Thesis (Ph.D.)--Medical University of Ohio, 2005. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Sciences." Major advisor: Joseph F. Margiotta. Includes abstract. Document formatted into pages: iii, 226 p. Title from title page of PDF document. Bibliography: pages 80-92,130-139,149-225.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 45-50).

A dispersive liquid-liquid microextraction (DLLME) method has been developed, optimized and validated for the extraction of seven beta-agonists (Cimaterol, Cimbuterol, Clenproperol, Clenbuterol, Ractopamine, Isoxsuprine and Ritodrine) from bovine muscle. The homogenized tissue samples were hydrolyzed enzymaticaly by beta-glucuronidase and extracted with DLLME. The extraction parameters (pH, extraction solvent, extraction solvent volume, disperser solvent) were accurately optimized. Separation of the beta-agonists was by gradient elution on C18 LC column using acetonitrile and formic acid aqueous solutions as mobile phases, multiple reaction monitoring (MRM) scan mode was used. The seven beta-agonists were then simultaneous determined and identified in single analysis using 4000 Qtrap LC-MS/MS system. The DLLME method was validated using ISO 17025 and the EU criteria (Commission Decision 2002/657/EC) for validation of analytical method, good precision, repeatability and spiked recoveries were obtained. The limits of detection and quantification for the residues were between 0.0728 – 0.0922 μg/kg and 0.243 – 0.307 μg/kg respectively for beta-agonists. The overall recoveries were between 85% and 100% with the relative standard deviation of (RSDs) between 3.0% and 10%. The recoveries from the developed DLLME method were compared with those obtained from dSPE. DLLME proved to be comparable to SPE. The real samples test showed that the DLLME method developed is accurate and sensitive for the determination of beta-agonist residues in bovine muscle. / Chemistry / M. Sc. (Analytical Chemistry)

Exercise Induced Bronchoconstriction (EIB) is common amongst elite athletes. Short-acting β2-agonists represent the first-line treatment of EIB, however; limited data currently exists examining the ergogenic and pharmacokinetic impact of chronic short-acting β2-agonist administration. Furthermore, the ergogenic impact of acute and chronic administration of short-acting β2-agonists in asthmatic individuals is unknown. Whilst the short-acting β2-agonist salbutamol is permitted in and out of competition due to a known pharmacokinetic response, no urinary threshold has been established for the use of the alternative short-acting β2-agonist terbutaline. The purpose of study 1 was to investigate the ergogenic potential of the WADA upper daily limit of 1600 μg·day-1 salbutamol every day for 6 weeks versus placebo, alongside combined resistance and endurance training. Findings highlighted improvements in; 1 repetition maximum (1RM) bench press (Baseline: 65.6 ± 5.4 kg vs. 64.3 ± 4.9 kg – 6 weeks: 70.3 ± 4.9 vs. 72.5 ± 5.4 kg) and leg press (Baseline: 250 ± 26.9 vs. 217.9 ± 19 kg – 6 weeks: 282.5 ± 22.5 vs. 282.8 ± 18.3 kg); vertical jump test (Baseline: 53.5 ± 4.1 vs. 50.4 ± 2.1 cm – 6 weeks: 55 ± 3.5 vs. 52.4 ± 1.7 cm); 3 km running time-trial performance (Baseline: 988.7 ± 68.7 vs. 1040.5 ± 66.3 s – 6 weeks: 947.5 ± 54.9 vs. 1004.3 ± 70.5 s); isokinetic dynamometry (Baseline: 196.1 ± 47.3 vs. 184.6 ± 35.0 n.m. – 6 weeks: 179.5 ± 48.9 vs. 195.2 ± 28.9 n.m.); and body composition (Baseline: 32.1 ± 13.9 vs. 34.9 ± 10.4 mm – 6 weeks: 32.4 ± 14.5 vs. 34.5 ± 10 mm) for both the salbutamol group and the placebo group, respectively, over the 6 week period, with no difference observed between groups, indicating long-term therapeutic use of salbutamol at the WADA upper daily limit has no ergogenic effect. Of note, one participant exceeded the urinary threshold, presenting with an adverse 3 | P a g e analytical finding (AAF) showing that the upper daily limit can lead to AAF’s