scientifique a pour but d’expliquer les avance´s re´centes dans le domaine destechnologies de fabrication d’aliments concernant en particulier des changements controˆlables de qualite´lors d’un traitement thermique.Premie`rement,des ame´liorations de technologies de traitementthermique,comme le chauffage ohmique,permettent de re´duire le temps du traitement thermique duproduit durant sa ste´rilisation.Cette technologie permet de chauffer le produit directement et arrive a`de´passer les limitations de transfert thermique des traitements conventionnels.Dans un second temps,destechnologies non thermiques sont pre´sente´es,comme par exemple l’utilisation de haute pressionhydrostatique et le traitement par un champ e´lectrique pulse´.La capacite´des ces technologies a`prolongerla dure´e de vie de produits alimentaires sans utiliser de traitements thermiques et par conse´quent lapre´servation de certains attributs de qualite´sera discute´s.Finalement,une me´thode innovatricepermettant d’e´liminer les substrats de la re´action de Maillard des matie`res premie`res par l’application d’unchamp e´lectrique pulse´qui provoque une de´sinte´gration de cellule,suivi par une extraction et uneconversion enzymatique sera pre´sente´e.Le potentiel de combiner diffe´rents proce´de´s afin de controˆlerl’occurrence de la re´action de Maillard dans le domaine de la pre´servation alimentaire sera de´montre´.ß2009Elsevier Masson SAS.Tous droits re´serve´s.*Corresponding author.Adresse e-mail:henry.jaeger@tu-berlin.de(H.Jaeger).0369-8114/$–see front matterß2009Elsevier Masson SAS.All rights reserved.doi:10.1016/j.patbio.2009.09.0161.IntroductionThe Maillard reaction can be considered as one of the most important chemical reaction taking place during food processing. Its influence on food quality attributes such as color,flavor and nutritional value includes desired as well as unwanted effects and requires the consideration of processing conditions as well as physico-chemical properties of the food material.A multitude of reaction products can be formed in the food matrix and attributed to characteristics such as antioxidative,antimicrobial,mutagenic or cancerogenic[1–3].Apart from Maillard products generated in food materials during processing and storage,the Maillard reaction and glycosila-tion are also occurring in-vivo with important pathological consequences for biological systems[4].The paper aims to discuss the impact of food manufacturing processes on the formation of Maillard products focusing on alternative thermal processing as well as recent applications of non-thermal technologies in food preservation.2.Maillard reaction during food processingA series of chemical reactions between reducing sugars and amino compounds occurring during production and storage of foods can be summarized as Maillard reaction.The main variables affecting the extent of the Maillard reaction are temperature and time which depend on processing conditions as well as pH,water activity and type and availability of the reactants which are based on product properties but may be changed as a result of the processing of food and raw materials[5].Processes such as roasting,baking or frying rely on favorable effects of the Maillard reaction such as color andflavor formation whereas during drying,pasteurization and sterilization the occurrence of the Maillard reaction is unfavorable.Nutritional losses of essential amino acids that are involved in the reaction as well as the formation of reaction products are among those unwanted effects[6,7].The main challenge is therefore the specific design,the optimization and the control of the above-mentioned processes for the production of food with the desired quality and stability[8].Since temperature and time present the most significant processing factors influencing the Maillard reaction,the reduction of the thermal load to which a product is exposed during processing is a key factor to control the extent of the reaction. The below-mentioned concepts point out possible approaches that will be further described in following sections.The occurrence of the Maillard reaction is desired to a certain extent and responsible for the formation of color andflavor. However,these quality attributes mainly occur on the surface of the food(crust of bread or meat after baking and roasting).A reduction of the total thermal process intensity by a controlled thermal treatment of the product surface for color andflavor development can be achieved by the application of emerging technologies such as infrared heating[9].Thermal preservation processes and the inactivation of pathogenic and spoilage microorganisms and enzymes require a minimal treatment temperature and a corresponding holding time. Processing times for heating and cooling below a certain critical temperature do not contribute to inactivation but may lead to degradation of nutritionally valuable ingredients as well as to the formation of unwanted compounds.The reduction of processing times for heating to afinal temperature and cooling is possible by improving the heat transfer and/or by applying alternative thermal technologies such as direct steam injection or ohmic heating with direct heating of the product thus avoiding temperature gradients and heat transfer limitations.Preservation of food can be achieved not only by thermal inactivation of microorganisms and enzymes but also by non-thermal technologies that are based on alternative inactivation mechanisms.High hydrostatic pressure treatment as well as pulsed electricfield processing can be considered as new non-thermal preservation methods working at reduced treatment temperature and therefore avoiding the occurrence of heat induced product changes.The Maillard reaction requires reducing sugars and amino-compounds as reactants.The successful post-harvest removal of these compounds from the food raw material is a promising possibility to reduce the formation of Maillard products during subsequent processing.Enzymatic conversion of amino-acids as well as sugars have been proposed and pulsed electricfield pretreatments to improve diffusion processes are promising process combinations.With the goal to design fresh-like yet shelf stable products comes the need to optimise existing food processing technologies as well as to develop new concepts for gentle food preservation as mentioned above.3.Improving thermal processing of foodSince the microbial inactivation effect of heat increases faster with increasing temperature than undesired chemical reactions, application of high temperatures for short treatment times(HTST-processes)are favourable.In addition to that,a lethal effect on microorganisms and bacterial spores in particular requires a critical temperature.The process design therefore aims to raise temperature in a very short time to a critical level at which a certain holding time allows sufficient inactivation and apply rapid cooling afterwards.As shown in Fig.1methods applying indirect heat treatment like