Thesis (M.S.)--West Virginia University, 2003. / Title from document title page. Document formatted into pages; contains x, 43 p. Vita. Includes abstract. Includes bibliographical references (p. 25-26).

Thesis (Ph. D.)--University of Wisconsin, 1950. / Typescript (carbon copy). eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 39-41).

This study examined the effects of epinephrine, norepinephrine, AVP and ACh on fluid movement by the lungs of the late-term guinea pig fetus. Catecholamines and AVP are secreted in high amounts by the fetus during delivery, and could be important with respect to fetal lung fluid removal; this event is vital at the time of birth. The lungs were supported in vitro for a duration of three hours, and production rates were measured using a dye-dilution technique. The average resting production rate in terms of ml/kg‧h declined with gestational age (54-67 days gestation; n=171). There was a lesser decline in the average resting production rate in terms of ml/h. The average production rate of untreated preparations in the first hour was 1.60 ± 0.26 ml/kg body weight per hour, and rates did not change significantly during the remaining two hours of experimentation (n=30). This rate is comparable to those reported from chronically catheterized fetal sheep. Treatment was administered during the second hour of experimentation, following an ABA design. Lungs (n=36) were transferred to fresh Krebs-Henseleit saline containing one of the following concentrations of epinephrine: (a) 10‾⁵ M; (b) 10‾⁶ M; (c) 10‾⁷ M; (d) 5 x 10‾⁸ M; (e) 10‾⁸ M; and (f) 10‾⁹ M. With the exception of the top dose, epinephrine treatment caused an immediate reduction in fluid secretion, or fluid reabsorption. Sodium followed the movement of water in all cases. The effect of epinephrine at 10‾⁷ M was maximal, and the threshold dose for epinephrine was calculated at 1.78 x 10‾¹¹ M. Phentolamine and propranolol had no effect in control preparations. However, phentolamine completely blocked the effect of epinephrine, whereas propranolol was ineffective. Isoproterenol had no effect on pulmonary fluid production. Alpha-adrenergic receptors apparently mediate the effect of epinephrine on pulmonary fluid movement in the fetal guinea pig lung. This conclusion is different from that obtained in fetal sheep, in which beta-adrenergic receptors are utilized. A possible synergism between epinephrine and AVP was examined. Lungs (n=12) were transferred to fresh Krebs-Henseleit saline containing either (a) 0.6 mU/ml AVP, or b) 0.6 mU/ml AVP combined with epinephrine at 10‾⁷ M. Treatment with AVP caused a slow, prolonged reduction in fluid production. Treatment with AVP together with epinephrine did not demonstrate synergism. The effect of norepinephrine (NE) was examined. Lungs (n=36) were transferred to fresh Krebs-Henseleit saline containing one of the following concentrations of NE: (a) 1.24 x 10‾⁵ M; (b) 1.24 x 10‾⁶ M; (c) 1.24 x 10‾⁷ M; (d) 5.24 x 10‾⁸ M; (e) 1.24 x 10‾⁸ M; and (f) 1.24 x 10‾⁹ M. In all preparations, treatment with NE resulted in an immediate reduction in fluid production, and reabsorptions were observed at the higher doses. Sodium followed the movement of water in every case. The threshold dose was calculated at 3.16 x 10‾¹⁰ M. Phentolamine blocked the effect of NE, reinforcing the importance of pulmonary alpha-adrenergic receptors in the fetal guinea pig. There was no relationship between age and degree of response with treatment of either epinephrine or NE, but fetuses under 78.0 g did not respond to NE. The effect of ACh was examined. Lungs (n=24) were transferred to fresh Krebs-Henseleit saline containing one of the following concentrations of ACh: (a) 10‾⁴ M; (b) 10‾⁵ M; (c) 10‾⁶ M; and (d) 10‾⁸ M. At the three top doses, immediate and powerful reabsorptions of pulmonary fluid were observed in older fetuses (60 days gestation and above); significant falls were observed in the younger fetuses. This result was unexpected, as it was hypothesized that ACh would stimulate fluid production. The threshold dose for ACh was between 10‾⁶ M and 10‾⁸ M. Phentolamine blocked the effect of ACh. This result suggested that reabsorption is a result of an indirect effect of ACh acting through pulmonary alpha receptors. The results in this study show that epinephrine, NE, AVP and ACh are all important promoters of fetal pulmonary fluid removal in the fetal guinea pig. Pulmonary alpha-adrenergic receptors mediate the effects of epinephrine, NE and ACh (indirectly). The conclusions drawn from this study emphasize the importance of species' comparison in fetal research. LIST OF ABBREVIATIONS AVP Arginine Vasopressin NE Norepinephrine DOPA dihydroxyphenylalanine PNMT Phenylethanolamine n-methyltransferase ACh Acetylcholine / Science, Faculty of / Zoology, Department of / Graduate

