Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A hipertensão arterial sistêmica (HAS) caracteriza-se pelo aumento crônico da resistência vascular periférica, determinado essencialmente na microcirculação, que resulta de alterações vasculares funcionais e estruturais. Além disso, a redução da densidade arteriolar e capilar (rarefação da microcirculação) contribui para a elevação da pressão arterial na HAS. Nesse contexto, sabe-se que a hiperatividade do sistema nervoso simpático central está envolvida na fisiopatologia das alterações tanto funcionais quanto estruturais da HAS. No presente trabalho, investigamos os efeitos do tratamento crônico (28 dias) com anti-hipertensivos de ação central sobre a rarefação capilar funcional e/ou estrutural na pele, músculo esquelético e miocárdio de ratos espontaneamente hipertensos (SHR) adultos, modelo clássico de hipertensão arterial primária. Os ratos Wistar Kyoto (WKY) foram utilizados como controles normotensos. Foram utilizadas doses equipotentes de clonidina (0,1 mg/kg/dia), rilmenidina (1 mg/kg/dia) e moxonidina (10 mg/kg/dia), com relação ao efeito anti-hipertensivo. Também foram estudados os efeitos dos tratamentos sobre a massa ventricular esquerda. Para avaliação da densidade capilar funcional utilizamos microscopia por epi-iluminação e fluorescência e para avaliação da densidade capilar estrutural técnicas de marcação histoquímica dos capilares. Os resultados mostraram que houve aumento do número de capilares espontaneamente perfundidos (densidade funcional) na pele e no músculo esquelético de SHR tratados com todos os fármacos, com relação ao grupo SHR não tratado. Além disso, foi observada reversão da rarefação capilar estrutural no músculo esquelético de SHR com todas as drogas utilizadas. Por outro lado, não houve reversão da rarefação capilar estrutural no ventrículo esquerdo em nenhum grupo experimental. Finalmente, a hipertrofia do ventrículo esquerdo foi parcialmente revertida em SHR tratados com rilmenidina. Em conclusão, nossos resultados demonstraram que, além da redução da pressão arterial, a utilização de agentes anti-hipertensivos de ação central resulta na reversão de alterações microcirculatórias de ratos espontaneamente hipertensos e o uso de rilmenidina favorece a regressão da hipertrofia cardíaca. Os resultados também sugerem que a inibição da hiperatividade simpática central induz efeitos benéficos na microcirculação na hipertensão arterial. / Essential hypertension (EH) is characterized by chronic increases in peripheral vascular resistance, mainly resulting from functional and structural alterations of the microcirculation. Moreover, a reduction of arteriolar and capillary density (microvascular rarefaction) is involved in the increase of arterial pressure in EH. In addition, central sympathetic overactivity is involved in the pathophysiology of functional and structural alterations of the cardiovascular system in EH. In the present work, we investigated the effects of a long-term treatment (28 days) with centrally-acting antihypertensive drugs on functional and/or structural capillary rarefaction in the skin, skeletal muscle and heart of adult spontaneously hypertensive rats (SHR), a classical experimental model of EH. We also investigated the effects of the treatments on left ventricular mass in SHR. Wistar Kyoto rats were used as normotensive controls. We used equipotent anihypertensive doses of clonidine (0.1 mg/kg/day), rilmenidine (1 mg/kg/day) and moxonidine (10 mg/kg/day). Functional capillary density was evaluated using epi-illuminated fluorescence video-microscopy while structural capillary density was studied using a histochemical tracer of capillaries. Our results showed that there was an increase in the number of spontaneously perfused capillaries (functional density) in the skin and skeletal muscle of SHR in all treatment groups, when compared to the non-treated SHR group. Moreover, there was a reversion of structural capillary rarefaction in the skeletal muscle with all drug treatments. On the other hand, there was no reversion of structural capillary rarefaction of the left ventricle in any experimental group. Finally, left ventricular hypertrophy was partially reversed in the group of SHR treated with rilmenidine. In conclusion, our results showed that besides arterial pressure reduction, long-term treatment with centrally-acting antihypertensive drugs induces a reversal of microcirculatory alterations in SHR and rilmenidine favors the regression of left ventricular hypertrophy. The results also suggest that the modulation of central sympathetic overactivity induces beneficial effects on the microcirculation in the hypertensive disease.

