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O endotélio vascular é responsável por várias funções como o controle do tônus vascular pela produção e/ou liberação de substâncias vasoconstritoras (EDCFs) e relaxantes (EDRFs). Na hipertensão arterial ocorre disfunção endotelial caracterizada pelo desequilíbrio entre EDCFs e EDRFs. Vários autores sugerem que essas alterações são decorrentes do aumento nas concentrações de espécies reativas de oxigênio (EROs). As EROs podem afetar a sinalização, produção e/ou biodisponibilidade do óxido nítrico (NO), principal EDRF, assim como aumentar os níveis de prostanóides como prostaglandinas e tromboxanos, EDCFs produtos da COX. O principal alvo para o NO é a ativação da guanilil ciclase solúvel (GCs) no musculo liso vascular causando vasorelaxamento. No modelo de hipertensão arterial dois rins um clipe (2R-1C), ocorre aumento nos níveis de EROs e ativação da NADH/NADPH-oxidase, principal enzima produtora de EROs em células endoteliais. Em nosso estudo, utilizamos o composto NCX2121, que é estruturalmente formado por um doador de NO e inibidor da COX (indometacina). O estudo teve por objetivo caracterizar farmacologicamente a resposta relaxante do NCX2121 na aorta de ratos hipertensos 2R-1C e investigar a contribuição do endotélio vascular e das EROs para essa resposta. Verificamos que o composto NCX 2121 produz relaxamento da aorta de ratos 2R e 2R-1C, que é reduzido pela remoção do endotélio e inibição da enzima NO-Sintase (NOS). O relaxamento do composto NCX 2121 deve ser promovido pelo NO, uma vez que em aortas sem endotélio esse relaxamento foi abolido pelo ODQ. Porém, foi apenas reduzido em aortas com endotélio, isoladas de ratos normotensos (2R) e não foi alterado nas aortas com endotélio, isoladas de ratos 2R-1C. O NCX 2121 não alterou a fosforilação dos sítios de ativação ou inibição da eNOS. O NO não foi detectado em solução por análise amperométrica. O composto NCX2121 aumentou a concentração citosólica de NO, medida pela sonda fluorescente sensível a NO (DAF-2DA), por microscopia confocal. Na aorta de ratos 2R-1C, o relaxamento estimulado com o composto NCX2121 foi inibido pelas EROs e os níveis de EROs em células endoteliais isoladas, foi reduzido pelo composto NCX2121. O composto NCX 2121 reduziu os níveis de tromboxano na aorta de ratos 2R e 2R-1C. Os nossos resultados demonstram que o composto NCX2121 promove relaxamento pela liberação intracelular de NO e inibição da COX por reduzir a produção de prostanóides vasoconstrictores como o tromboxano. O composto NCX2121 não interfere com a ativação da NOS, mas reduz as EROs nas células endoteliais. / The vascular endothelium plays multiple roles on the tone control by the production and/or release of contractile factors (EDCFs) and relaxing factors (EDRFs). There is an imbalance between EDCFs and EDRFs in hypertension that is defined by endothelial dysfunction. In accordance to several authors, these alterations are due to increased production of reactive oxygen species (ROS). The ROS can affect the nitric oxide (NO) signaling, production and bioavailability that is the major EDRF. ROS can also increase the levels of prostaglandins and thromboxane (TX) that are EDCFs products of COX. The main target for NO is the activation of soluble guanylyl-cyclase (sGC) in the vascular smooth muscle cells causing vasorelaxation. In renal hypertensive rats (2K-1C), there is an increased production of ROS by NADH-NADPH-oxidase in the rat aorta endothelial cells. In the present study we used the compound NCX2121, in which chemical structure there is a NO donor and a non-selective COX inhibitor indomethacin. This study aimed to pharmacologically characterize the NCX2121 relaxing effect in 2K-1C rat aorta, and to investigate the contribution of the endothelial factors and ROS for this response. We verified that the relaxation-induced by NCX2121 was impaired by the endothelium removal and NO-synthase (NOS) inhibition. The relaxation induced by NCX2121 is due to NO, since sGC inhibition by ODQ completely abolished its effect in denuded endothelium 2K-1C rat aorta. However, in intact endothelium normotensive 2K rat aorta, the relaxing effect of NCX2121 was only partially inhibited whereas in 2K-1C it was not changed. NCX2121 did not change the phosphorylation sites of activation or inhibition of NOS. NO was not detected by amperometry in the organ bath during the relaxation induced by NCX2121, but it was measured in the cell cytoplasm by confocal microscopy. The vasorelaxation was inhibited by ROS, and NCX2121 decreased the ROS in isolated endothelial cells. NCX2121 reduced TX in 2K and 2K-1C rat aortas. Therefore, our results indicate that the compound NCX2121 induces relaxation by intracellular NO release and COX inhibition by the reduced production of contractile prostanoids such as TX. The compound NCX2121 does not modulate NOS, but it decreases ROS in the endothelial cells.