Phenylethanolamine-N-methyltransferase (Pnmt), is the enzyme that catalyzes the conversion of noradrenaline to adrenaline. It has been found in the embryonic heart and in certain adult heart cells, including intrinsic cardiac adrenergic cells, intracardiac neurons, and cardiomyocytes, but their physiological role in the heart is not well understood. To determine the function of Pnmt-expressing cells in the developing heart, a novel genetically-targeted mouse model that causes selective cellular suicide of Pnmt-expressing cells was created by mating Pnmt-Cre Recombinase knock-in mice (PnmtCre/Cre) with ROSA26-eGFP-DTA (R26R+/DTA). The “cellular suicide” allele is the Diptheria Toxin A (DTA) gene fragment. Activation of the DTA suicide allele is dependent upon Cre expression, which is under the control of the endogenous Pnmt gene locus (i.e., expression is restricted to adrenaline-producing “adrenergic” cells). Ongoing studies in Dr. Ebert’s laboratory have shown that Pnmt-Cre/DTA mice have a loss of adrenergic cells in the adrenal gland and begin developing serious cardiac and neurological deficits within one month after birth. The purpose of my project is to examine the potential cardiac consequences of selective adrenergic cell ablation in this model. Aim 1 of this study is to analyze echocardiography data from mice with genetic ablation of adrenergic cells compared to age-matched (littermate) controls over the first 6-months after birth. Preliminary evidence indicates that there is substantial loss of function that progressively worsens with age in the ablation group compared to controls. Aim 2 of this study seeks to uncover evidence of adrenergic cell ablation in the heart using histological and immunofluorescence staining techniques. We predict that these experiments will provide physiological and anatomical evidence showing that Pnmt-expressing cells in the heart make significant contributions to cardiac development and function. This knowledge is expected to increase our basic understanding about the specific roles adrenergic cells play during heart, and could lead to the development of novel treatment strategies for certain types of cardiac defects in the future.

Naloxone (NX) potentiated epinephrine (EPI) induced submaximal vasoconstriction in canine renal and skeletal muscle arterial segments, yet had no vasoconstrictor action alone. Developed tension generated in-vitro by 4 x 1mm. O.D. rings from 1st degree branches of canine femoral arteries was expressed as % of KCI induced maximum response. NX (10^-5 M) potentiated EPI induced submaximal contractions (34.2%) significantly more than contractions induced by norepinephrine, phenylephrine, lofexidine, ADH, KCI and serotonin (13.8,13.4,4.7,13.5,14.4 and 11.4% respectively). The NX response was unaffected by beta-adrenergic blockade and NX did not reverse an isoproterenol mediated vasodilation. Alphaadrenergic blockade with phentolamine completely eliminated EPI plus NX induced vasoconstriction. After washout, vessels exposed to EPI plus NX relaxed by 50% significantly faster than vessels exposed to EPI alone (18.5 and 27.9 min respectively). EPI induced vasoconstrictions were potentiated by 10^-5 M corticosterone (49.0%) which inhibits extraneuronal catecholamine uptake, but not by 10^-7 M desipramine (1.1%) which inhibits neuronal uptake. EPI induced vasoconstrictions were also potentiated by 10^-4 M pyrogallol (33.0%) which inhibits catechol-o-methyl transferase activity, but not by 10^-5 M pargyline (-1.1%) which inhibits monoamine oxidase activity. The NX effect was endothelium independent. The dose-response of various opioid receptor agonists and antagonists were compared to the NX response. A specific opioid receptor subclass could not be identified as the mediator of the NX effect. The ED_50s for NX (3.7x^-6 M) and (+)NX (8.1x^-7M) indicated a significant stereoselectivity for the (+)enantiomer. A variety of sigma receptor ligands, steroids and steroid metabolites were tested for the ability to augment EPI vasoconstrictions. Several of the opioid, sigma and steroid ligands, all with polycyclic structures, induced responses similarto those of NX. NX exerted its effect independent of traditional opiate receptors and may have influenced the cellular uptake or degradation of EPI. Endogenous compounds with sigma or steroid activity may modulate these processes in-vivo.