Objetivos: Avaliar a influência da adição de clonidina a sedação e analgesia com morfina e midazolan em infusão contínua em crianças submetidas à ventilação mecânica. Métodos: Estudo randomizado, duplo cego e placebo controlado, realizado na UTI Pediátrica do Hospital Geral de Caxias do Sul. Incluídas crianças submetidas à ventilação mecânica que utilizaram morfina e midazolan em infusão contínua. Foram randomizados a receber clonidina (5 μg/kg/cada 8 horas) ou placebo associados a infusão dos sedativos. Diariamente eram anotadas as doses infundidas nas 24 horas, assim como as doses de sedação intermitente e aplicado o escore de Finnegan para definir e quantificar abstinência. Os grupos foram comparados quanto a doses de sedativos administradas, tempo de uso de infusão contínua, presença e duração da abstinência.Resultados: Foram incluídas 69 crianças (31 no grupo clonidina e 38 no placebo). Completaram o estudo 59 pacientes, 25 no grupo clonidina e 34 no placebo. Os grupos foram semelhantes nas características gerais (peso, idade, sexo, indicação de ventilação mecânica). Não houve diferença nas doses de sedativos utilizadas, tanto em infusão contínua quanto intermitente. A prevalência da abstinência foi semelhante (72 e 75%, respectivamente), da mesma forma que sua duração, além de não haver diferença no tempo de ventilação mecânica. Conclusão: Neste estudo, a adição de clonidina ao esquema de sedação não influiu nas doses diárias e cumulativas de sedativos utilizados e também não alterou a prevalência ou a evolução da abstinência. Atribuímos à ausência de eficácia ao elevado grau de sedação utilizado neste serviço para crianças em ventilação mecânica. / Objective: To evaluate the sedative effect of associating clonidine to the morphine plus midazolan intravenous infusion in children submitted to mechanical ventilation Methods: Randomized, double blind, placebo controlled, carried through clinical assay in the PICU of the Hospital Geral of Caxias do Sul. It has been enclosed children submitted to mechanical ventilation, which had used morphine and midazolan in continuous infusion. It’s had been randomized to received clonidine (5μg/kg/8/8h) and placebo associated to infusion of sedative. Daily it’s written the administered doses in the 24 hours, beyond the doses of intermittent sedation and the Finnegan Score applied to define and to quantify the withdrawal. The groups had been compared to managed doses of sedatives, time of use of continuous infusion, presence and duration of the abstinence. Results: 69 patients had been enclosed to project (31 in clonidine group and 38 in the placebo group). The two groups had been similar in general characteristics (weight, age, gender, indication of mechanical ventilation). It did not have difference in the midazolan and morphine doses used between the groups, in the necessity of extra sedation as well. 59 patients had completed the study, 25 in clonidine group and 34 in placebo group. The prevalence of the abstinence was similar (72% and 75%, respectively), in the same way that its duration. It hasn’t been any difference in the mechanical ventilation time also. Conclusion: The clonidine did not show effectiveness in the evolution of the abstinence in this study, probably for objectives of sedation used in this service.

