Thesis (Ph. D.)--Ohio State University, 2003. / Title from first page of PDF file. Document formatted into pages; contains xii, 152 p.; also includes graphics (some col.). Includes bibliographical references (p. 137-150). Available online via OhioLINK's ETD Center

Thesis (Ph.D.)--Marshall University, 2009. / Title from document title page. Includes abstract. Document formatted into pages: contains 117 p. Includes bibliographical references p. 114.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1949. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph.D.)--Ohio University, November, 2006. / Includes bibliographical references (leaves 155-168).

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

The design of new, improved NO-donor drugs is an important pharmacological objective due to the biological importance of nitric oxide. N-Hydroxyguanidines represent a useful class of NO donors where the mechanism of action is based on the biosynthetic pathway for NO. Thirty new N-arylalkyl-N’-hydroxyguanidines were synthesized and their vasodilatation activity examined by myography in rat aortic rings. The observed relaxations were reversed by ODQ, which is an inhibitor of the guanylate cyclase, implying that this was an NO dependent vasodilatation. The most active compounds were also tested in the isolated perfused kidney (IPK) giving the vasodilatation properties. Preliminary results indicated that N-phenyl-N’- hydroxyguanidine showed the best pharmacological profile with EC₅₀= 19.9 μM and ca. 100% reversibility with ODQ. A series of N-phenylalkyl-N’-hydroxyguanidines were synthesised. NO donor activity was found to be fairly constant up to three methylene groups, and then decreased. Substitutions in the benzene ring of N-phenylethyl-N’-hydroxyguanidine demonstrated that various electron-withdrawing and electron-donating groups in the para position did not significantly affect the NO donor activity of this series of analogues. The nitro and trifluoromethyl substituted compounds gave the best biological profiles. Additionally, a novel heterocyclic, N–furfuryl-N’–hydroxyguanidine possessed very promising vasodilatation properties. In general, almost all the N-arylalkyl-N’-hydroxyguanidines behaved as potent NO donors in the rat aorta assay. In order to establish the influence of the free NH₂ group in the hydroxyguanidine functionality on the vasodilatation properties, N,N-dimethyl and N-methyl-N’- hydroxyguanidines were successfully synthesised. Unfortunately, they have not been tested yet in the biological assay. However, their NMR spectra showed some unusual features and their detailed analysis and X-ray data are presented herein. In addition a series of hydroxamic acids was synthesised and the NO donor activity investigated using the same biological methodology. It was found that the 3-phenylpropionohydroxamic acid was the most potent compound with EC₅₀ = 6 μM and ODQ = 96%. However, behavior in the IPK indicated that hydroxamic acids did not undergo the same biological pathway as in the rat aorta. Two different types of enzyme-activated pro-drugs were designed using N-hydroxyguanidines as the NO donating molecule. Synthetic studies towards these targets were carried out using various synthetic approaches. The desired molecules have not yet been synthesised but the chemistry explored so far has indicated potentially more successful approaches that could be attempted.