Purpose: To determine possible differences in the pain level and soft tissue anesthesia duration of plain polocaine versus epinephrine-containing articaine and lidocaine during intraoral injections. Methods: Forty-eight subjects received plain polocaine and one epinephrine-containing anesthetic. Injections were randomized according to the first injection a)left or right buccal sulcus and b)epinephrine or not. The second injections were the opposite conditions. Subjects then recorded discomfort on a VAS and the time anesthesia wore off. Result: The second injection’s pain rating was influenced by the first. This carry-over effect makes it impossible to analyze all of the data. An analysis of the first injection showed no significant difference between the three anesthetics. The duration of anesthesia for epinephrine-containing anesthetic was significantly longer than plain polocaine. Conclusion: This pilot study was intended to create a sample size for a pediatric population. However, due to the carry-over effect, future split-mouth studies may not be justified.

Introdução: Este estudo prospectivo, randomizado, duplo-cego investigou, em valvopatas, alterações hemodinâmicas durante o tratamento odontológico com o uso do anestésico local contendo adrenalina e sem a mesma. Métodos: O estudo foi conduzido na Unidade de Odontologia do Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (Brasil 2004-2005). Os pacientes foram alocados em dois grupos através de tabela de números aleatórios: LSA (lidocaína a 2% sem adrenalina, n= 31, 42.2 ± 10.3 anos) e LCA (lidocaína a 2% com adrenalina 1:100.000, n= 28, 40.3 ± 10.9 anos). O volume anestésico foi registrado. Um monitor multiparamétrico DIXTAL (São Paulo- Brasil) registrou os valores da pressão arterial sistêmica, freqüência cardíaca, saturação de oxigênio e traçado eletrocardiográfico. Registrou-se também o volume anestésico aplicado em cada procedimento realizado. Resultados: 22 homens e 37 mulheres foram incluídos. Valores da pressão arterial sistêmica, freqüência cardíaca e saturação de oxigênio, antes, durante e após administração da anestesia local não mostraram diferenças estatísticas entre os dois grupos (P > 0.05). Arritmias observadas em alguns pacientes antes do início do tratamento odontológico não sofreram alterações de morfologia ou gravidade após injeção anestésica. Relatos de dor durante a realização do procedimento odontológico foram mais freqüentes no grupo LSA com conseqüente aumento no volume de anestésico local administrado. Conclusão: lidocaína 2% com adrenalina 1:100.000 mostrou maior eficácia anestésica em comparação com a lidocaína 2% sem adrenalina sem causar alterações hemodinâmicas em pacientes portadores de valvopatias. / Introduction: This prospective, randomized double-blinded study investigated hemodynamic changes in valvular cardiac patients during dental treatment with the use of a local anesthesia containing epinephrine. Methods: The study was conducted in the Dental Department of the Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (Brazil 2004- 2005). Patients were allocated into two groups through an aleatory numbered table: PL (plain 2% lidocaine, n= 31) and LE (2% lidocaine with 1:100.000 epinephrine, n= 28). The anesthetic amount was registered. DIXTAL monitor (São Paulo- Brazil) captured blood pressure, heart rate, oxygenation and electrocardiogram records. Results: 22 men and 37 women were included (LE age 40.3 ± 10.9 and PL age 42.2 ± 10.3). Blood pressure, heart rate and pulse oximetry values before, during and after local anesthesia injection did not show any difference between the two groups (P > 0.05). Any arrhythmias observed in some patients prior to dental anesthesia did not suffer alterations of shape or gravity after it. Complains of pain during dental procedure were more often in the PL group with a higher amount of local anesthesia needed. Conclusion: 2% lidocaine with epinephrine 1:100.000 showed a superior anesthetic efficiency without leading to hemodynamics changes in patients with cardiac valvular compromise.