O presente estudo comparou os efeitos da raquianestesia com o anestésico local bupivacaína isobárica a 0,5% isolado ou associado ao agonista alfa adrenérgico clonidina em gatas anestesiadas com propofol e isofluorano para realização de ovariosalpingohisterectomia. Trinta gatas foram pré-tratadas com meperidina; decorridos 15 minutos, a indução da anestesia foi realizada com propofol, seguido de isofluorano para manutenção anestésica. As gatas foram distribuídas em três grupos, onde receberam, na raquianestesia: solução fisiológica (GSF); bupivacaína isobárica (GB), ou bupivacaína isobárica e clonidina (GBC). Todos os animais foram submetidos a ovariosalpingohisterectomia. As frequências cardíaca e respiratória, pressão arterial e temperatura retal foram mensuradas durante todos os momentos de avaliação. Durante a anestesia, foram incluídas as análises da fração expirada de dióxido de carbono, fração expirada de isofluorano e saturação da oxihemoglobina periférica. A hemogasometria foi realizada previamente a raquianestesia a ao término do procedimento cirúrgico. O grau de sedação, foi analisado no período de recuperação com auxílio de escore A raquianestesia com bupivacaína e clonidina não promoveu alterações na frequência e ritmo cardíaco, pressão arterial nem depressão respiratória tendo em vista que os valores de frequência respiratória e fração expirada de dóxido de carbono permaneceram dentro dos valores fisiológicos. O emprego de bupivacaína isolada e em associação à clonidina promoveu redução da concentração expirada de isofluorano (respectivamente 63,5% e 70) quando comparados ao grupo controle. O uso de clonidina determinou sedação no período de recuperação. O uso da raquianestesia com bupivacaína isobárica a 0,5% isolada ou em associação à clonidina demonstrou boa estabilidade hemodinâmica e significativa diminuição no requerimento de anestésico geral; a clonidina potencializou o efeito da bupivacaína isobárica no momento cirúrgico e apresentou grau satisfatório de sedação no período pós operatório / This study compares effects of spinal anesthesia with isobaric bupivacaine at 0,5% either isolated or associated to clonidine administered to female cats undergoing ovariohysterectomy under the effect of propofol and isoflurane. Meperidine was administered to thirty female cats whose anesthetic induction was performed 15 minutes later with the help of propofol followed by isoflurane for maintenance of anesthesia. The female cats were split into three different groups which received one of the following substances each for spinal anesthesia: physiological saline solution (GSF); isobaric bupivacaine (GB); isobaric bupivacaine and clonidine (GBC). All thirty animals underwent ovariohysterectomy. Heart and respiratory rate, blood pressure and rectal temperature were measured throughout the procedures. Under anesthesia, the fraction of expired carbon dioxide, the fraction of expired isoflurane and the saturation of oxihemoglobin were analyzed. Arterial blood gasometry was performed before spinal anesthesia and after surgical procedures. The level of sedation was analyzed during recovery with the help of scores from Selmi et al. (2004) Spinal anesthesia associated to bupivacaine and clonidine did not alter the heart rate, blood pressure or respiratory depression once the respiratory rate numbers and the fraction of expired carbon dioxide numbers ranged within the normal physiological values. The use of bupivacaine, either isolated or associated to clonidine, led to the reduction of the concentration of expired isoflurane (63,5% and 70% respectively) when compared to the control group. The use of clonidine led to sedation during recovery. The use of spinal anesthesia combined with isobaric bupivacaine at 0,5%, isolated or associated to clonidine, demonstrated good hemodynamic stability and a significant decrease in the need of general anesthesia; clonidine optimized the effect of isobaric bupivacaine throughout surgical procedures and also showed a satisfactory level of sedation during the postoperative period