Evidências sugerem que os leucotrienos (LTs) e óxido nítrico (NO) podem apresentar um papel na liberação de vasopressina (AVP) que ocorre durante a fase inicial da sepse. Além disso, é conhecido que os LTs afetam a produção de NO. Nosso objetivo foi analisar o efeito do MK-886, um inibidor da síntese de LTs, na produção de NO e na liberação de AVP durante sepse experimental. Ratos Wistar receberam injeções i.p. de MK-886 (1.0, 2.0 ou 4.0mg/kg) ou veículo (DMSO 5%) 1h antes da ligadura e perfuração cecal (CLP) ou operação fictícia. Em um grupo a taxa de sobrevida foi monitorada durante 3 dias. Em outro grupo, os animais foram decapitados em 0, 4 e 24h após CLP ou operação fictícia, e o sangue foi coletado para a determinação da osmolalidade, sódio sérico, hematócrito, proteínas plasmáticas, nitrato sérico e cis-LTs e AVP plasmáticos. Além disso, foi avaliado o recrutamento de neutrófilos para a cavidade peritoneal dos ratos. O CLP aumentou os níveis de nitrato sérico, perda de proteínas, hematócrito e AVP plasmática 4h após a cirurgia, além disso, causou uma mortalidade de 80% após 3 dias de observação. Os níveis de sódio sérico e a osmolalidade apresentaram reduções pequenas, enquanto os níveis de cis-LTs e o recrutamento de neutrófilos permaneceram inalterados. O pré-tratamento com qualquer concentração de MK-886 não diminuiu a produção de nitrato sérico, a perda de proteínas plasmáticas e o hematócrito. Além disso, não alterou os níveis de sódio sérico, osmolalidade, cis-LTs plasmáticos, o recrutamento de neutrófilos e a taxa de sobrevida. Porém, a liberação de AVP foi afetada de uma maneira dose-dependente na fase inicial da sepse. Na fase tardia, a AVP plasmática se manteve em concentrações basais e a administração de MK-886 não alterou essas concentrações. Os resultados sugerem que o MK-886, um inibidor da síntese de leucotrienos, pode afetar a liberação de vasopressina na fase inicial da sepse e esse efeito parece ser independente da produção de óxido nítrico. / Evidence suggests that leukotrienes (LTs) and nitric oxide (NO) may have a role in vasopressin (AVP) release that occurs during the early phase of sepsis. Moreover, LTs are thought to affect NO production. Our objective was to analyze the effect of MK-886, a LTs synthesis inhibitor, on NO production and AVP release. Male Wistar rats received i.p. injections of MK-886 (1.0, 2.0 or 4.0mg/kg) or vehicle (DMSO 5%) 1h before cecal ligation and puncture (CLP) or sham operation. In one group the survival rate was monitored for 3 days. In another group, the animals were decapitated at 0, 4 and 24h after CLP or sham operation, and blood was collected for osmolality, serum sodium, hematocrit, plasma protein, serum nitrate and plasma cys-LTs and AVP levels measurement. Moreover, was evaluated neutrophil recruitment into the peritoneal cavities of rat. CLP increased serum nitrate levels, protein leakage, hematocrit, plasma AVP 4h after CLP, besides causing 80% mortality after 3 days of observation. The serum sodium levels and osmolality presented small reduction, while cys-LT levels and neutrophil recruitment remained unchanged. Pretreatment with any dose of MK-886 did not diminish nitrate production, protein leakage and hematocrit. Besides, not did it alter serum sodium levels, osmolality, plasma cys-LT levels and neutrophil recruitment. It also did not affect survival rate. AVP release was, however, affected in a dose-dependent manner in the early phase of sepsis. In the final phase of sepsis, plasma AVP levels remained basal and the administration of MK-886 did not alter these hormone levels. The results suggest that the MK-886, a LTs synthesis inhibitor, may affect the release of vasopressin in the early phase of sepsis and that this effect seems to be independent of nitric oxide production.