traditional pasteurisation using plate heat exchangers require longer times for temperature increase and subsequent cooling in comparison to processes based on direct heat treatment such as direct steam injection[10]or ohmic heating [11]which result in an instantaneous and uniform temperature increase.In case of direct steam injection,the thermal energy can also be removed quickly by vacuum-flash cooling whereas the cooling process still remains the limiting factor for the reduction of the thermal load when ohmic heating is applied.In the following section,ohmic heating is used to exemplify the potential for a rapid heating of foods taking advantage of the specific potentials and opportunities of the technology and food properties due to the direct heatingmechanism.parison of the temperature–time profile of direct(e.g.steam injection) and indirect(e.g.plate heat exchanger)heat treatments.H.Jaeger et al./Pathologie Biologie58(2010)207–213 208Ohmic heating uses the electrical resistance of foods to convert electricity to heat[12].The heat is generated within the product and the thermal conductivity of the food is no limiting factor.The process can be used for UHT treatment of foods,especially particulate and high viscous foods[13].In comparison to microwave or radio frequency heating,the penetration depth is no limiting factor but direct contact between electrodes and the food is required for ohmic heating.The food is heated rapidly and evenly and heat transfer coefficients do not limit the rate of heating.Therefore,heat sensitive components are not degraded since no localized over-heating occurs.Ohmic heating allows a high temperature short time process application to solid/liquid food mixtures with a high retention of nutrients and vitamins and the reduction of other heat induced changes.Leizerson and Shimoni[14]studied the impact of ohmic heating on stability and sensory characteristics of orange juice and found a higher retention offlavor compounds due to the rapid and uniform heating process.Mc Kenna et al.[15]investigated the impact of radio frequency and ohmic heating on meat quality.A shortening of cooking times and the avoidance of quality losses in the outer regions of the product which often occur as a result of a higher heat exposure due to the low rate of heat penetration during steam or hot water cooking could be obtained.Color changes as a result of non-enzymatic browning during hot water sterilization and ohmic heating of pea puree have been compared by Icier et al.[16]. Enzyme inactivation was found to occur at lower processing times than conventional hot water sterilization and color changes as a result of non-enzymatic browning were less pronounced in the samples treated by ohmic heating.Since the heat is generated inside the food and no temperature gradient is required for thermal conduction and convection,product contact with hot surfaces such as the plates of heat exchangers can be avoided and wall-overheating with protein and mineral fouling can be limited.This phenomena was studied by Fillaudeau et al.[17]and a comparison of an UHT treatment of milk using ohmic heating and a conventional plate heat exchanger was conducted and processing parameters like flow characteristics in the treatment chamber were considered to be relevant for the prevention of deposits on the electrode surface during ohmic heating.The relevance of occurring deposits and protein fouling during ohmic heating and conven-tional heat exchangers was also studied by Avadi et al.[18]who reported similar results.Ohmic heating represents a promising alternative thermal method for the processing of particulate products where conven-tional heat transfer techniques require over-processing of the liquid phase to ensure the sufficient sterilization of each particulate.Rapid heating rates and uniformity of the temperature increase without limitation by conductive and convective heat transfer can be considered as the main advantages.4.Application of non-thermal technologiesThis chapter shows how two alternative non-thermal proces-sing methods,high hydrostatic pressure(HP)and pulsed electric field(PEF)treatment[19,20]contribute to the production of fresh-like and shelf stable foods minimizing the detrimental effect of traditional thermal processing.4.1.High hydrostatic pressure(HHP)The application of HHP processing has shown considerable potential as an alternative technology to heat treatments,in terms of assuring safety and quality attributes in minimally-processed food products[21].High pressure pasteurization is currently the main application in industrial high pressure processing working at pressures from300to600MPa at ambient or refrigerated temperature for2to30min and increasing interest in HP sterilisation processes is also developing[22].Complex reaction effects like inactivation of enzymes or microorganisms are altered in their reaction rates by pressure as well as by temperature.Proteins are particularly affected by pressure treatments[23].They may unfold and denature, reversibly or irreversibly,depending on the kind of protein and the intensity of the treatment but covalent chemical bonds are not affected during HP treatments resulting in minimal modifications in nutritional and sensory quality of foods.Microbial inactivation by HP has been concluded to be the result of a combination of factors.Modifications of the cell membrane permeability and ion exchange capability,changes in cell morphology and biochemical reactions as well as protein denaturation and inhibition of genetic mechanisms can be considered as the relevant mechanisms[24,25].During traditional thermal treatment and high pressure processing desired reactions such as inactivation of pathogenic microorganisms are the main target.At the same time,unwanted reactions which would lead to quality losses need be to taken into account.Such reactions have different temperature or pressure dependencies and show different rate constants in comparison to the microbial inactivation[26].An illustration of wanted and unwanted reactions and their pressure and temperature depen-dencies enables the p–T diagram(Fig.2).As to be seen in Fig.2, inactivation at high hydrostatic pressure allows the reduction of the treatment temperature resulting in a non-thermal pasteurisa-tion process although a synergism between temperature and pressure occurs.On the other hand,it is possible to decrease the applied pressure by increasing the process temperature but the occurrence of unwanted reactions has to be considered at the same time.Since chemical reactions are also influenced by pressure according to the principle of Le Chatelier,the Maillard reaction must be taken into account during high pressure processing of foods[27].Fig.2.p–T diagram for the illustration of process parameters during HP treatment. The points represent the same summarized effect of wanted reactions,e.g.microbial inactivation.The dashed lines represent a similar summarized effect of unwanted reactions.After increasing the dwell times from t1to t2,the lines are shifted to the left. (Illustration according to V.Heinz,DIL,2008,personal communication)H.Jaeger et al./Pathologie Biologie58(2010)207–213209The influence of high hydrostatic pressure up to600MPa on the Maillard reaction was studied in model systems containing amino acids orß-caein and sugars by Schwarzenbolz et al.