O uso de vasoconstritores associados a soluções anestésicas locais em pacientes que fazem uso de antidepressivos tricíclicos gera controvérsias por seu possível efeito sobre o sistema cardiovascular. Este estudo teve por objetivo avaliar alterações na pressão arterial e frequência cardíaca de ratos tratados ou não com antidepressivos tricíclicos, após a infiltração em fundo de sulco vestibular e injeção intravenosa de adrenalina, felipressina e fenilefrina, em doses equivalentes (DE) às quantidades presentes em 2, 8 e 32 tubetes de anestésico local. Foram utilizados 42 ratos Wistar machos pesando de 300 a 500 gramas, tratados por gavagem durante sete dias com cloridato de amitriptilina (0,3mg/Kg). No oitavo dia, após anestesia do animal, um cateter foi implantado na artéria carótida, a cânula arterial foi conectada a um transdutor de pressão acoplado ao sistema PowerLab 4/30 de registro invasivo de pressão arterial, utilizando software adequado. Após a infiltração e injeção intravenosa, um intervalo de 30 minutos foi respeitado entre as doses para evitar efeito cumulativo. Para a análise dos resultados foi utilizada análise de variância de medidas repetidas a um ou dois critérios de classificação, seguido do teste de Holm-Sidak. Observou-se que o tratamento com amitriptilina provocou elevação significativa na frequência cardíaca no grupo tratado em relação ao controle (n=21) (258,252 ± 6,32 e 221,790 ± 7,22, respectivamente, p<0,001) e queda significativa na pressão arterial do grupo tratado comparado ao grupo controle (101,80 ± 2,52 e 110,12 ± 2,91, respectivamente, p<0,05). A adrenalina mesmo utilizada em via infiltrativa apresentou efeito cronotrópico positivo em todas as doses (2 DE 197.15 ± 3,74 e 240.67 ± 8,14, 8 DE 212.44 ± 6,72 e 238.17 ± 10,05, e 32 DE 246.45 ± 11,13 e 251.32 ± 10,46 bpm, para controle e tratado, respectivamente, p>0,05). Na injeção intravenosa, mesmo com o nítido aumento de pressão e da frequência cardíaca, não houve diferença significativa entre o grupo controle e tratado. O tratamento com amitriptilina potencializa ligeiramente a resposta hipertensora após infiltração de adrenalina. A felipressina promove menores alterações de pressão arterial e a fenilefrina mostrou-se o vasoconstritor mais potente dos três estudados, produzindo alterações importantes de pressão arterial e de frequência cardíaca, mesmo por via infiltrativa, em doses superiores a 8 tubetes. / The use of vasoconstrictors associated with local anesthetic solutions in patients taking tricyclic antidepressants generates controversies because of its possible effect on the cardiovascular system. The aim of this study was to evaluate changes in blood pressure and heart rate of rats treated or not with tricyclic antidepressants after infiltration in buccal groove and intravenous injection of epinephrine, felypressin and phenylephrine in equivalent doses (ED) to the amounts present in 2, 8 and 32 local anesthetic tubes. We used 42 male Wistar rats weighing 300 to 500 grams, treated by gavage for seven days with amitriptyline hydrochloride (0.3mg / kg). On the eighth day, after anesthesia of the animal, a catheter was implanted in the carotid artery, the arterial cannula was connected to a pressure transducer coupled to invasive blood pressure recording PowerLab 4/30 system using appropriate software. After infiltration and intravenous injection, a 30-minute interval was observed between doses to avoid cumulative effect. For the analysis of the results we used Repeated measures analysis of variance to one or two classification criteria, followed by the Holm-Sidak test. It was observed that treatment with amitriptyline caused a significant increase in heart rate in the treated group in relation to the control (n = 21) (258,252 ± 6.32 and 221,790 ± 7,22, respectively, p <0.001) and a significant decrease in blood pressure of the treated group compared to the control group (101.80 ± 2.52 and 110.12 ± 2.91, respectively, p <0.05). The epinephrine used in the infiltrative route showed a positive chronotropic effect at all doses (2 ED 197.15 ± 3,74 and 240.67 ± 8,14, 8 ED 212.44 ± 6,72 and 238.17 ± 10,05, and 32 ED 246.45 ± 11,13 and 251.32 ± 10,46 bpm, for control and treated, respectively, p <0.05). In intravenous injection, even with the clear increase in blood pressure and heart rate, there was no statistically significant difference between the control and treated groups. Treatment with amitriptyline slightly potentiates the hypertensive response after infiltration of epinephrine. Felypressin promotes lower blood pressure changes and phenylephrine proved to be the most potent vasoconstrictor of the three studied, producing important changes in blood pressure and heart rate, even through infiltration, in doses greater than 8 tubes.