in susceptible individuals. Athletes who respond poorly to salbutamol treatment are able to apply for the use of the short-acting β2-agonist terbutaline via a therapeutic use exemption (TUE) certificate. Urinary upper limits are unknown for terbutaline and as such it is prohibited at all times without the presentation of a TUE. The purpose of study 2 was to investigate the urinary excretion of terbutaline following single and repeated use of inhaled or oral terbutaline. The aim of the study was to establish a differential distinction between routes of administration which could assist the WADA with regard to anti-doping policy and procedure. Results demonstrated a significant difference in urine concentration of terbutaline between inhaled and oral administration for female Caucasian (670.1 ± 128.3 vs. 361.8 ± 43.8 ng·ml-1; P=0.019; 680.8 ± 91 vs. 369.9 ± 41.9 ng·ml-1; P=0.006), male Afro-Caribbean (343.18 ± 45 vs. 231.3 ± 32.95 ng·ml-1; P=0.044; 389.73 ± 67.4 vs. 212.4 ± 50.3 ng·ml-1; P=0.008) and male Asian (266.4 ± 23.7 vs. 143.3 ± 22 ng·ml-1; P=0.004; 379.5 ± 50.4 vs. 197.5 ± 38.6 ng·ml-1; P=0.000) groups for single (5 mg oral vs. 2 mg inhaled) and repeated (4 x 5 mg oral vs. 8 x 1 mg inhaled) administration trials, respectively. No difference was observed in male Caucasians. High intra- and inter-individual variability between samples meant that a clear distinction between routes of administration could not be established. The study was able to identify an upper urinary threshold following inhaled administration of 1284.3 ng·ml-1 and an upper urinary threshold following oral use of 2376.3 ng·ml-1 which may inform the process of distinguishing between inhaled and oral use. Athletes are permitted to use inhaled terbutaline therapeutically through the TUE process. The purpose of study 3 was to investigate the ergogenic effect of terbutaline at high (2 mg and 4 mg) therapeutic inhaled doses on 3 km running time-trial performance in males and females. The 4 | P a g e study found that inhaled terbutaline, when used at the highest therapeutic dose, has no impact upon 3 km time-trial performance in males (956.3 s vs. 982 s) and females (1249 s vs. 1214.7 s) for placebo vs. 4 mg inhaled terbutaline, respectively. The majority of studies investigating the ergogenic potential of salbutamol have been in healthy individuals. It is not yet understood whether the exercise response differs in asthmatic individuals. The purpose of study 4 was to investigate the use of inhaled salbutamol (400 μg) during a 3 km running time-trial in eucapnic voluntary hyperpnoea positive (EVH+ve) and negative (EVH-ve) individuals, in a low humidity environment. Results demonstrated increased FEV1 in both groups following salbutamol inhalation, which did not translate to improved performance. No performance differences were found between salbutamol and placebo (Sal: 1012.7 ± 50 vs. 962.1 ± 37.5 s – Pla: 1002.4 ± 46.5 vs. 962 ± 28.8 s) in the EVH+ve group vs. the EVH-ve group, respectively. This thesis is the first to investigate the effects of long-term use of salbutamol at the WADA upper daily limit on exercise performance. It is also the first study to establish upper urinary thresholds for terbutaline use, and the effects of therapeutic inhaled terbutaline on exercise performance. The effect of salbutamol on exercise performance at low humidity in asthmatic individuals has also never previously been investigated. Overall, the findings from this thesis support previous research that inhaled β2-agonist use does not provide any ergogenic potential. With β2-agonists being an essential therapy for the treatment of EIB their current position on the WADA List of Prohibited Substances and Methods is appropriate. Further research is warranted to fully elucidate the upper urinary threshold for terbutaline to inform WADA and support the re-introduction of terbutaline as a therapeutic tool in the treatment of EIB in athletes.