[28].The formation of the amino acid derivate pentosidine was found to be increased by increasing the pressure whereas the formation of pyralline was reduced.Other studies found the acceleration of early Maillard reaction pathways with pressure, e.g.reaction products formed from tryptophan and glucose or xylose,and the slowdown of subsequent reaction steps[29].High-pressure effects on the Maillard reaction between glucose and lysine were investigated by Moreno et al.[30]and the pressure-induced changes in pH were found to strongly influence the HP effects of different stages of the Maillard reaction.The formation and subsequent degradation of Amadori rearrangement products was accelerated by HP(400MPa,608C)and resulted in increased levels of intermediate and advanced reaction products. Similar results have been reported by Hill et al.[31].The impact of HP processing on color,texture andflavor of fruit-and vegetable-based food products was reviewed by Oey et al.[32].Rada-Mendoza et al.[33]studied the impact of differentdenaturation conditions on the susceptibility of proteins to the Maillard reaction and the effect of high pressure on lactosylation of ß-lactoglobulin was found to be lower than the one of the applied thermal treatments.On the other hand,the study of Campus et al.[34]investigated the effects of high-pressure treatment on chemical characteristics of dry cured loin where a reduction of severalflavour compounds deriving from Maillard reactions was observed in comparison to the untreated sample.Thisfinding again underlines the fact,that on the one hand,non-thermal processing retains fresh-like characteristics but that the reduction of the Maillard reaction may also lead to a decrease of the formation of typical color and flavor characteristics.Nienaber[35]investigated the stabilization of fresh orange juice by HP treatment and conducted a shelf life study showing the potential of HP processing to produce a shelf-stable juice with fresh-like quality for several months when stored under refrigeration.HP used as a food preservation method is able to reduce deteriorative effects on food quality characteristics occurring during conventional processing.However,the effect of HP in combination with elevated temperatures and occurring shift of pH during treatments with the resulting impact on Maillard reaction pathways requires consideration.4.2.Pulsed electricfields(PEF)The application of pulsed electricfield treatment of foods is based on the permeabilization of biological membranes.PEF processing involves the application of short pulses(in the range of m s to ms)of high electricfields.The result of PEF treatment is the disintegration of the cell membrane consisting of a bilayer of phospholipids.Depending on treatment intensity,the generated membrane pores can be permanent or temporary.In the case of irreversible electroporation the semipermeable character of the membrane becomes permanently destroyed which results in cell death and can be used for microbial inactivation and the non-thermal pasteurization of liquid foods[36,37].Effective inactivation for most of the spoilage and pathogenic microorganisms has been shown and the potential to achieve sufficient reduction of microbes in various food products like fruit or vegetable juices[38–41],model beer[42]or milk[43,44]has been investigated.In order to avoid detrimental changes in sensory and nutritive properties pulsed electricfield pasteurisation of fruit juices is a promising preservation method.Although conventional heat treatments ensure safety and extend the shelf life of juices,undesirable brown colour development as a result of the Maillard reaction between amino and carbonyl compounds and the subsequent formation of5-hydroxymethylfurfural(HMF)occurs. HMF can be used as an indicator for the freshness and quality of juices since HMF is almost absent in fresh and untreated juices but the concentration is increased after heat-treatment or long-term storage.Aguilo´-Aguayo et al.[45]investigated the non-enzymatic browning after PEF pasteurisation of fruit and vegetable juices. Fig.3shows the HMF contents in strawberry,tomato and watermelon juice after thermal and PEF treatment.The PEF processed juices had a lower HMF concentration than those treated by heat,a fact that can be attributed to the reduced thermal load to which the product is exposed during PEF preservation.However, pulse frequency,pulse width and polarity of the pulse were found to have a significant influence on HMF content in strawberry and tomato juice whereas in watermelon juice changes in HMF concentration were minor by applying PEF treatments.The effect of PEF on physicochemical characteristics of citrus juices was investigated by Cserhalmi et al.[46].Non enzymatic browning index(NEBI)and hydroxymethyl furfural content did not change due to the PEF treatments and volatile aroma compounds have been retained.Table1summarizes the values obtained by the authors for different citrus juices.The impact of PEF preservation on color,browning and hydroxymethylfurfural during storage of orange juice was investigated by Corte´s et al.[47]and compared to conventional pasteurisation.The non-thermal treated orange juice showed less non-enzymatic browning than the pasteurised one after a storage period of6weeks as measured photometrically by the browning index.The HMF content directly after treatment was higher in the pasteurised juice than in the PEF treated one but differences were found to diminish during storage.Microbial inactivation coupled with quality retention during non-thermal PEF treatment of liquid foods makes it anappropriate Fig.3.HMF content of unprocessed,heat-treated(908C for60s)and PEF treated (35kV/cm,treatment time1000m s,frequency150Hz,monopolar pulses,pulse width4m s)juices according to Aguilo´-Aguayo et al.[45].Table1Non enzymatic browning index(NEBI)and hydroxymethyl furfural(HMF)content (standard deviation in brackets)in unprocessed and PEF-treated(28kV/cm; treatment time100m s)citrus juices according to Cserhalmi et al.[46].Unprocessed juice PEF processed juiceNEBI HMF(mg/l)NEBI HMF(mg/l) Grapefruit0.105(0.0016)0.49(0.02)0.106(0.0013)0.49(0.02) Lemon0.0884(0.0045)0.19(0.05)0.0957(0.0034)0.25(0.04) Orange0.1091(0.0026)0.25(0.08)0.1094(0.0018)0.22(0.03) Tangerine0.1130(0.0011)0.17(0.03)0.1140(0.0007)0.18(0.06)H.Jaeger et al./Pathologie Biologie58(2010)207–213 210process to fulfill the consumer demands for high quality,minimally processed but safe foods with extended shelf life.5.Removal of substrateAmong the harmful Maillard reaction compounds,acrylamid received great attention in the recent years.It is spontaneously formed during heat treatment such as cooking and frying of foods rich in reducing sugars and amino-acids,mainly L -asparagine,as part of the Maillard reaction [48].Lowering the content of these substrates and the related Maillard reaction products can be either achieved by means of selecting appropriate raw materials or technological process parameters [49].For the reduction of the acrylamid content,the application of L -asparaginase as well as the addition of glycine as a competitor for the precursor asparagines was suggested by Vass et al.and Capuano et al.