O endotélio vascular é responsável por várias funções como o controle do tônus vascular pela produção e/ou liberação de substâncias vasoconstritoras (EDCFs) e relaxantes (EDRFs). Na hipertensão arterial ocorre disfunção endotelial caracterizada pelo desequilíbrio entre EDCFs e EDRFs. Vários autores sugerem que essas alterações são decorrentes do aumento nas concentrações de espécies reativas de oxigênio (EROs). As EROs podem afetar a sinalização, produção e/ou biodisponibilidade do óxido nítrico (NO), principal EDRF, assim como aumentar os níveis de prostanóides como prostaglandinas e tromboxanos, EDCFs produtos da COX. O principal alvo para o NO é a ativação da guanilil ciclase solúvel (GCs) no musculo liso vascular causando vasorelaxamento. No modelo de hipertensão arterial dois rins um clipe (2R-1C), ocorre aumento nos níveis de EROs e ativação da NADH/NADPH-oxidase, principal enzima produtora de EROs em células endoteliais. Em nosso estudo, utilizamos o composto NCX2121, que é estruturalmente formado por um doador de NO e inibidor da COX (indometacina). O estudo teve por objetivo caracterizar farmacologicamente a resposta relaxante do NCX2121 na aorta de ratos hipertensos 2R-1C e investigar a contribuição do endotélio vascular e das EROs para essa resposta. Verificamos que o composto NCX 2121 produz relaxamento da aorta de ratos 2R e 2R-1C, que é reduzido pela remoção do endotélio e inibição da enzima NO-Sintase (NOS). O relaxamento do composto NCX 2121 deve ser promovido pelo NO, uma vez que em aortas sem endotélio esse relaxamento foi abolido pelo ODQ. Porém, foi apenas reduzido em aortas com endotélio, isoladas de ratos normotensos (2R) e não foi alterado nas aortas com endotélio, isoladas de ratos 2R-1C. O NCX 2121 não alterou a fosforilação dos sítios de ativação ou inibição da eNOS. O NO não foi detectado em solução por análise amperométrica. O composto NCX2121 aumentou a concentração citosólica de NO, medida pela sonda fluorescente sensível a NO (DAF-2DA), por microscopia confocal. Na aorta de ratos 2R-1C, o relaxamento estimulado com o composto NCX2121 foi inibido pelas EROs e os níveis de EROs em células endoteliais isoladas, foi reduzido pelo composto NCX2121. O composto NCX 2121 reduziu os níveis de tromboxano na aorta de ratos 2R e 2R-1C. Os nossos resultados demonstram que o composto NCX2121 promove relaxamento pela liberação intracelular de NO e inibição da COX por reduzir a produção de prostanóides vasoconstrictores como o tromboxano. O composto NCX2121 não interfere com a ativação da NOS, mas reduz as EROs nas células endoteliais. / The vascular endothelium plays multiple roles on the tone control by the production and/or release of contractile factors (EDCFs) and relaxing factors (EDRFs). There is an imbalance between EDCFs and EDRFs in hypertension that is defined by endothelial dysfunction. In accordance to several authors, these alterations are due to increased production of reactive oxygen species (ROS). The ROS can affect the nitric oxide (NO) signaling, production and bioavailability that is the major EDRF. ROS can also increase the levels of prostaglandins and thromboxane (TX) that are EDCFs products of COX. The main target for NO is the activation of soluble guanylyl-cyclase (sGC) in the vascular smooth muscle cells causing vasorelaxation. In renal hypertensive rats (2K-1C), there is an increased production of ROS by NADH-NADPH-oxidase in the rat aorta endothelial cells. In the present study we used the compound NCX2121, in which chemical structure there is a NO donor and a non-selective COX inhibitor indomethacin. This study aimed to pharmacologically characterize the NCX2121 relaxing effect in 2K-1C rat aorta, and to investigate the contribution of the endothelial factors and ROS for this response. We verified that the relaxation-induced by NCX2121 was impaired by the endothelium removal and NO-synthase (NOS) inhibition. The relaxation induced by NCX2121 is due to NO, since sGC inhibition by ODQ completely abolished its effect in denuded endothelium 2K-1C rat aorta. However, in intact endothelium normotensive 2K rat aorta, the relaxing effect of NCX2121 was only partially inhibited whereas in 2K-1C it was not changed. NCX2121 did not change the phosphorylation sites of activation or inhibition of NOS. NO was not detected by amperometry in the organ bath during the relaxation induced by NCX2121, but it was measured in the cell cytoplasm by confocal microscopy. The vasorelaxation was inhibited by ROS, and NCX2121 decreased the ROS in isolated endothelial cells. NCX2121 reduced TX in 2K and 2K-1C rat aortas. Therefore, our results indicate that the compound NCX2121 induces relaxation by intracellular NO release and COX inhibition by the reduced production of contractile prostanoids such as TX. The compound NCX2121 does not modulate NOS, but it decreases ROS in the endothelial cells.