Made available in DSpace on 2014-06-11T19:23:44Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-12-10Bitstream added on 2014-06-13T19:09:54Z : No. of bitstreams: 1 silva_gb_me_jabo.pdf: 1117997 bytes, checksum: 88ee7014b706d275943b075b58aba825 (MD5) / A medula espinhal tem importante papel no mecanismo de transmissão dos impulsos nervosos nociceptivos. O bloqueio desses impulsos interrompe ou minimiza a dor derivada da liberação de mediadores inflamatórios deletérios ao organismo. Assim ela tem sido sede de administração de fármacos, tanto para a realização de bloqueios anestésicos, quanto para a prevenção da dor pós-operatória. Em éguas é comum a indicação do uso da via peridural caudal para a administração de fármacos como nos casos de prolapsos uterinos e vaginais, lacerações vulvo-perineais decorrentes de distocias ou de monta natural, nos casos de pneumovagina e torções uterinas. Avaliou-se 3 grupos com 7 éguas cada, após receberem injeção peridural de 0,25 mg/kg de lidocaína associada com solução de cloreto de sódio 0,9% (GLS) ou lidocaína, na mesma dose, associada à 0,17 mg/kg de xilazina (GLX) ou 0,02 mg/kg detomidina (GLD). A avaliação considerou o perfil clínico por meio da aferição das frequências cardíaca (FC) e respiratória (f), da pressão arterial média (PA) e da avaliação da sensibilidade cutânea (SCP) com o uso de filamentos de von Frey em éguas submetidas a incisões cutâneas na região glútea. Em decorrência da diminuição da sensibilidade cutânea promovida pelos tratamentos, os valores de FC, f e de PA mantiveram-se estáveis, com pequeno declínio nos grupos GLX e GLD. As associações de lidocaína com xilazina ou com detomidina (GLX e GLD) diminuíram significativamente a sensibilidade cutânea pós-incisional (SCP) logo a partir de T15, quando comparadas ao grupo que recebeu apenas lidocaína associada á solução de cloreto de sódio 0,9% (GLS). Os três grupos apresentaram diminuíção significativa da SCP em todos os tempos após as aplicações quando comparados ao T0... / The spinal cord plays an important role the mechanism of tranmission of nociceptive nerve impulses. Blocking these impulses stop or minimize the pain derived from the release of inflammatory mediators deleterious to the body. So it has been the seat of administration of drugs, both the anesthetic blocks, and for the prevention of postoperative pain. In mares is common to indicate the use of epidural caudal to the administration of drugs as in cases of uterine prolapse and vaginal, vulvo-perineal lacerations resulting from dystocias natural mating or in cases of uterine pneumovagina and twists. We evaluated 3 groups of 7 mares each, after receiving epidural injection of 0.25 mg/kg of lidocaine mixed with sodium chloride 0.9% (GLS) or lidocaine, the same dose associated with 0.17 mg/kg xylazine (GLX) or 0.02 mg/kg detomidine (GLD). The evaluation considered the clinical profile through measurement of heart rate (HR) and respiratory rate (RR), mean arterial pressure (BP) and the evaluation of skin sensitivity (PCS) using von Frey filaments in mares undergoing skin incisions in the gluteal region. Due to the decrease in skin sensitivity promoted by the treatments, the values of FC, fe, BP remained stable, with small decline in GLD and GLX groups. Combinations of lidocaine and xylazine or detomidine (GLD and GLX) significantly decreased the sensitivity of the skin post-incision (SCP) as early as T15, compared with the group receiving only lidocaine associated with the solution of sodium chloride 0.9% (GLS). The three groups showed a significant decrease in SCP at all times after the applications when compared to T0. The GLS group showed significant differences between the values of the sides and incised not incised in the times T45 to T105, the GLX group from T60 to T1440 (except T75), and the GLD group from T90 to T1440... (Complete abstract click electronic access below)

