Ischemic injury is a common and debilitating outcome of natural illness and as a complication of commonly performed medical procedures. Whereas naturally occurring ischemic insults are often the result of unpredictable events, such as in the case of stroke or heart attack, the risk of operative and perioperative ischemia is somewhat better characterized in the clinical setting. Given the prevalence and severity of outcomes in ischemic injury, there is significant interest in developing better pharmacological and procedural approaches to improve patient outcomes. One approach that has shown significant promise in the laboratory setting, particularly in the context of planned medical procedures, is the use of delayed anesthetic preconditioning. Delayed anesthetic preconditioning is a phenomenon whereby a prior exposure to clinical concentrations of commonly used inhaled anesthetics, including isoflurane, induces the production of endogenous protective proteins that are able to provide robust protection against subsequent, potentially toxic, ischemic insults. Although many aspects of delayed anesthetic preconditioning have been previously described, a complete understanding of preconditioning mechanism has yet to emerge. The studies described in this dissertation aim to further our understanding of molecular mechanisms involved in delayed anesthetic preconditioning. In the first project, I used DNA microarray to identify genes that were differentially expressed in adult rat liver, kidney and heart following a clinically relevant exposure to the inhaled anesthetic isoflurane. By selecting those genes that were differentially expressed in multiple tissues, I was able to identify a small group of interesting genes for further study. In my second study, I chose from our list two related genes, metallothioneins I + II, to analyze for a role in anesthetic-mediated protection. Using a combination of approaches, I was able to establish that metallotioneins I + II play an essential role in delayed anesthetic preconditioning. In the final study of this dissertation I explore a possible role for metallothioneins I + II as sensor molecules, involved in detecting cellular oxidative stress. Taken together, these three studies represent an important contribution to our understanding of the mechanisms of delayed anesthetic preconditioning and how they might contribute to protecting against ischemic stroke.

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

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