Sleep loss alters both the concentration and activity of various aspects of the immune system. These alterations lead to increased susceptibility to infection and the progression of pathologies such as insulin resistance and atherosclerosis. Two proposed mechanisms of this alteration in immune function are the changes in both cortisol and sympathetic nervous system activity that accompany sleep deprivation. This work reviewed literature that measured the effects of periods of sleep restriction upon both cortisol and catecholamine concentrations within human subjects. Furthermore, studies which measured the effects of sleep loss upon these hormone levels and the associated changes in immune parameters were included. This thesis asserts that there is no defined pattern in reference to alterations of cortisol levels as a result of sleep deprivation. Furthermore, more evidence must be collected before implementing cortisol as a main effector of sleep loss upon immune system function. This dissertation, although repeatedly noting increased levels of norepinephrine following periods of sleep restriction, similarly argues that more research must be completed in order to declare that altered catecholamine concentrations as a result of sleep loss is a mechanism for altered immune function.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Os anestÃsicos locais sÃo as drogas mais amplamente utilizadas na prÃtica odontolÃgica. O presente estudo teve como objetivo reportar a eficÃcia clÃnica e a seguranÃa terapÃutica da MepivacaÃna 2% com Epinefrina 1:100.000 (MEPI-E) e MepivacaÃna 2% com Norepinefrina 1:100.000 (MEPI-N) em infiltraÃÃo anestÃsica de dentes caninos superiores em voluntÃrios saudÃveis. Realizou-se um estudo do tipo ensaio clÃnico, prospectivo, randomizado, cruzado, triplo cego. Trinta pacientes foram randomizados e receberam 0,6 mL de ambas as soluÃÃes anestÃsicas, por meio de anestesia terminal infiltrativa, em caninos superiores. Foi avaliado o grau de dor durante a infiltraÃÃo anestÃsica por meio da escala visual analÃgica de dor (EVA). O tempo de induÃÃo anestÃsica foi mensurado pelo teste elÃtrico pulpar mensurando assim, o tempo necessÃrio para a efetivaÃÃo do bloqueio. Os dentes foram submetidos a testes elÃtricos em ciclos periÃdicos e avaliados por 60 minutos com a finalidade de verificar a eficÃcia anestÃsica em tecido dentÃrio. O teste de picada foi utilizado para mensurar a eficÃcia clÃnica em tecido mole, nos seguintes sÃtios: gengiva inserida vestibular, mucosa alveolar superior, mucosa labial superior e pele. TambÃm foi verificada difusÃo vestÃbulo-palatina da soluÃÃo anestÃsica. PressÃo arterial sistÃlica e diastÃlica, frequÃncia cardÃaca, saturaÃÃo de oxigÃnio e glicemia serviram como parÃmetros sistÃmicos de avaliaÃÃo da seguranÃa terapÃutica. Estabeleceu-se o nÃvel de significÃncia em 0,05 (5%), foram utilizados os software GraphPad Prism e o software SPSSÂ. Foram analisados um total de 60 punÃÃes anestÃsicas em 30 voluntÃrios do estudo. O grupo MEPI-N apresentou menor nÃvel de dor e desconforto durante a infiltraÃÃo anestÃsica, com diferenÃa estatisticamente significante (P = 0,0106) quando comparado ao grupo MEPI-E. 86,7% dos pacientes quando anestesiados com MEPI-N se apresentaram negativos ao teste elÃtrico num tempo &#8804; 30 segundos, contra 43,3% do grupo MEPI-E (P = 0,002). Na avaliaÃÃo da eficÃcia anestÃsica pulpar, resultados estatisticamente significantes foram observados nos tempos de 40, 50 e 60 minutos de avaliaÃÃo (P = 0,031, P = 0,021, P = 0,039 respectivamente) mostrando maior potÃncia ao grupo MEPI-N, na anÃlise