[50,51]for bakery and cracker products and by Zyzak et al.[52]for potato products.Whereas the addition of asparaginase and other additives to basic formulations of bakery products and subsequent blending allows sufficient dispersion of the components,the application of the above-mentioned strategies for textured raw materials like potato slices or chips and the sufficient diffusion of the components into the tissue remains limited.Therefore,PEF technology could be applied as a new method for cell disintegration.The occurring increase in membrane permea-bilization by exposure of biological cells to an external electric field positively affects the mass transfer rate.The consequence is that the diffusion of intracellular components in extracellular liquid is increased,while leaving the product matrix relatively unchanged [53–55].On the other hand,infusion of molecules into the food matrix can be facilitated as well [56].Post-harvest PEF pretreat-ment of food raw materials is therefore considered to be a method able to facilitate mass transfer processes and to assist in removing sugars or amino acids that represent the necessary substrates for the Maillard reaction.Own experiments using PEF for the disintegration of potato tissue prior to further processing to French fries showed the potential of removing substrates by two ways:increased release of sugars during blanching;increased infusion of enzymes (glucose oxidase or asparaginase)for enzymatic conversion of the substrates.Fig.4shows the reduction of the sugar content of potato slices achieved after PEF pretreatment and blanching in comparison tonon PEF pretreated samples.A 50%increase in glucose reduction in comparison to the untreated potato could be shown for the PEF pretreated sample.Pore formation in the cell membranes of the potato tissue and disintegration lead to enhanced mass transfer during blanching and an increased release of sugars.The cell disintegration index (percent of electroporated cells)was determined by impedance measure-ment [57]and amounted to 36%after the PEF pretreatment.In addition to the release of sugar and the removal of substrate by diffusion,the impact of PEF cell disintegration on the infusion of glucoseoxidase was investigated in order to obtain a higher penetration rate and a better distribution of the enzyme in the potato tissue to allow a high glucose oxidation rate.The same principles apply for the utilization of asparaginase.Fig.5shows the enzymatic decrease of the glucose content in the potato slices.A reduction of 52%was achieved by the application of glucoseoxidase without prior cell disintegration whereas the decrease could be enhanced by the PEF treatment to 65%.The electroporation proved to be an effective method to improve the diffusion of the enzyme as well as the enzyme substrate accessibility due to the cell disintegration.In addition to the application of PEF induced cell disintegration for subsequent removal of sugars or amino acids,the electropora-tion pretreatment and the enhanced diffusion properties can also be used to accelerate thermal processes like drying or frying of plant raw materials [58].Reduced thermal processing times in turn contribute to the avoidance of heat induced quality losses.6.ConclusionNon-uniform heating and the occurrence of over-processing during heat treatments of foods can be reduced by the application of improved thermal processing methods like ohmic heating which allows a shortening of processing times and improvement in product quality by avoiding the limitations of heat transfer occurring during indirect heating processes.Nevertheless,thermal processing for preservation or the modification of food structure still relies on the effects of the application of thermal energy for microbial and enzymatic inactivation as well as the alteration of the properties of food ingredients.The application of non-thermal technologies for ‘‘cold pasteur-ization’’of foods as well as for structural modifications allows to overcome the necessity of heating the food matrix and therefore reduces heat induced changes in product quality including nutritional and sensorialproperties.Fig.4.Difference in sugar content in potato slices after PEF treatment (1.5kV/cm and 20pulses)and hot water blanching (708C for 90s)in comparison to not PEF treatedsamples.Fig.5.Reduction of glucose in potato slices as a result of treatment with glucose oxidase and PEF-pretreatment (1.5kV/cm,20pulses)to enhance enzyme diffusion in the potato tissue.H.Jaeger et al./Pathologie Biologie 58(2010)207–213211。
R E V I E W A RT I C L EAlpha-2and imidazoline receptor agonists Their pharmacology and therapeutic roleZ.P.Khan,1C.N.Ferguson2and R.M.Jones31Lecturer,2Honorary Lecturer and3Professor,Department of Anaesthetics,Imperial College School of Medicine,St Mary’s Hospital,London W21NY,UKSummaryClonidine has proved to be a clinically useful adjunct in clinical anaesthetic practice as well as inchronic pain therapy because it has both anaesthetic and analgesic-sparing activity.The moreselective alpha-2adrenoceptor agonists,dexmedetomidine and mivazerol,may also have a role inproviding haemodynamic stability in patients who are at risk of peri-operative ischaemia.Theside-effects of hypotension and bradycardia have limited the routine use of alpha-2adrenoceptoragonists.Investigations into the molecular pharmacology of alpha-2adrenoceptors have elucidatedtheir role in the control of wakefulness,blood pressure and antinociception.We discuss thepharmacology of alpha-2adrenoceptors and their therapeutic role in this review.The alpha-2adrenoceptor agonists are agonists at imidazoline receptors which are involved in central bloodpressure control.Selective imidazoline agonists are now available for clinical use as antihypertensiveagents and their pharmacology is discussed.Keywords Receptors;alpha-2,imidazoline. ......................................................................................Correspondence to:Dr Z.P.Khan.Present address:Department ofAnaesthesia and Intensive Care,City Hospital NHS Trust,DudleyRoad,Birmingham B187QH,UKAccepted:24June1998The widespread use of alpha-2adrenoceptor agonists in veterinary practice has provided extensive experience over 20years.In addition,alpha-2adrenoceptor agonists have been used to a limited degree in clinical practice and their molecular pharmacology has been elucidated.This has also cast some light on the mechanisms