Submitted by SAMUEL DOS SANTOS SOUSA null (samuerr@hotmail.com) on 2016-11-25T13:56:01Z No. of bitstreams: 1 DOC. FINAL - DISSERTAÇÃO.pdf: 1281598 bytes, checksum: da30a95bebfc6a71081a5f812835a040 (MD5) / Approved for entry into archive by Felipe Augusto Arakaki (arakaki@reitoria.unesp.br) on 2016-11-29T13:18:47Z (GMT) No. of bitstreams: 1 sousa_ss_me_jabo.pdf: 1281598 bytes, checksum: da30a95bebfc6a71081a5f812835a040 (MD5) / Made available in DSpace on 2016-11-29T13:18:47Z (GMT). No. of bitstreams: 1 sousa_ss_me_jabo.pdf: 1281598 bytes, checksum: da30a95bebfc6a71081a5f812835a040 (MD5) Previous issue date: 2016-08-18 / Existem poucos protocolos para a contenção e sedação de jumentos . Os agonistas alfa-2 são os fármacos mais amplamente administrados e é sabido que essa classe de fármacos pode produzir alguns efeitos deletérios no sistema cardiorrespiratório do animal. Os fármacos da classe dos opioides vêem ganhando espaço na prática anestésica com asininos, pois esses fármacos são utilizados como uma alternativa para a sedação desses animais. Além de produzirem certo grau de sedação, possuem característica analgésica, sem promover efeitos adversos. Na literatura pesquisada não foi encontrado, nenhum estudo sobre o uso associado de xilazina em infusão contínua com meperidina e seus efeitos hemodinâmicos nos muares. Diante deste exposto, objetivou-se estudar os efeitos da associação da infusão contínua da xilazina com bollus intramuscular de meperidina como protocolo de sedação em jumentos. Para tal, foram utilizados seis jumentos, SRD, sendo um macho e cinco fêmeas, com peso médio de 141±23 kg. Os animais foram submetidos a três protocolos experimentais dividos em três grupos, Grupo A: infusão contínua intravenosa de 1,1 mg/kg/hora de xilazina a solução salina por via intramuscular; Grupo B: infusão contínua intravenosa de 0,8 mg/kg/hora de xilazina e solução salina por via intramuscular e Grupo C: infusão contínua intravenosa de 0,8 mg/kg/hora de xilazina e 4 mg/kg de meperidina por via intramuscular. Foi observado redução na frequência respiratória, pressão arterial sistólica nos animais do grupo A e C, diminuição da pressão arterial diastólica e média em todos os grupos. Foi observada redução na altura da cabeça em todos os grupos. A associação da meperidina com xilazina em infusão contínua não provocou alterações cardiorrespiratórias significativas e produziu grau de sedação satisfatório / To the present, there has been few descriptions of anesthetic protocol for restraint and sedation in donkey (Equus asinus). Alpha-2-agonists are widely administered class of drugs. Known to produce some deleterious effects over the cardiopulmonary system. The use of opioids in donkeys has sained popularity anesthetic practicioners, since these drugs are used as an alternative sedative with analgesic characteristics with minimal side effects. To our knowledge, there has not been study evaluating the effects of the association of continuous rate infusion of xilazine with meperidine given intramuscularly over the cardiovascular parameters of donkeys. Therefore, the objective of our study evaluate was to the capacity of sedation and the cardiorespiratory implications of the anesthetic association in donkeys. In order to performe the study, six mixed breed, one male and five females, were used. The average weight has 141 ± 23 kg. The animals were subjected to three experimental protocols. Group A: Continuous intravenous infusion of 1.1 mg / kg / hour of xylazine and saline solution intramuscularly; Group B: Continuous intravenous infusion of 0.8 mg / kg / hour of xylazine and saline solution intramuscularly and Group C: continuous intravenous infusion of 0.8 mg / kg / hour of xylazine and 4 mg / kg of meperidine intramuscularly. Respiratory rate and systolic blood pressure decreased in animals of group A and C. While diastolic blood pressure and mean arterial pressure decreased in all three groups. Head Height lowered following treatment in all groups. The combination of meperidine with continuous rate infusion of xylazine did not cause significant cardiorespiratory implications and produced satisfactory degree of sedation.