Orientador: Eneida de Paula / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-23T12:15:29Z (GMT). No. of bitstreams: 1 Braga_MarioAntonio_M.pdf: 2842926 bytes, checksum: f402efe6ac374c0c0a33cc9d3c87fbd5 (MD5) Previous issue date: 2013 / Resumo: A clonidina (CND) é um composto imidazólico que foi sintetizado em 1960 e utilizado inicialmente como descongestionante nasal por sua ação vasoconstritora. Após o início do uso clínico deste fármaco, foram observados efeitos sistêmicos surpreendentes como hipotensão arterial, sedação e bradicardia. Como consequência de seu efeito hipotensor, este fármaco foi utilizado com eficácia no tratamento da hipertensão arterial durante 25 anos. Com a elucidação do seu mecanismo de ação, outras indicações foram sendo propostas na prática clínica e assim o fármaco ganhou expressivo interesse na anestesiologia, sendo utilizado como medicação pré-anestésica, adjuvante na anestesia geral, anestesia regional e pós-operatória, inclusive em pacientes pediátricos. Apesar da amplitude de indicações no tratamento da dor e anestesia, o fármaco apresenta reações adversas, tornando-se necessário manipular suas propriedades físico-químicas no intuito de aperfeiçoar seu efeito terapêutico e diminuir reações adversas. Neste trabalho objetivamos veicular a CND em hidroxipropil-beta-ciclodextrina (HP-?-CD), com o intuito de otimizar a ação do fármaco, reforçando seu uso na prática clínica como analgésico e adjuvante na anestesia infiltrativa. Para este fim complexos de inclusão da CND com o carreador proposto foram preparados e caracterizados; além disso, o efeito anestésico in vivo da CND livre e complexada, associada ao anestésico local bupivacaína, foi avaliado pelo teste de tail-flick, após injeção intratecal em ratos Wistar. Uma relação estequiométrica 1:1 (CND:HP-?-CD) foi determinada e o tempo de equilíbrio foi de 24 horas. O complexo foi caracterizado por medidas de calorimetria exploratória diferencial, difração de raios-X, microscopia eletrônica de varredura e cinética de liberação. Estes ensaios forneceram indícios da associação da CND com a HP-?-CD, haja visto a diferença entre os picos endotérmicos, padrões de difração, padrão de cristalinidade e retardo em liberação, respectivamente. Os ensaios de ressonância magnética nuclear de hidrogênios mostraram baixa afinidade entre a CND e a HP-?-CD (Ka = 20 L/M-1), porém foi possível evidenciar os detalhes moleculares da inserção do anel aromático na cavidade da HP-?-CD. Apesar disso, o efeito anestésico do complexo CND:HP-?-CD, avaliado em animais, foi pronunciadamente superior ao dos fármacos CND e bupivacaína, isoladamente, indicando a viabilidade desta formulação para uso associado a anestésicos locais, na anestesia operatória / Abstract: Clonidine (CND) is an imidazole compound synthesized in 1960 and originally used as a nasal decongestant for its vasoconstrictor action. After initial clinical use, unexpected systemic effects were observed as hypotension, bradycardia and sedation. As a consequence of its hypotensive effect, this drug has been successfully used in the treatment of hypertension for over 25 years. With the elucidation of its mechanism of action, other indications were proposed in clinical practice. CND has gained significant interest in anesthesiology, being used as an adjuvant to general and regional anesthesia, during surgery or in the postoperative period, even in children. Despite its breadth of indications in the treatment of pain and anesthesia, CND has adverse reactions, making it necessary to manipulate its physicochemical properties in order to improve the therapeutic efficacy and decrease adverse reactions. In this work we proposed to complex clonidine with hydroxypropyl-beta-cyclodextrin (HP-?-CD) in order to optimize drug action enhancing its use as an analgesic adjuvant in infiltration anesthesia. For that, in addition to the preparation and characterization of a CND:HP-?-CD, inclusion complex, we evaluated the in vivo anesthetic effect of free and complexed CND, associated with the local anesthetic bupivacaine. A 1:1 stoichiometric ratio (CND:HP-?-CD) was determined after an equilibrium time of 24 hours. The complex was characterized by differential scanning calorimetry, X-ray diffraction, scanning electron microscopy and release kinetics. These trials provided evidences for the inclusion complexation of CND in HP-?-CD, considering the differences between endothermic peaks, diffraction patterns, standard crystallinity and sustained release, respectively. Nuclear magnetic resonance experiments revealed a low binding constant between clonidine and HP-?-CD (Ka = 20 L/M-1) but provided molecular details on the insertion of the aromatic ring inside the HP-?-CD macromolecular cavity. Despite that, the anesthetic effect of clonidine:HP-?-CD complex in animals was considerably higher than that evoked by clonidine and bupivacaine alone, pointing out the future use of this drug delivery formulation in association with local anesthetics, for surgical anesthesia procedures / Mestrado / Fármacos, Medicamentos e Insumos para Saúde / Mestre em Biociências e Tecnologia de Produtos Bioativos

No description available.