of action of a variety of other drugs not directly associated with alpha-2 adrenoceptors.Alpha-2adrenoceptor agonists are not routinely used by the majority of anaesthetists despite having many desirable effects,including anxiolysis,analgesia, sedation,anaesthetic-sparing and peri-operative haemo-dynamic-stabilising effects.Their potential thus remains to be fully realised.This may be because there are no highly specific alpha-2adrenoceptor agonists currently available for anaesthesia(clonidine has some alpha-1activity)and there is a possibility of undesirable haemodynamic effects at certain doses.Indeed there is still debate as to whether these drugs offer real clinical benefits.Clonidine,mivazerol and to a lesser extent dexmed-etomidine are not pure alpha-2adrenoceptor agonists but are also able to combine with nonadrenergic imidazoline receptors[1].These receptors are binding sites specifically recognising the imidazoline or oxazoline chemical struc-ture and have been classified into I1found in the brain,and I2found in the brain,kidney and pancreas.Imidazoline-receptor stimulation mediates a central hypotensive and anti-arrhythmogenic action.It may be possible that some of the effects of alpha-2adrenoceptor agonists are medi-ated by imidazoline receptors.Moxonidine and rilmeni-dine are thefirst orally active imidazoline receptor agonists to be introduced into clinical practice.In this review we discuss the clinical pharmacology of alpha-2adrenoceptorAnaesthesia,1999,54,pages146–165 ................................................................................................................................................................................................................................................146ᮊ1999Blackwell Science Ltdagonists and reflect on their potential use in anaesthesia as well as critical-care practice.Molecular pharmacologyReceptor classificationHistoryIn1948Ahlquist challenged the view that adrenergic receptors were either excitatory or inhibitory by differ-entiating adrenergic receptors into alpha and beta[2].In 1969,Paton and co-workers found that a subclass of alpha adrenoceptors located presynaptically regulated the release of neurotransmitter[3].This led to the subdivision of alpha adrenoceptors into postsynaptic alpha-1and presynaptic alpha-2[4,5].However,this proved to be misleading with the characterisation of alpha-2adrenoceptors postsynapti-cally and extrasynaptically[6].A functional classification of alpha-2adrenoceptors as inhibitory and alpha-1as excita-tory also proved to be inaccurate,as not all alpha-2 adrenoceptors are inhibitory[7].Stimulation of alpha-1 and alpha-2adrenoceptors in vascular smooth muscle results in vasoconstriction.Clearer characterisation of alpha-1and alpha-2adrenoceptors on a pharmacological basis followed the discovery of selective antagonists,pra-zosin being more potent at alpha-1adrenoceptors and yohimbine being more potent at alpha-2adrenoceptors[8]. Bylund and co-workers[215]defined three alpha-2 isoreceptors;alpha-2a,alpha-2b and alpha-2c based on their affinity for alpha adrenoceptor ligands.The regional distribution of the isoreceptors has been demonstrated autoradiographically using radiolabelled probes.The genes responsible for encoding alpha-2adrenoceptors in the human platelet have been identified on chromosome10 [9]and the human kidney on chromosome4[10].Further alpha-2adrenoceptors have been cloned from genes located on chromosome2[11].Therefore the alpha-2 adrenoceptors can be further classified as alpha-2C10, alpha-2C4and alpha-2C2and these correspond with alpha-2a,alpha-2c and alpha-2b,respectively.The three alpha-2adrenoceptor subtypes bind alpha-2agonists and antagonists with similar affinities.Structure of alpha-2adrenoceptorsThe alpha-2adrenoceptor is a transmembrane receptor. This is an excitable protein which traverses the cell mem-brane and reacts selectively with extracellular ligands (endogenous hormones or exogenous molecules such as drugs)to initiate a cascade of events leading to a physio-logical effect.The long chain of amino acids making up the alpha-2adrenoceptor protein contains hydrophobic and hydrophilic areas.It winds in and out of the cell membrane,crossing the cell membrane seven times at the hydrophobic areas.The seven hydrophobic segments are made up of20–25amino acids forming alpha helices that are embedded in the membrane.The three alpha-2recep-tor subtypes are72–75%identical to each other with respect to amino acid sequence in the membrane-spanning domains.This sequence homology can be compared with a similarity between different adrenoceptors of42–45% and alpha-2and muscarinic receptors of35%.This indi-cates that the transmembrane area of the receptors is important for selectivity of ligand binding.T o bind a ligand,a receptor must have charged counterbalancing ions located within it,but the transmembrane region itself is nonpolar.This apparent inconsistency can be explained by the way the side-chain groups in critical amino acids are charged and coalesce to form a binding pocket permitting access from the extracellular space for binding charged ligands.The third and fourth transmembrane domains are most important[12]with more minor involvement from the sixth and seventh domains.It can be inferred that these domains are closely related in the three-dimensional structure of the molecule.The structure of the ligand determines whether it has agonistic or antagonistic effects on the receptor.Mutation of amino acids in these regions affects the binding of agonists and antagonists and their physiological effects.The cytoplasmic aspect of the recep-tor protein forms a contact point for the G-protein providing a means of signal transduction and therefore rapid stimulation of the effector system.G-proteinsAlpha-2adrenoceptors are examples of G-protein-coupled receptors.G-proteins are ubiquitous transmem-brane signalling mediators[13].They are proteins that bind the guanine nucleotides,GDP(guanosine diphos-phate)and GTP(guanosine triphosphate).The adrenergic receptors and opioid receptors are also coupled to G-pro-teins.Other receptors,which are also G-protein coupled include the following:adenosine(AI),acetylcholine(M2), GABA B,dopamine(D2)and histamine(H2).The G-pro-teins are composed of three polypeptide subunits desig-nated as alpha,beta and gamma in order of decreasing molecular mass.The G-proteins can be classified according to their action on adenyl cyclase and the sensitivity of their alpha subunit to ribosylation by Bordetella pertussis toxin.The alpha-2 adrenoceptors are coupled to pertussis-toxin-sensitive G-proteins,G o which has no effect on adenylyl cyclase, and G i which supports inhibition of adenylyl cyclase[14]. Beta adrenoceptors are coupled to the G-protein G s which is not pertussis-toxin sensitive and stimulates the activation of adenylyl cyclase.In the inactive state,the G-protein is not closely associated with the alpha-2receptor and is bound to GDP.When an agonist