Orientador: José Antonio Marques / Banca: Carlos Augusto Araujo Valadão / Banca: Roberto Pimenta de Pádua Foz Filho / Resumo: A medula espinhal tem importante papel no mecanismo de transmissão dos impulsos nervosos nociceptivos. O bloqueio desses impulsos interrompe ou minimiza a dor derivada da liberação de mediadores inflamatórios deletérios ao organismo. Assim ela tem sido sede de administração de fármacos, tanto para a realização de bloqueios anestésicos, quanto para a prevenção da dor pós-operatória. Em éguas é comum a indicação do uso da via peridural caudal para a administração de fármacos como nos casos de prolapsos uterinos e vaginais, lacerações vulvo-perineais decorrentes de distocias ou de monta natural, nos casos de pneumovagina e torções uterinas. Avaliou-se 3 grupos com 7 éguas cada, após receberem injeção peridural de 0,25 mg/kg de lidocaína associada com solução de cloreto de sódio 0,9% (GLS) ou lidocaína, na mesma dose, associada à 0,17 mg/kg de xilazina (GLX) ou 0,02 mg/kg detomidina (GLD). A avaliação considerou o perfil clínico por meio da aferição das frequências cardíaca (FC) e respiratória (f), da pressão arterial média (PA) e da avaliação da sensibilidade cutânea (SCP) com o uso de filamentos de von Frey em éguas submetidas a incisões cutâneas na região glútea. Em decorrência da diminuição da sensibilidade cutânea promovida pelos tratamentos, os valores de FC, f e de PA mantiveram-se estáveis, com pequeno declínio nos grupos GLX e GLD. As associações de lidocaína com xilazina ou com detomidina (GLX e GLD) diminuíram significativamente a sensibilidade cutânea pós-incisional (SCP) logo a partir de T15, quando comparadas ao grupo que recebeu apenas lidocaína associada á solução de cloreto de sódio 0,9% (GLS). Os três grupos apresentaram diminuíção significativa da SCP em todos os tempos após as aplicações quando comparados ao T0 ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The spinal cord plays an important role the mechanism of tranmission of nociceptive nerve impulses. Blocking these impulses stop or minimize the pain derived from the release of inflammatory mediators deleterious to the body. So it has been the seat of administration of drugs, both the anesthetic blocks, and for the prevention of postoperative pain. In mares is common to indicate the use of epidural caudal to the administration of drugs as in cases of uterine prolapse and vaginal, vulvo-perineal lacerations resulting from dystocias natural mating or in cases of uterine pneumovagina and twists. We evaluated 3 groups of 7 mares each, after receiving epidural injection of 0.25 mg/kg of lidocaine mixed with sodium chloride 0.9% (GLS) or lidocaine, the same dose associated with 0.17 mg/kg xylazine (GLX) or 0.02 mg/kg detomidine (GLD). The evaluation considered the clinical profile through measurement of heart rate (HR) and respiratory rate (RR), mean arterial pressure (BP) and the evaluation of skin sensitivity (PCS) using von Frey filaments in mares undergoing skin incisions in the gluteal region. Due to the decrease in skin sensitivity promoted by the treatments, the values of FC, fe, BP remained stable, with small decline in GLD and GLX groups. Combinations of lidocaine and xylazine or detomidine (GLD and GLX) significantly decreased the sensitivity of the skin post-incision (SCP) as early as T15, compared with the group receiving only lidocaine associated with the solution of sodium chloride 0.9% (GLS). The three groups showed a significant decrease in SCP at all times after the applications when compared to T0. The GLS group showed significant differences between the values of the sides and incised not incised in the times T45 to T105, the GLX group from T60 to T1440 (except T75), and the GLD group from T90 to T1440... (Complete abstract click electronic access below) / Mestre

Orientador: Roberto Rittner / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-11T06:54:29Z (GMT). No. of bitstreams: 1 daSilva_JulioCesarAraujo_M.pdf: 2287772 bytes, checksum: ee8613d61a9f9feb9fa6894b5197e36f (MD5) Previous issue date: 2008 / Resumo: Neste trabalho é apresentado o estudo conformacional dos agonistas muscarinicos da acetilcolina (ACh+): carbacol, metacolina e pilocarpina. O estudo baseou-se na análise das constantes de acoplamento 3JHH e nos dados obtidos pelos cálculos teóricos ab initio. O comportamento conformacional destes compostos é descrito principalmente por apenas dois dos seus ângulos diedros. Os resultados dos cálculos teóricos realizados com o nível teórico B3LYP/6- 311+G(d,p), bem como os dados experimentais, apontaram a conformação gauche como a predominante para todos os compostos estudados para o diedro responsável pela atividade farmacológica dos agonistas independente do solvente