Study objective - The aim was to determine whether areas in the periaqueductal grey matter, medial dorsal raphé, or ventrolateral medulla might be involved with the integration of blood pressure and heart rate during isometric exercise.Design - Cats were anaesthetised with α chloralose (75 mg·kg-1) and catheters inserted into the right jugular vein and carotid artery. Isometric contractions were generated using a microprocessor controlled stimulator and sleeve electrode around the tibial nerve. Bilateral lesions were made in the dorsal periaqueductal grey matter (P1.0, LR 2.0, HD + 1.5 mm) or two sites in the ventrolateral medulla (P12.0, RL 2.0, HD -10 mm; or P12.0, RL 2.0, HD -8.5 mm). Lesions were also made in the medial dorsal raphé nuclei (P1.0, RL 0.0, HD +1.5 mm). Clonidine was injected into the cerebral aqueduct to determine whether it would exert an antipressor effect during muscle contraction after the lesions were made. Only one site of lesion was made in a group of animals. Bilateral injections of clonidine (250 ng in 0.5 μl) were made into the intact ventrolateral medulla (P11.5, RL 4.0, HD -8.5 mm) to explore its role further. Fatiguing contractions were performed before and after the lesions were made, or clonidine was injected, and changes in arterial blood pressure and heart rate were measured. Verification of the lesion sites or the microinjection sites, and the extent of the lesion or spread of the clonidine, was made from histological examination of brain tissue after each experiment.Experimental material - Adult cats of either sex, n = 20, weight 2.4 (SD 0.4) kg, were used.Measurements and main results - Fatiguing isometric contractions in control conditions caused mean arterial pressure to increase by 45-50 mm Hg and heart rates by 20-25 beats·min-1. Bilateral lesions in the dorsal periaqueductal grey matter did not alter resting mean arterial pressure but attenuated the pressor response during contractions. Injections of clonidine into the cerebral aqueduct had no further antipressor effects after the lesions. Lesions of the medial dorsal raphé nuclei or injections of clonidine into the intact medial dorsal raphé nuclei did not affect the pressor response to fatiguing isometric contractions. Injections of clonidine into the intact ventrolateral medulla eliminated the pressor response to isometric contractions. Bilateral lesions of the ventrolateral medulla near the rostral lateral border of the inferior olivary tract nuclei (P12.0, LR 2.0, HD -10 mm) also attenuated the muscle pressor response, while subsequent injections of clonidine into the cerebral aqueduct depressed the changes in blood pressure further.Conclusions - Ergoreceptor information may be processed through the periaqueductal grey matter through the ventrolateral medulla to control arterial blood pressure during isometric exercise to fatigue.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Diss. Linköping : Univ., 2004.

Το αιμορραγικό shock (H/S) έχει δειχθεί πως προκαλεί οξειδωτικό stress (OS) σε διάφορους ιστούς λόγω της υπερπαραγωγής ελευθέρων ριζών οξυγόνου στη φάση της επαναιμάτωσης και επίσης σχετίζεται με την ανάπτυξη ενδοτοξιναιμίας. Επίσης, το είδος της καταστολής που χρησιμοποιείται στις Μονάδες Εντατικής Θεραπείας (ΜΕΘ) έχει επίπτωση στη νοσηρότητα και τη θνητότητα των ασθενών. Η κλονιδίνη, ένας α2-αδρενεργικός αγωνιστής, που έχει χρησιμοποιηθεί τόσο περιεγχειρητικά όσο και για καταστολή στη ΜΕΘ, φαίνεται πως ασκεί προστατευτική δράση σε μοντέλα ισχαιμίας/επαναιμάτωσης. Σκοπός: Σκοπός της παρούσας μελέτης ήταν η εκτίμηση της επίδρασης της προχορήγησης κλονιδίνης στο οξειδωτικό φορτίο στο έντερο, το ήπαρ και τους πνεύμονες και στην ανάπτυξη ενδοτοξιναιμίας στην