binds to the receptor,the structure of the receptor changes and it associates with the147ᮊ1999Blackwell Science Ltdalpha subunit of the G-protein.This results in a reducedaffinity of the G-protein for GDP and in the presence ofmagnesium,it is replaced by GTP .The alpha subunit thenuncouples from the beta and gamma subunits and coupleswith the effector,resulting in a decrease in the affinity ofthe receptor for the agonist and the agonist leaves its receptorsite.The duration of binding of the agonist to the receptordetermines the amount of amplification of the intracellularresponse.The GTPase on the alpha subunit is then acti-vated and hydrolyses GTP to GDP ,releasing an inorganicphosphate;the receptor then returns to the inactive state[15].A number of effector mechanisms (see below)havebeen described:each alpha-2receptor may stimulate morethan one effector mechanism and although each may notrepresent a pathway to a biological response,the physio-logical and clinical relevance remains to be elucidated.Adenylyl cyclaseAn important consequence of alpha-2adrenoceptor stimu-lation is the inhibition of adenylyl cyclase and this results indecreased formation of 3H 5H -cyclic adenosine monophos-phate (cAMP).This is an important regulator of manycellular functions by controlling the phosphorylation stateof regulatory proteins by cAMP-dependent protein kinase[16].Although the inhibition of adenylyl cyclase is analmost universal effect of alpha-2adrenoceptor activation,the decrease in intracellular cAMP cannot explain many ofthe physiological results.Alternative effector mechanismsThese include activation of G i -protein-gated potassiumion channels [17],causing hyperpolarisation of the neuronal cell and so reducing the rate of firing of excitable cells in the central nervous system [18].The increase in potas-sium-ion conductance is calcium dependent in many systems and the inhibition of adenylyl cyclase may also play a permissive role.Alpha-2-adrenoceptor stimulation resulting in inhibition of neurotransmitter release is mediated through a decrease in calcium-ion conductance.The decrease in calcium-ion conductance involves direct regulation of calcium entry by voltage-gated calcium ion channels [19]and these may be coupled to a G o -protein [20].Activation of alpha-2adrenoceptors can also accele-rate sodium–hydrogen-ion exchange causing alkalinisation of the interior of platelets and stimulating an increase in phospholipase A 2activity resulting in increased formation of thromboxane A 2[21].Alpha-2receptors can modulate the actions of phospholipase C that mediate the hydrolysis of phosphatidyl inositol biphosphate into diacyglycerol and inositol triphosphate (Fig.1).Distribution of alpha-2adrenoceptors Presynaptic alpha-2adrenoceptors are present in sympa-thetic nerve endings and noradrenergic neurones in the central nervous system where they inhibit the release of noradrenaline [22].Postsynaptic alpha-2adrenoceptors exist in a number of tissues where they have a distinct physio-logical function;these include the liver,pancreas,platelets,kidney,adipose tissue and the eye.The medullary dorsal motor complex in the brain has a high density of alpha-2adrenoceptors and activation of these may be responsible for the hypertensive and bradycardic effects of alpha-2adrenoceptor agonists.The locus coeruleus is a small neuronal nucleus located 148ᮊ1999Blackwell ScienceLtdbilaterally in the upper brainstem and is the largest nor-adrenergic cell group in the brain.The locus coeruleus is an important modulator of wakefulness and may be the major site for the hypnotic action of alpha-2adrenoceptor agonists mediated by alpha-2a adrenoceptors located there [23].The locus coeruleus has a number of efferent con-nections.Cortical activity is influenced by the connection with the subthalamic relay nucleus and the thalamus via noradrenergicfibres.Nociceptive transmission at a spinal level is decreased via descendingfibres in the dorsolateral funiculus tracts.There are also efferentfibres to the reticu-lar formation with connections to the vasomotor centres [24].There are afferent connections from the rostral ven-trolateral medullary nuclei.A high density of alpha-2 adrenoceptors has also been demonstrated in the vagus nerve,intermediolateral cell column and the substantia gelatinosa.The dorsal horn of the spinal cord contains alpha-2a subtype adrenoceptors,while the primary sen-sory neurones contain both alpha-2a and alpha-2c sub-types of adrenoceptors.Imidazoline receptor agonistsBlood pressure controlThe ventromedial(depressor)and the rostral-ventrolateral (pressor)areas of the medulla are responsible for the central regulation of cardiovascular tone and blood pressure.They receive afferentfibres from the carotid and aortic baro-receptors,which form the tractus solitarius via the nucleus tractus solitarius.V ariations in blood pressure are detected by the carotid and aortic baroreceptors and theirfiring is altered.This results in an increase or decrease in both sympathetic outflow and vagal impulses to maintain blood pressure.Sympathetic overactivity and decreased parasym-pathetic tone is present in human hypertension[25]. HistoryFirst generation centrally acting antihypertensives such as clonidine and a-methyl dopa were originally thought to decrease sympathetic tone by stimulating alpha-2adreno-ceptors in the medulla.When substances with an imidazo-line or catecholamine structure were injected directly into the medulla of anaesthetised animals only imidazolines had hypotensive effects and there was no correlation between their affinity for alpha-2adrenoceptors and their hypo-tensive effects[26].In the early1980s,Bousquet et al.[27, 28]proposed the existence of receptors specifically recog-nising the imidazoline or similar chemical structure and which were not adrenergic receptors.This was because the central hypotensive effects of clonidine-like drugs could not be explained by their alpha-2receptor actions alone.It was suggested that these receptors might be found in the nucleus reticularis lateralis of the ventrolateral medulla,the site of the hypotensive action of these drugs.In1987, Ernsberger and co-workers[29]were thefirst to verify the existence of specific imidazoline-binding sites in the ven-trolateral medulla which were insensitive to catecholamines. T wo subtypes of imidazoline receptor(I)have been iso-lated,I1and I2.I1receptors have a more restricted dis-tribution in the ventrolateral medulla[30].They are thought to be G-protein linked although the signalling pathway remains to be fully elucidated.However,it is likely that activation of phospholipase A2leading to the release of arachidonic acid and the subsequent generation of prostaglandins plays a major role[31].I1receptors are involved in blood-pressure regulation.I2receptors have been found in the liver,platelets,adipocytes,kidneys, adrenal medulla and brain,including the frontal cortex [32–36].They have been implicated in neuroprotection in the animal model of