utilizado. Atribui-se a estabilização da forma gauche a interação eletrostática entre o atomo de nitrogênio positivamente carregado e o átomo de oxigênio da porção éster (OCH2). Os cálculos teóricos mostraram que os conformeros mais estáveis possuem uma distância N+/O menor. Em adição, estudos de NBO mostraram a importância das interações hiperconjugativas sC5H5 s* C6N7 e sC5H5s* O4C5 na maior estabilização dos conformeros gauche. Os conformeros mais estáveis para cada composto sao: aceticolina, TG-; carbacol, AG+; metacolina, TG+; pilocarpina, TG+C / Abstract: This work describes the conformational analysis of muscarine agonists of acetylcholine (ACh+): carbachol, metacholine and pilocarpine. It was performed from the analysis of 3JHH coupling constants and from ab initio theoretical calculations. Their conformational behavior is discussed taking into account the most important dihedral angles. Both the results from theoretical calculations at B3LYP/6-311+G(d,p) as the experimental data indicated that the gauche conformer is predominant, considering the dihedral angle wich is responsible by their pharmacological activity regardless the solvente employed. The stabilization of the gauche conformer was ascribed to the eletrostatic interaction between the positively charged nitrogen atom and the (OCH2) oxygen atom of the ester fragment. This was confirmed by the N+/O smaller distance for the most stable conformers. In addition, NBO data showed the relevant role of sC5H5 s* C6N7 e sC5H5s* O4C5 hyperconjugative interactions of the gauche conformers. The most stable conformers for the above compounds are: : acetycholine, TG-; carbachol, AG+; methacholine, TG+; pilocarpine, TG+C / Mestrado / Quimica Organica / Mestre em Química

Vasoconstriction can be initiated via the interaction of a number of chemicals with specific "receptive sites" known as the receptors. This thesis examines two distinctly different modes by which drugs initiate a contractile response, namely, (i) the interaction of angiotensin analogues with a heterogeneous population of angiotensin receptors in vascular smooth muscles, and (ii) the conditions whereby B-adrenoceptor antagonists interact with a-adrenoceptor antagonists thereby causing a pressor response. Conscious, unrestrained, instrumented-rats were used for the study. It has been suggested that angiotensin receptors in vascular and non-vascular tissues may not be of a homogeneous population. The first study examined whether a heterogeneous population of angiotensin receptors was responsible for increasing vascular tone. Dose-response curves were constructed for angiotensin II (ANG II) and des Asp¹ angiotensin II (ANG III) on mean arterial pressure (MAP) and mean circulatory filling pressure (MCFP), an index of total body venous tone, in the presence or absence of [Sar¹, Ile⁸]ANG II. The i.v. infusion of ANG II or ANG III caused dose-dependent increases in MAP and MCFP. In the presence of [Sar¹, Ile⁸]ANG II, the MAP and MCFP curves for ANG II were displaced to the right with pA₂ values of 9.2 and 8.4 for the arterioles and veins, respectively. However, the antagonist displaced dose-MCFP but not the dose-MAP response curve of ANG III. This suggests that ANG II and ANG III act on the same receptor in veins but not arterioles. This concept was further investigated by obtaining dose-MAP and dose-MCFP response curves for ANG II in the presence of ANG II or ANG III. Dose-MAP response curve to ANG II was displaced to the right in the presence of ANG II but not ANG III. Dose-MCFP response curve for ANG II was displaced to the right in the presence of ANG III but not ANG II. These results again suggest that ANG III acts on the same receptors as ANG II in the veins but not arterioles. In the last series of experiments two analogues of angiotensin III were compared as antagonists of the pressor response to ANG II and ANG III. In the presence of [Ile⁷]ANG III, the dose-MAP response curves for ANG II and ANG III were displaced to the right while in the presence of [Sar¹, Ile⁷]ANG III, the dose-MAP response curve for ANG III but not ANG II was displaced. This suggests that [Sar¹, Ile⁷]ANG III is a selective antagonist of ANG III in the arterioles. In summary, the results indicate that ANG III acts on a different sub-class of angiotensin receptors than ANG II in the arterioles but it may act as a partial agonist on the same type of receptors as ANG II in the venous bed. Thus, ANG II receptors in the arterioles appear to be different from those in veins. The administration of a non-selective β-antagonist propranolol into animals subjected to non-selective α-blockade has been observed to cause a paradoxical pressor response. This second study examines whether the paradoxical pressor response to