da eficÃcia anestÃsica em lÃbio superior nos tempos 30, 35 e 40 minutos (P = 0,031) a superioridade tambÃm foi atribuÃda a soluÃÃo MEPI-N. NÃo houve diferenÃa estatÃstica na anÃlise intergrupos sob os parÃmetros de seguranÃa terapÃutica. NÃo foi observada significÃncia estatÃstica na anÃlise intergrupo em relaÃÃo aos parÃmetros sistÃmicos. Na anÃlise intragrupo observou-se que a pressÃo arterial sistÃlica e diastÃlica, a frequÃncia cardÃaca foram significantemente menores que a basal para alguns tempos em ambos os grupos. A mÃdia glicÃmica aos 30 minutos foi superior e estatisticamente significante ao basal. Resultados apontam que bloqueios anestÃsicos com MepivacaÃna 2% com Norepinefrina 1:100.000 sÃo capazes de conferir um melhor padrÃo anestÃsico sem contudo resultar em alteraÃÃes sistÃmicas. / Local anesthetics are the most widely drugs used in dental practice. The present study aimed to report the clinical efficacy and safety of therapeutic Mepivacaine 2% with Epinephrine 1:100,000 (MEPI-E) and Mepivacaine 2% with 1:100,000 norepinephrine (MEPI-N) in infiltration anesthesia of upper canine teeth in healthy volunteers. We conducted a clinical trial, prospective, randomized, crossover, triple blind. Thirty patients were randomly and received either 0.6 ml of both anesthetic solution through terminal infiltrative anesthesia in canines. The degree of pain during anesthetic infiltration was made by visual analog scale of pain (VAE). The induction time was measured by measuring electrical test pulp thus the time required for ensuring the locking. The teeth were subjected to electrical tests in periodic cycles and evaluated by 60 minutes in order to verify the effectiveness of anesthesia in dental tissue. The prick test was used to measure the clinical efficacy in soft tissue, at the following sites: buccal gingiva, upper alveolar mucosa, superior labial mucosa and skin. We also observed vestibular-palatal diffusion of the anesthetic. Systolic and diastolic blood pressure, heart rate, oxygen saturation and blood glucose were used as parameters for assessing the systemic therapeutic safety. Established the significance level of 0.05 (5%) were used GraphPad Prism  and SPSS Â. Were analyzed a total of 60 punctures anesthetic in 30 study volunteers. The MEPI-N group showed lower levels of pain and discomfort during the anesthetic infiltration, which was statistically significant (P = 0.0106) when compared to the MEPI-E. 86.7% when anesthetized with MEPI-N the electric test were negative a time &#8804; 30 seconds, against 43.3% of MEPI group-E (P = 0.002). In evaluating the anesthetic efficacy pulp, statistically significant results were observed in intervals of 40, 50 and 60 minutes of evaluation (P = 0.031, P = 0.021, P = 0.039 respectively) showing greater power to the MEPI-N group, in analyzing the effectiveness anesthesia in the upper lip at 30, 35 and 40 minutes (P = 0.031) showed superiority was also attributed to MEPI-N solution. There was no statistical difference between groups in the analysis under the parameters of therapeutic safety. There was no statistical significance in the intergroup analysis in relation to systemic parameters. Intragroup analysis showed that the systolic and diastolic blood pressure, heart rate were significantly lower than baseline for some time in both groups. The mean glucose at 30 minutes was higher and statistically significant at baseline. Results indicate that anesthetic blocks with 2% Mepivacaine with 1:100,000 norepinephrine are able to provide a better standard anesthetic but without result in systemic changes.