ischaemic infarction[37].I2receptors are found mainly on the mitochondrial membrane and are not G-protein linked[37].Unlike the I1receptors,I2 receptors are not found on neuronal plasma membranes [38].The imidazoline receptor protein has a molecular mass of70kDa but the exact amino acid sequence is not yet known.Several endogenous ligands for I receptors, collectively termed clonidine-displacing substances(CDSs), have been detected in tissues and serum.The only CDS whose structure is known is agmatine.It is bioactive and widely distributed and binds to alpha-2adrenceptors and all classes of imidazoline receptors[39].The exact role of agmatine remains to be elucidated but its presence in specific neuronal pathways,as well as in serum,suggests that it might be a novel neurotransmitter or hormone[40]. It has been suggested that imidazoline receptors play a role in the genesis of adrenaline-induced dysrhythmia under halothane anaesthesia.Rilmenidine dose dependently inhi-bits adrenaline-induced dysrhythmias under halothane anaesthesia in dogs[41].This action was blocked by bilateral vagotomy and by pretreatment with a nonspecific alpha-2adrenoceptor and imidazoline receptor antagonist idazoxan intracisternally.Pretreatment with rauwolscine, an alpha-2adrenoceptor antagonist,also intracisternally, did not affect the anti-arrhythmic effect of rilmenidine. Therefore it can be said that activation of central imidazo-line receptors and vagal tone are critical to the anti-arrhythmic action of rilmenidine.Moxonidine,which is selective for the I1receptor,increased the threshold for oubain-induced cardiac dysrhythmias in guinea pigs,this suggests that the I1subtype may be responsible for the anti-arrhythmic effects[42].Agonists(Table1)RilmenidineThe oxazoline,rilmenidine,has a structure similar to that of imidazolines and is a centrally acting imidazoline receptor149ᮊ1999Blackwell Science Ltdagonist (Fig.2).It is one of a new generation of centrallyacting antihypertensive agents.The safety and efficacy ofrilmenidine as a treatment for human hypertension hasbeen demonstrated in clinical trials [43].It was found to beequally efficacious in elderly hypertensive patients [44]andthose who also suffered from diabetes [45],renal impair-ment [46]or left ventricular hypertrophy [47].In animalstudies,rilmenidine has been shown to increase sodiumexcretion and urine flow rates [48].It is comparable withatenolol [49]and hydrochlorothiazide [47]as a first lineantihypertensive.Both rilmenidine and idazoxan,an imi-dazoline receptor antagonist,have neuroprotective effectsin the animal model of ischaemic infarction.The precisenature of this is not known,but an interaction with theimidazoline I2receptors on the mitochondrial membraneof astrocytes in the cerebral cortex,causing a calcium sink,is one hypothesis.Rilmenidine is rapidly absorbed after oral administra-tion,with a peak plasma concentration within 1.5–2h.It undergoes some oxazoline-ring hydrolysis and oxidation,but 65%of the dose is eliminated through the kidneys unchanged.Rilmenidine is 10%protein bound and its elimination half-life is 8h.Unlike clonidine,there appears to be no withdrawal syndrome following the cessation of treatment [50].Moxonidine A more potent and selective agonist for the imidazoline I1receptor is moxonidine.It is three times more selective for the I1receptor in the ventrolateral medulla than rilmeni-dine and has a 40–70times greater affinity for I1receptors than alpha-2adrenoceptors.Clonidine is twice as potent as moxonidine at the I1receptor but has a similar affinity for alpha-2and I receptors.Moxonidine acts by decreasing systemic vascular resistance secondary to a reduction in central sympathetic tone,reducing plasma catecholamine and renin levels [51].Moxonidine may also increase sodium and water excretion.It was shown to be as effective and well tolerated as atenolol [52],nifedipine [53],captopril [54]and prazosin [55]in controlling hypertension.After oral administration,moxonidine is rapidly and almost completely absorbed.Maximum plasma concentration is achieved in 1h.It has a plasma half-life of 2h and is 90–96%excreted by the kidneys,51%as unchanged drug.A dose of 0.4mg daily will effectively lower the blood pressure over 24h,although the dose should be reduced if there is renal impairment.The imidazoline receptor agonists have few of the adverse effects of clonidine such as dry mouth,sedation,depression and tiredness and can be given as a once-daily dose.The hypotensive effects of these drugs can be antagonised by idazoxan and efaroxan which are antagonists at both imida-zoline receptors and alpha-2adrenoceptors,but not by 2-MI a selective alpha-2adrenoceptor antagonist [56–58].Alpha-2receptor agonists (Table 2)Clonidine is an imidazoline and is the only alpha-2adreno-ceptor agonist currently available for use in anaesthetic practice (Fig.3).It is available as 100/250/300m g tablets for oral administration,as a transdermal patch releasing 100/200/300m g over 24h and in an injectable solution containing 150m g.ml À1for intravenous,intramuscular,local and regional use.It is a partial agonist with an alpha-2a-to-alpha-1selectivity ratio of 39[59].The alpha-2a-to-imidazoline selectivity ratio is 16.The adult oral dose is 100–600m g administered 8hourly;the corre-sponding intravenous dose is 150–300m g,a dose of 150m g 150ᮊ1999Blackwell Science LtdTable 1Imidazoline receptor agonists in order of preference forimidazoline receptor.MoxonidineRilmenidineClonidineDexmedetomidineMivazerolas been used epidurally.Methyldopa’s use is limited to thecontrol of blood pressure in pregnancy;it has a slow onsetof action because the active component is the metabolitemethylnoradrenaline.Currently under investigation is dexmedetomidine,amore specific and shorter-acting alpha-2adrenoceptoragonist with an alpha-2a-to-alpha-1ratio of 1300[59]and alpha-2a-to-imidazoline selectivity ratio of 32.Dex-medetomidine is a potent drug,at plasma concentrationsless than 1.0ng.ml À1it can produce profound physio-logical alterations.Dexmedetomidine is an isomer and the active component of medetomidine.Although initially designed to prevent myocardial ischaemia,mivazerol is an alpha-2agonist which may have potential for peri-operative use;it has an alpha-2a-to-alpha-1selectivity ratio of 119and an alpha-2a-to-imidazoline selectivity ratio of 215,the specificity is between clonidine and dexmedetomidine [59].Alpha-2receptor antagonists (Table 3)A drug which could cross the blood–brain barrier and selectively reverse the central effects of alpha-2adreno-ceptors would be a useful adjunct to anaesthetic practice.Atipamezole,idazoxan and yohimbine are selective and centrally acting alpha-2adrenoceptor antagonists;all have been used in veterinary practice.Currently ,the more selective alpha-2adrenoceptor antagonists are not available for clinical application.However,Karhuvaara and colleagues [60]gave atipamezole intravenously to human volunteers to reverse the effects of a preceding dose