πυλαία και συστηματική κυκλοφορία σε επίμυες που υποβλήθηκαν σε σημαντικού βαθμού H/S. Υλικό και Μέθοδος: Η μελέτη πραγματοποιήθηκε σε 64 επίμυες και αποτελείται από δύο σκέλη: ένα για τον προσδιορισμό του οξειδωτικού φορτίου και ένα για τη μέτρηση της ενδοτοξίνης. Σε κάθε σκέλος, τα ζώα μοιράστηκαν σε 4 ομάδες: (1) ομάδα ελέγχου (Sham), όπου τα ζώα καθετηριάστηκαν χωρίς να πραγματοποιηθεί αφαίμαξη, (2) ομάδα H/S (H/S) και δύο ομάδες στις οποίες προχορηγήθηκε κλονιδίνη, (ομάδα 3,Clonidine) και (ομάδα 4, Clonidine-H/S). Το H/S, διάρκειας μίας ώρας, στόχευε σε τιμές μέσης αρτηριακής πίεσης 30-40mmHg και ολοκληρώθηκε με επαναχορήγηση του απολεσθέντος αίματος. Τρεις ώρες μετά την αναζωογόνηση, το οξειδωτικό φορτίο εκτιμήθηκε με δύο μεθόδους: (α) τη μέτρηση των οργανικών υδροϋπεροξειδίων (LOOHs) και (β) τη μέτρηση της ρίζας του υπεροξειδίου (O2.-) στο έντερο, στο ήπαρ και τους πνεύμονες ενώ για τη μέτρηση της ενδοτοξίνης, ελήφθησαν δείγματα αίματος από την πυλαία φλέβα και την αορτή. Αποτελέσματα: Οι επίμυες που υπεβλήθησαν σε H/S παρουσίασαν στατιστικά σημαντική αύξηση του οξειδωτικού φορτίου σε όλα τα όργανα. Η προχορήγηση κλονιδίνης προκάλεσε μείωση της παραγωγής LOOHs μετά από H/S στο έντερο (Ρ<0.001), στο ήπαρ (Ρ<0.05) και τους πνεύμονες (Ρ<0.05), σε σχέση με την ομάδα H/S. Επίσης, η ομάδα Clonidine-H/S παρουσίασε μειωμένο ρυθμό παραγωγής του O2.- σε σχέση με την ομάδα H/S, στο έντερο (P< 0.001), στο ήπαρ (P< 0.001) και τους πνεύμονες (Ρ<0.005). Τέλος, όσον αφορά τα επίπεδα ενδοτοξίνης, βρέθηκαν στατιστικά σημαντικά αυξημένα μετά από H/S τόσο στην πυλαία (Ρ<0.05), όσο και στη συστηματική (Ρ<0.001) κυκλοφορία, ενώ η προχορήγηση κλονιδίνης οδήγησε σε μείωση της ενδοτοξίνης και στις δύο κυκλοφορίες (πυλαια: Ρ<0.05 και συστηματική: Ρ<0.001) σε σχέση με την ομάδα H/S. Συμπέρασμα: Στην παρούσα μελέτη βρέθηκε για πρώτη φορά ότι η κλονιδίνη ασκεί αντιοξειδωτική δράση στο έντερο, στο ήπαρ και στους πνεύμονες όταν χορηγείται προ του H/S, το οποίο, ως γνωστόν, προκαλεί σημαντικού βαθμού OS σε αυτά τα όργανα. Μάλιστα, αυτό εκτιμήθηκε για πρώτη φορά σε μοντέλο H/S με την εφαρμογή μιας νέας άμεσης και ποσοτικής μεθόδου προσδιορισμού του O2.-. Τα αποτελέσματα αυτά αποκτούν ιδιαίτερη σημασία, καθώς το επαγόμενο από σοβαρή αιμορραγία OS ενέχεται στην παθογένεια του MODS (Multiple Organ Dysfunction Syndrome). Επιπλέον, η κλονιδίνη περιόρισε την επαγόμενη από το H/S ενδοτοξιναιμία, γεγονός που μπορεί να αποδοθεί, τουλάχιστον μερικώς στην αντιοξειδωτική της δράση στον εντερικό βλεννογόνο. Αυτή η παρατηρούμενη μείωση της ενδοτοξιναιμίας, ενδέχεται να συμβάλλει με τη σειρά της στο μειωμένο OS στα όργανα. Αν και τα αποτελέσματα πειραματικών μελετών σε ζώα δεν μπορούν πάντα να αναχθούν σε συμπεράσματα που αφορούν τους ανθρώπους, αυτή η μελέτη συνηγορεί υπέρ της χρήσης της κλονιδίνης σαν συμπληρωματικό αναισθητικό παράγοντα εκλογής σε ασθενείς επιρρεπείς σε απώλεια αίματος, με στόχο την άμβλυνση των παθοφυσιολογικών επιπτώσεων του H/S που μπορούν να οδηγήσουν σε MODS. / Hemorrhagic shock (H/S) leads to the development of oxidative stress (OS) as a result of the excessive production of reactive oxygen species (ROS) in various tissues during reperfusion. Likewise, ischemia and ROS are believed to compromise the integrity of the intestinal barrier, resulting in endotoxemia. Moreover, it is now clear that the choice of sedation in ICU (Intensive Care Unit) patients affects their outcome. The a2-adrenergic agonist clonidine that is used as an adjunct to anesthesia, as well as in the ICU setting, has been shown to exert protective effects in models of ischemia/reperfusion injury. Aim of the study: To test the effect of clonidine pre-treatment of rats in the H/S-induced OS in the gut, liver and lung