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In the 19th century, halothane hepatitis became a sensitive and well-known subject in human anesthesiology due to the production of a noxious metabolite further discovered, trifluoroacetic acid. Subsequently, isoflurane, enflurane, and desflurane were also investigated for potentially causing hepatitis through the same metabolite. Sevoflurane, however, does not generate trifluoroacetic acid and is quickly conjugated and excreted. For more than four decades these anesthetics have been experimentally developed for intravenous injection by having added either a lipid or fluorocarbon-based carrier to produce general anesthesia with less drug and faster onset of action. The use of intravenous emulsified halogenated anesthetics as an alternative to inhalation brought contradictory findings, therefore they are still not utilized in the clinical settings of veterinary and human anesthesia. The high solubility of these anesthetic emulsions increases their tissue uptake, volume of distribution, and potency. By this means, the amount of anesthetic necessary to establish general anesthesia could be significantly reduced but would still carry the risk of causing hepatic toxicity. On the other hand, because the emulsified anesthetics have a higher tissue uptake and are liposoluble, they remain for longer periods in the cellular membrane providing cellular pre- and postconditioning effects by minimizing cellular deleterious responses to a critical environment. Emulsified isoflurane and sevoflurane are the most investigated anesthetics for this purposein the heart, brain, kidneys, liver, and central nervous system of laboratory animals and human volunteers. The focus of this study is to evaluate the cellular effects of the loaded-lipid emulsified isoflurane and sevoflurane at different concentrations on cultured primary canine hepatocytes considering their viability and apoptosis response. Specifically, the overall objective is to establish a basis for in vitro metabolism of these emulsified anesthetics on canine hepatocytes under normal oxygen tension and on canine hepatocytes exposed to extreme hypoxia (1% O2). Thus, this study is sectioned into three major chapters followed by conclusions and future studies to determine the safety and indication of these anesthetic formulations in canine hepatocytes to be further explored in the clinical setting with live animals.

Although adenosine receptors have been implicated in the induction of preconditioning in a variety of experimental models, there is controversy concerning the specific adenosine receptor subtypes mediating this effect. Concentration-protection relationships for adenosine and adenosine agonists in rabbit cardiomyocytes were used to characterize the role of adenosine receptor subtypes in preconditioning. Isolated cells were ischemically preconditioned or pre-incubated for 10 min with increasing concentrations of adenosine, CCPA (2-chloro-N6-cyclopentyladenosine) APNEA (N6-2-(4-aminophenyl)ethyladenosine), or BNECA (N6-benzyl-5'-N-ethyl-carboxamidoadenosine) in the presence or absence of 1 or 10 μM of the selective A1-adenosine antagonist DPCPX (8-Cyclopentyl-1,3-dipropylxanthine). Following a 30-min post-incubation period, cells were pelleted, layered with oil and ischemically incubated for 180 min. Injury was assessed by osmotic swelling and trypan blue exclusion of sequential samples, and determination of the areas beneath the mortality curves. Adenosine produced a broad concentration-protection curve which was displaced to the right by DPCPX. The curve for A1-selective agonist CCPA was biphasic, with an initial response below 1 nM and a second above 1 μM. DPCPX abolished the early response leaving a steep monophasic curve between 0.1 and 10 μM CCPA. The APNEA curve appeared monophasic, the major slope occurring between 1-100 nM; DPCPX (1 μM) shifted the concentration-response curve ≃ 30-fold and decreased the slope. Adenosine receptor agonist BNECA produced preconditioning characterized by a shallow monophasic concentration-protection curve with a maximal effect of 49% and an EC50 of ≃ 5 nM; DPCPX shifted the BNECA concentration-protection relationship ≃ 40-fold with only a modest increase in slope. Analysis of the data suggests that induction of preconditioning results from interaction of agonists with the A1 receptor and a second adenosine receptor having properties consistent with the A3 receptor. Adenosine, CCPA, APNEA, BNECA and DPCPX each appear to be selective for the A1 adenosine receptor subtype in isolated rabbit cardiomyocytes.