of dexmedetomidine.Atipamezole,the most selective of the alpha-2adrenoceptor antagonists,was able to reverse the sedation and hypotension caused by dexmedetomidine.Pharmacokinetics Clonidine is lipid soluble and so has both rapid and com-plete absorption after oral administration,reaching a peak plasma level in 60–90min.Time release transdermal patches are also available;2days of administration are required before therapeutic plasma concentrations are achieved.Because of its high lipid solubility clonidine crosses the blood–brain barrier and disappears rapidly from the cerebrospinal fluid (CSF).The elimination half-life after epidural injection of clonidine 150m g is 30min.It is 20%bound to plasma proteins and the volume of distribution is 1.7–2.5l.kg À1.Clonidine is less than 50%metabolised in the liver to inactive metabolites,the remain-ing drug being excreted unchanged in the kidney;about 151ᮊ1999Blackwell Science Ltd Table 2Selective and nonselective alpha-2adrenoceptor agonistsin order of preference for alpha-2adrenoceptor.Non-selective alpha-2adrenoceptor agonists Selective alpha-2adrenoceptor agonistsNoradrenaline DexmedetomidineAdrenaline MivazerolClonidinea-MethyldopaTable 3Selective and nonselective alpha-2adrenoceptor anta-gonists in order of preference for alpha-2adrenoceptor.Non-selective alpha-2adrenoceptor antagonists Selective alpha-2adrenoceptor antagonist Phentolamine Atipamezole Tolazoline Idazoxan Yohimbine Efaroxan Rauwolscine20%is excreted in the faeces.The elimination half-life is of the order of6–23h and is prolonged if renal impairment exists;the clearance is1.9–4.3ml.minÀ1.kgÀ1. Dexmedetomidine has a volume of distribution ofϷ200l and a systemic clearance of0.5l.minÀ1after administra-tion of an intravenous infusion.Dexmedetomidine exhi-bits a concentration-dependent nonlinear pharmacokinetic profile[61].At high concentrations following an intra-venous bolus,dexmedetomidine decreases the initial volume of distribution and intercompartmental clearance due to its peripheral vasoconstrictive action.Dexmedetomidine behaves in a biphasic manner,as the concentration declines vasodilatation occurs due to its central effect.Therefore, dexmedetomidine should not be administered rapidly as it can result in undesirable hypertension as well as altered pharmacokinetics.The decline in the plasma concentra-tion of dexmedetomidine following the cessation of an infusion is described by its context-sensitive half-life, which is similar to that of fentanyl.The intramuscular route probably offers the better predictability as well as reasonably rapid onset,the peak plasma concentration occurring within15min.Mivazerol given as a bolus dose followed by an infusion achieved a steady plasma concentration within30min of the initial dose.The plasma half-life is4h and it isϷ50% protein bound.About40–45%is excreted unchanged by the kidneys and about20–25%undergoes conjugation in the liver.PharmacodynamicsCentral nervous system effectsWhen adrenaline has been administered intracerebroven-tricularly,so that the blood–brain barrier is avoided in a number of mammals including man,sedation ranging from sleep to surgical anaesthesia has been described[62–65]. This effect may be mediated by postsynaptic alpha-2a sub-type adrenoceptors located in the locus coeruleus,causing a decrease in noradrenergic activity[66].The use of clonidine as an antihypertensive has been limited by its sedative effects,but offers advantages in anaesthetic prac-tice.When clonidine was given in a sufficient dose to produce sleep,the EEG showed an increase in stage I and2 sleep and decrease in rapid eye movement sleep[67]. Alpha-2adrenoceptor agonists and benzodiazepines pro-duce comparable anxiolysis[68].Clonidine at high doses can be anxiogenic owing to alpha-1[69],but paradoxically it has been used to treat panic disorders.Dexmedetomi-dine decreases cerebral bloodflow in dogs during anaes-thesia with both halothane and isoflurane,without evidence of global ischaemia occurring[70,71].It has little effect on intracranial pressure and in the animal models of brain ischaemia has been shown to be neuroprotective[72].The analgesic and reduction in anaesthetic requirements of alpha-2adrenoceptor agonists are discussed later. Cardiovascular system effectsThere are both alpha-1and alpha-2postjunctional recep-tors in the arterial and venous vasculature where they both mediate vasoconstriction[73].The alpha-1and alpha-2 adrenoceptors differ in their location and their utilisation of calcium.In the arterial vasculature,the alpha-1adreno-ceptors are junctional and the alpha-2adrenoceptors are extra-junctional,while the reverse is true of the venous vasculature.Alpha-1adrenoceptor stimulation produces vasoconstriction by utilising intracellular calcium while the alpha-2-adrenoceptor-mediated vasoconstriction uses extracellular calcium[74].This makes the alpha-2adreno-ceptor agonist’s pressor response more sensitive to calcium antagonists[75].Intravenous alpha-2adrenoceptor agonist administration leads to a decrease in heart rate and a transient increase in arterial blood pressure and systemic vascular resistance,but a decrease in cardiac output due to the activation of postjunctional vascular alpha-2adreno-ceptors.This is followed by a longer lasting decrease in heart rate and blood pressure due to a centrally mediated decrease in sympathetic tone and an increase in vagal activity.Neither the exact location nor the specific recep-tors responsible for the central hypotensive action of alpha-2adrenoceptor agonists are yet known.It seems that postsynaptic alpha-2adrenoceptors and imidazoline receptors in the brainstem are involved[76].Clonidine lowers the‘set point’around which arterial blood pressure is regulated.It also increases the gain of the baroreceptor system,resulting in lower heart rates for a given increase in blood pressure,and broadens the range of heart-rate responses to changes in blood pressure[77].The brady-cardia commonly seen after administration of alpha-2 adrenceptor agonists may be due to the central sympatho-lytic action of these drugs leaving vagal tone unopposed.It may also be due to presynaptic-mediated reduction of noradrenaline release or a direct vagomimetic action[78]. Although bradycardia can be a problem with the admin-istration of alpha-2adrenoceptor agonists,dexmedetomi-dine has been shown to protect against adrenaline-induced arrhythmia during halothane anaesthesia in dogs[79].This anti-arrhythmic action may be due to stimulation of imidazoline receptors.There are no known directly mediated alpha-2adreno-ceptor effects on the myocardium.Alpha-2adrenoceptor reduction in sympathetic tone and increase in parasym-pathetic tone results in a reduced heart rate,systemic metabolism,myocardial contractility and systemic vascular resistance.These all result in a decrease in the myocardial oxygen requirements.This is may be why clonidine has been successful in the treatment of angina pectoris[80].152ᮊ1999Blackwell Science Ltd。