β-antagonists was due to: (i) an interaction of a β-antagonist with an α-antagonist, (ii) blockade of vasodilator β₂-adrenoceptors or (iii) an increase in the release of catecholamines. Cumulative dose-response curves for propranolol, atenolol (β₁-antagonist) and ICI 118,551 (β₂-antagonist) were obtained in rats subjected to a continuous i.v. infusion of phentolamine, a non-selective α-antagonist. The administration of each of the β-antagonists caused a dose-dependent increase in MAP suggesting that the pressor response was not due to the blockade of vasodilator β₂-adrenoceptors. Another four groups of phentolamine-treated rats were given a single i.v. bolus injection of saline, propranolol, atenolol or ICI 118,551, and sampling of arterial blood for the determination of adrenaline (A) and noradrenaline (NA) concentration by HPLC/ec. Phentolamine caused a decrease in MAP and an increase in the plasma levels of A and NA. Subsequent injection of propranolol, atenolol and ICI 118,551 but not saline increased MAP. Neither saline nor any of the β-antagonists increased plasma NA or A levels suggesting that the pressor response was not associated with an acute increase in the release of catecholamines. It was also shown that prior injection of a β-antagonist partially antagonized the hypotensive effect of phentolamine suggesting that the pressor response was related to an interaction between α- and β-antagonists. It was further shown that a continuous infusion of either prazosin or rauwolseine caused a small but not significant decrease in MAP which was reversed by propranolol. Concurrent infusions of prazosin and rauwolscine caused a large decrease in MAP. Subsequent injection of propranolol caused a large pressor response. On the contrary, sodium nitroprusside or metha-choline each decreased MAP but the hypotension was not antagonized by propranolol. These results were consistent with the existence of a specific interaction between α- and β-antagonists. These experiments demonstrated that although the mechanisms involved in the initiation of a change in vascular tone did not share a common pathway, the final outcome shared a common denomination. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Orientador: Paulo Sergio Patto dos Santos / Resumo: Objetivou-se com este trabalho avaliar os efeitos na hemodinâmica, respiração, motilidade ruminal e sedação, da associação de detomidina e nalbufina em ovinos. Foram utilizados 8 ovinos hígidos, jovens, fêmeas ou machos, pesando 54,85 ± 20,31kg. Foi instalado na veia jugular esquerda um introdutor e, posteriormente, posicionado um cateter de Swan-Ganz com a extremidade distal alocada no lumen da artéria pulmonar. Foi administrado pela via intramuscular detomidina (10μg/kg) associado a nalbufina (0,1mg/kg). Foram avaliadas FC, PAS, PAD, PAM, PVC, PAPm, IC, IS, IRVS, FR, pH, PaO2, PaCO2, HCO3, TC, sedação e motilidade ruminal antes do início da administração dos fármacos (MB) e a cada quinze minutos após a aplicação durante sessenta minutos (M15, M30, M45 e M60). Houve redução do IC, FR e aumento da PAS, PAPm, temperatura central, PaCO2 e HCO3 após administração dos fármacos. A sedação foi considerada satisfatória durante 45 minutos. Com os resultados obtidos neste estudo, conclui-se que a neuroleptoanalgesia promovida pela associação de detomidina e nalbufina em ovinos, nas doses utilizadas, promove sedação satisfatória. As alterações hemodinâmicas, respiratórias e na motilidade ruminal observadas podem ser bem toleradas por animais sadios. / Abstract: The aim of this study was to evaluate the effects on hemodynamics, respiration, ruminal motility and sedation of the combination of detomidine and nalbuphine in sheep. Were used eight healthy young, female or male sheep, weighing 54.85 ± 20.31kg. A Percutaneous Sheath Introducer was placed in the left jugular vein and then a Swan-Ganz catheter was positioned with the distal port allocated to the lumen of the pulmonary artery. Association of detomidine (10µg/kg) and nalbuphine (0,1mg/kg) was administered intramuscular. HR, SAP, DAP, MAP, CVP, MPAP, CI, SI, SVRI, RR, pH, PaO2, PaCO2, HCO3, CT, sedation and ruminal motility before drug administration (MB) and at each fifteen minutes after application for sixty minutes (M15, M30, M45 and M60). There was a reduction in CI, RR and increase in SAP, mPAP, CT, PaCO2 and HCO3 after drug administration. Sedation was considered satisfactory for 45 minutes. The results of this study allowed us to conclude that neuroleptoanalgesia promoted by the association of detomidine and nalbuphine in sheep at the doses used, promotes satisfactory sedation for short procedures. The hemodynamic, respiratory and ruminal motility changes observed can be well tolerated by healthy animals. / Mestre