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Collagenous tissues such as ligaments and tendons are viscoelastic materials. They exhibit a slow continuous increase in strain over time, or creep, when subjected to a constant stress and a slow continuous decrease in stress over time, or stress relaxation, when subjected to a constant strain. Moreover, the loading and unloading stress-strain curves are different when the tissues are subjected to cyclic loading, showing hysteresis and softening phenomena. The micro-structural origin of the viscoelasticity of these tissues is still unknown and the subject of debate among experts in biomechanics. Therefore, formulating viscoelastic models by accounting for the mechanical contributions of the structural components of these tissues can help in understanding the genesis of viscoelasticity. A nonlinear viscoelastic modeling framework has been developed to describe the elastic and viscoelastic properties of ligaments and tendons by considering their main structural components, the collagen fibers and proteoglycan-rich matrix. The mathematical models derived within this framework can illustrate the tensile behavior, stress relaxation and creep by as suming that the collagen fibers are elastic and the surrounding proteoglycan-rich matrix is viscoelastic. The collagen fibers are represented by linear elastic springs that are engaged to support load at different values of the tissue's strain according to a Weibull distribution function. The mechanical contribution of the matrix is introduced via a Maxwell-type viscoelastic element arranged in parallel with the collagen fibers. According to the proposed mathematical framework, both the collagen fibers and the proteoglycan-rich matrix are responsible for resisting tensile loads. However, the collagen fibers play a significant role in creep while the proteoglycan-rich matrix has a dominant role in stress relaxation. The model parameters that define the stress relaxation and strain stiffening phenomena are estimated by using published experimental on rabbit medial collateral ligaments and are then used to predict creep. The above modeling framework has been also extended to capture the in uence of preconditioning on the mechanical properties of ligaments and tendons. The stress softening and decrease in hysteresis that are observed during successive loading cycles in preconditioning are assumed to be determined by a decrease in the elastic properties of the collagen fibers and proteoglycan-rich matrix. Preliminary data collected on stress relaxation and preconditioning on rat medial collateral ligaments by collaborators are used to evaluate the model parameters and analyze its predictions. The elastic and viscoelastic properties of single collagen fibers are studied by formulating a nonlinear viscoelastic framework by accounting for their main components: microfibrils, cross-links and proteoglycan-rich matrix. The model illustrates tensile behavior and stress relaxation of a single collagen fiber by assuming that the microfibrils and the cross-links are elastic and the surrounding proteoglycan-rich matrix is viscoelastic. The mechanical contribution of the microfibrils is included via a linear elastic spring while the cross-links are represented by linear elastic springs that progressively fail at different values of the tissue's strain according to an exponential distribution function. The matrix is defined by linear dashpots arranged in parallel with each single spring that represents an individual cross-link. The viscous properties of the matrix associated with the unbroken and broken cross-links are assumed to have different values. In the model formulation, the microfibrils and the cross-links are assumed to determine the elastic response of the fibers while the proteoglycan-rich matrix determines the stress relaxation. Microfibrils, cross-links and the proteoglycan-rich matrix are responsible for resisting the loading force during tensile behavior. Experimental data collected by performing incremental stress relaxation tests by other investigators on reconstituted rat tail tendons are used to estimate the parameters in the model and evaluate its performance. / Ph. D.

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A interrupção do fluxo sanguíneo, ou isquemia, representa um dos problemas mais importantes de doenças cardiovasculares e cerebrovasculares enfrentados pelos médicos na sua rotina. Em relação ao miocárdio muitos estudos têm sido realizados nessa área e sabe-se que os anestésicos inalatórios e os opiódes podem protege as células cardíacas contra a lesão de isquemia e reperfusão. O propofol por sua parece não ter efeito de précondicionamento, porém apresenta características similares as ações antioxidantes da vitamina E, neutralizando os efeitos nocivos da produção de radicais livres. A associação de sevoflurano, sufentanil e propofol não está descrita na literatura. O objetivo deste estudo foi examinar a potencialização de cardioproteção entre sevoflurano, propofol e sufentanil por meio de análise do tamanho da área de infarto e inibição de apoptose em células miocárdicas. Ratos foram submetidos a 5 protocolos de pré-condicionamento diferentes e divididos em grupos agudos e crônicos. Os resultados indicaram que a associação destes anestésicos não conferiu proteção maior do que quando administrados isoladamente. Além disso, o sevoflurano conferiu proteção ao miocárdio no pós-infarto agudo e crônico. Já o propofol conferiu cardioproteção no pós-infarto crônico / The interruption of blood flow, or ischemia, represents one of the major problems of cardiovascular and cerebrovascular diseases seen by physicians in their routine. With respect to the myocardium, many studies have been conducted in this area and it is a known fact that inhaled anesthetics and opiates may protect cardiac cells against the ischemia and reperfusion injury. Propofol, in turn, seems to have no preconditioning effect, but it has similar characteristics to the antioxidant actions of vitamin E by neutralizing the harmful effects of free radical production. The combination of sevoflurane, sufentanil and propofol has not been described in literature. The aim of this study was to survey cardioprotection potentiation among sevoflurane, propofol and sufentanil by analyzing the size of infarct area and the inhibition of apoptosis in cardiac cells. Rats were subjected to five different preconditioning protocols and divided into acute and chronic groups. Results indicated that the combination of these anesthetics did not confer greater protection than when they were administered alone. Furthermore, sevoflurane conferred myocardial protection in the postacute and chronic infarction stage. Propofol, in turn, conferred cardioprotection in the chronic post-infarction stage