NSAIDs are among the most used drugs in the world. It is estimated that 30 million people take NSAIDs daily world-wide, without including drugs sold over the counter. They are effective in alleviating pain and inflammation. Even though they are very common there does not appear to be any clear-cut guidelines to when which NSAID should be used. It has therefore been the purpose of this thesis to analyze if there is a need to differentiate between different NSAIDs according to contemporary evidence. Since the withdrawal of rofecoxib in 2004 there has been a general idea that coxibs as a group are cardiotoxic, recent evidence suggests that this holds true for all NSAIDs however. As such this work included 5 drugs, three common over the counter non-selective NSAIDs; naproxen, ibuprofen and diclofenac as well as the two coxibs currently on the Swedish market; celecoxib and etoricoxib. Pubmed and google scholar were searched for relevant studies on the subject. The results showed that there is a need to differentiate between NSAIDs, however the clinical setting is complex and a one-size fits all solution is difficult to come by. Naproxen and moderate doses of celecoxib (100 mg b.i.d.) show the best cardiovascular profiles whilst etoricoxib, celecoxib and diclofenac show the best gastrointestinal profiles. Coxibs show similar upper GI-profiles as tNSAIDs if combined with PPI however PPI are not without adverse events and the lower GI is not affected by PPI. Longer half-life is in general the better option in situations with lasting pain since it has been shown that lower dosing intervals increase adherence. In terms of pain management there does not appear to be any differences in efficacy amongst different NSAIDs

<p>Patients with peritonitis or malignant obstructive jaundice (HPB⁺) have an increased morbidity and mortality due to sepsis. An altered cell-mediated immunity in the intestinal mucosa might promote gut barrier failure, increased endotoxin and cytokine release and bacterial translocation (BT) in these conditions. A clinically relevant rat model of polymicrobial peritonitis induced sepsis by cecal ligation and puncture (CLP) was used. Septic animals demonstrated a superficial injury in the small intestinal mucosa, and a significant reduction in T lymphocytes in the villi, as well as increased number of macrophages in the villi and in the MLNs as compared to sham. CLP caused increased concentration of TNF-α and IL-6 in ascitic fluid. CLP + the immunomodulator Linomide decreased the TNF-α level, reduced mucosal damage and attenuated the changes in T lymphocytes and macrophages observed following CLP. CLP + selective cyclooxygenase (COX)-2 inhibitor (SC-236) or nonselective COX inhibitor (indometacin) decreased the amount of macrophages in the mucosa and the MLNs compared to untreated CLP. CLP + indometacin decreased T lymphocytes in the villi and MLNs. SC-236 + CLP reduced mucosal injury and cytokine release as compared to indometacin. An increased rate of apoptosis in both the mucosa and MLNs was seen following CLP; COX inhibitors enhanced this phenomenon in the MLNs.</p><p>BT occurred infrequently in patients with acute peritonitis and in HPB⁺ there was no evidence of BT. Peritonitis and HPB⁺causes significant inflammatory cellular reactions as increased endotoxin and cytokine plasma levels and an altered immune cell distribution in MLNs, in HPB⁺a high rate of apoptosis in MLNs was observed. </p><p>An altered pattern of immunocompetent cells within the mucosa and in MLNs was found in experimental and clinical peritonitis as in HPB⁺.Lymphocyte depletion may be a result of increased apoptosis, which could reduce the ability of septic or jaundice patients to eradicate infection.</p>

Patients with peritonitis or malignant obstructive jaundice (HPB+) have an increased morbidity and mortality due to sepsis. An altered cell-mediated immunity in the intestinal mucosa might promote gut barrier failure, increased endotoxin and cytokine release and bacterial translocation (BT) in these conditions. A clinically relevant rat model of polymicrobial peritonitis induced sepsis by cecal ligation and puncture (CLP) was used. Septic animals demonstrated a superficial injury in the small intestinal mucosa, and a significant reduction in T lymphocytes in the villi, as well as increased number of macrophages in the villi and in the MLNs as compared to sham. CLP caused increased concentration of TNF-α and IL-6 in ascitic fluid. CLP + the immunomodulator Linomide decreased the TNF-α level, reduced mucosal damage and attenuated the changes in T lymphocytes and macrophages observed following CLP. CLP + selective cyclooxygenase (COX)-2 inhibitor (SC-236) or nonselective COX inhibitor (indometacin) decreased the amount of macrophages in the mucosa and the MLNs compared to untreated CLP. CLP + indometacin decreased T lymphocytes in the villi and MLNs. SC-236 + CLP reduced mucosal injury and cytokine release as compared to indometacin. An increased rate of apoptosis in both the mucosa and MLNs was seen following CLP; COX inhibitors enhanced this phenomenon in the MLNs. BT occurred infrequently in patients with acute peritonitis and in HPB+ there was no evidence of BT. Peritonitis and HPB+ causes significant inflammatory cellular reactions as increased endotoxin and cytokine plasma levels and an altered immune cell distribution in MLNs, in HPB+ a high rate of apoptosis in MLNs was observed. An altered pattern of immunocompetent cells within the mucosa and in MLNs was found in experimental and clinical peritonitis as in HPB+. Lymphocyte depletion may be a result of increased apoptosis, which could reduce the ability of septic or jaundice patients to eradicate infection.