tissues and endotoxemia as well. Materials and Methods: The study consisted of two arms (64 rats): one for the measurement of the oxidative load in the organs and one for the measurement of endotoxin. Four animal groups (n=8 per group) were used for each arm (Sham, Clonidine, H/S and Clonidine-H/S group). The duration of Η/S was one hour, targeting to a mean arterial pressure of 30-40mmHg, at the end of wich rats were rescusitated by reinfusion of the shed blood. Three hours after rescusitation, the oxidative load was estimated with the measurement of lipid hydroperoxides (LOOHs) and superoxide radical (O2.- ) production in the liver, gut and lungs of the animals, while the levels of endotoxin were determined in both the systemic and portal circulation. Results: Rats subjected to H/S exerted increase in the oxidative load in all the tested organs. Clonidine pre-treatment resulted in a statistically significant reduction of LOOHs production after H/S in the gut (P < 0.001), liver and lungs of the rat (P < 0.05). Rats in the Clonidine-H/S group exhibited a statistically significant reduction (P< 0.001) in the production of O2.- in the gut and liver, and to a lesser extent in the lungs ( P < 0.05) compared to H/S group. H/S induced endotoxemia in the portal and systemic circulation, whereas clonidine pre-treatment reduced the amount of endotoxin detected both in the portal (P<0.05) and systemic (P<0.01) circulation compared to H/S. Conclusion: This study documents for the first time that clonidine pre-treatment prior to H/S results in a significant reduction of the OS observed in the gut, liver and lungs of the rat. Moreover, this antioxidant effect was estimated for the first time in a model of H/S with a new, direct and quantitative method of O2.- production. These results are of great value, since the H/S-induced OS is implicated in the pathogenesis of MODS (Multiple Organ Dysfunction Syndrome). Furthermore, clonidine prevented H/S induced endotoxemia in both portal and systemic circulations, probably due to its antioxidant effect on the intestinal epithelium. The reduced endotoxemia after clonidine pre-treatment may contribute to the decreased OS observed in the liver and lungs. Although laboratory results on animals should not be easily extrapolated to humans, we believe that clonidine merit consideration as an adjunctive sedative agent of choice in patients susceptible to develop H/S, as it may prevent the development of MODS, improving likewise their outcome.

We have shown previously [Hosohata, K., Logan, J.K., Varga, E., Burkey, T.H., Vanderah, T.W., Porreca, F., Hruby, V.J., Roeske, W.R., Yamamura, H.I., 2000. The role of the G protein γ2 subunit in opioid antinociception in mice. Eur. J. Pharmacol. 392, R9-R11] that intracerebroventricular (i.c.v.) treatment of mice with a phosphorothioate oligodeoxynucleotide antisense to the γ2 subunit (Gγ2) of the heterotrimeric G proteins (antisense ODN) significantly attenuates antinociception by a δ-opioid receptor agonist. In the present study, we examined the involvement of Gγ2 in antinociception mediated by other (μ- or κ-opioid, cannabinoid, α2-adrenoreceptor) analgesic agents in a warm (55°C) water tail-flick test in mice. Interestingly, i.c.v. treatment with the antisense ODN attenuated antinociception by each analgesic agent. Missense phosphorothioate oligodeoxynucleotide treatment, on the other hand, had no effect on antinociception mediated by these agonists. The antinociceptive response recovered in 6 days after the last antisense ODN injection, indicating a lack of nonspecific tissue damage in the animals. These results suggest a pervasive role for the G protein γ2 subunits in supraspinal antinociception.