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / O Ãxido nÃtrico (NO) à uma espÃcie endÃgena responsÃvel pela dilataÃÃo dos vasos sanguÃneos, sendo tambÃm ativo no cÃrebro e em outros processos fisiolÃgicos. Doadores de NO sÃo substÃncias farmacologicamente ativas que liberam espontaneamente ou sÃo metabolizadas. Nitroprussiato de sÃdio, Na2[Fe(CN)5NO].2H2O, faz parte de uma classe de compostos que liberam NO espontaneamente e à o Ãnico complexo metÃlico usado clinicamente. Problemas associados com o uso de nitroprussiato incluem suscetibilidade a fotÃlise e aÃÃo oxidativa do sistema imune, no qual conduz à liberaÃÃo de cianeto. Neste trabalho foi realizado o estudo e acompanhamento cinÃtico da reaÃÃo dos complexos cis-[Ru(bpy)2LNO](PF6)n (L = imidazol e sulfito) com cisteÃna, glutationa, metionina e histidina, para a obtenÃÃo de dados cinÃticos e espectroscÃpicos que possam contribuir para a elucidaÃÃo de seu mecanismo de aÃÃo. Os resultados cinÃticos para a reaÃÃo dos nitrosilo complexos com a cisteÃna e glutationa sugerem que hà formaÃÃo de dois intermediÃrios: o primeiro com banda de absorÃÃo em 450 nm à referente ao ataque do enxofre dos tiÃis e o Ãxido nÃtrico. O segundo intermediÃrio com banda de absorÃÃo caracterÃsticas em 380 nm se deve ao ataque da segunda molÃcula dos redutores ao aduto formado. As constantes de velocidade da reaÃÃo com cisteÃna apresentaram dependÃncia com relaÃÃo ao pH. Isto ocorre, provavelmente, devido à desprotonaÃÃo no enxofre da cisteÃna, facilitando a interaÃÃo deste tiÃl com o Ãxido nÃtrico coordenado ao rutÃnio (II).As reaÃÃes com metionina e histidina mostram que nÃo hà o aparecimento dos intermediÃrios, devido à ausÃncia do grupo SH nos aminoÃcidos. O acompanhamento realizado com HPLC nos mostra a existÃncia do mesmo mecanismo entre os complexos cis-[Ru(bpy)2SO3NO](PF6) e cis- [Ru(bpy)2ImN(NO)](PF6)3 com cisteÃna e glutationa. No caso da interaÃÃo com metionina e histidina, ocorre à diminuiÃÃo do pico referente aos nitrosilos complexos e o aparecimento do pico atribuÃdo ao aqua complexo. Os resultados obtidos com o eletrodo seletivo de NO, de ressonÃncia paramagnÃtica de elÃtrons e RMN, mostraram que o Ãxido nÃtrico à reduzido e liberado nos complexo sem que haja a formaÃÃo do nitrosotiÃl. Baseado em estudos cinÃticos e no espectro de EPR, a reaÃÃo dos nitrosilo complexos com cisteÃna e glutationa apresenta o seguinte esquema de reduÃÃo e liberaÃÃo do Ãxido nÃtrico: / The oxide nitric (NO) is a responsible endogenous species by dilation of the blood vessels, being also active in the brain and in other physiologic processes. Donors of NO are pathophysiologically active healthy substances that liberate spontaneously or they are metabolized. Sodium nitroprusside, Na2[Fe(CN)5NO].2H2O, is part of a class of compounds that liberate NO spontaneously and it is the only metallic compound used clinically. Associated problems with the use of nitroprusside include susceptibility the photolysis and oxidative action of the immune system, in which it leads to the liberation of cyanide. In this work it was accomplished the study and kinetic monitoring of the reaction of the compounds cis-[Ru(bpy)2LNO](PF6)n (L = imidazole and sulphite) with cysteine, glutathione, methionine and histidine, for the obtaining of kinetic and spectroscopic data that can contribute to the elucidation of your action mechanism. The kinetic results for the reaction of the nitrosyl complex with the cysteine and glutathione suggest that there is two intermediates formation: the first with absorption band in 450 nm is regarding the attack of the sulfur of the thiols and the nitric oxide. The second intermediate with characteristics band of absorption in 380 nm is due to the attack of the second molecule of the reducers to the formed adduct. The rate constants of the reaction with cysteine presented dependence regarding the pH. This occurs, probably, due to the deprotonated in the sulfur of the cisteÃna, facilitating the interaction of this thiol with the coordinated nitric oxide to the ruthenium (II). The reactions with methionine and histidine show that there are not the intermediates, due to the absence of the group SH in the amino acids. The monitoring accomplished with HPLC reveal the existence of the same mechanism among the compounds cis-[Ru(bpy)2SO3NO](PF6) and cis- [Ru(bpy)2ImN(NO)](PF6)3 with cysteine and glutathione. In the case of the interaction with methionine and histidine, occurs the decrease of the peak regarding the nitrosyl complex and the appearance of the peak attributed to the aqua complex. The obtained results with the NO sensor, of electron paramagnetic resonance and RMN, they showed that the nitric oxide is reduced and release in the complex without there is the formation of the nitrosothiol. Based on kinetic studies and in the spectrum of EPR, the reaction of the nitrosyl complex with cysteine and glutathione presents the following reduction scheme and liberation of the nitric oxide:

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 4 uppsatser.