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8.
Am J Physiol Heart Circ Physiol ; 297(3): H930-48, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19542485

RESUMO

In septic shock, cardiovascular collapse is caused by the release of inflammatory mediators. We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression and arterial vasodilation that develop in canine models of septic shock. To cause vasodilation, Lzm-S generates hydrogen peroxide (H(2)O(2)) that activates the smooth muscle soluble guanylate cyclase (sGC) pathway, although the mechanism of H(2)O(2) generation is not known. To cause myocardial depression, Lzm-S binds to the endocardial endothelium, resulting in the formation of nitric oxide (NO) and subsequent activation of myocardial sGC, although the initial signaling event is not clear. In this study, we examined whether the myocardial depression produced by Lzm-S was also caused by the generation of H(2)O(2) and whether Lzm-S could intrinsically generate H(2)O(2) as has been described for other protein types. In a canine ventricular trabecular preparation, we found that the peroxidizing agent Aspergillus niger catalase, that would breakdown H(2)O(2), prevented Lzm-S- induced decrease in contraction. We also found that compound I, a species of catalase formed during H(2)O(2) metabolism, could contribute to the NO generation caused by Lzm-S. In tissue-free experiments, we used a fluorometric assay (Ultra Amplex red H(2)O(2) assay) and electrochemical sensor techniques, respectively, to measure H(2)O(2) generation. We found that Lzm-S could generate H(2)O(2) and, furthermore, that this generation could be attenuated by the singlet oxygen quencher sodium azide. This study shows that Lzm-S, a mediator of sepsis, is able to intrinsically generate H(2)O(2). Moreover, this generation may activate H(2)O(2)-dependent pathways leading to cardiovascular collapse in septic shock.


Assuntos
Doenças Cardiovasculares/metabolismo , Peróxido de Hidrogênio/metabolismo , Muramidase/metabolismo , Contração Miocárdica/fisiologia , Choque Séptico/metabolismo , Animais , Aspergillus niger/enzimologia , Doenças Cardiovasculares/imunologia , Catalase/farmacologia , Cães , Inibidores Enzimáticos/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Consumo de Oxigênio/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Choque Séptico/imunologia , ômega-N-Metilarginina/farmacologia
9.
Am J Physiol Heart Circ Physiol ; 294(4): H1724-35, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18263714

RESUMO

In septic shock, systemic vasodilation and myocardial depression contribute to the systemic hypotension observed. Both components can be attributed to the effects of mediators that are released as part of the inflammatory response. We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression that develops in a canine model of septic shock. Lzm-S binds to the endocardial endothelium, resulting in the production of nitric oxide (NO), which, in turn, activates the myocardial soluble guanylate cyclase (sGC) pathway. In the present study, we determined whether Lzm-S might also play a role in the systemic vasodilation that occurs in septic shock. In a phenylephrine-contracted canine carotid artery ring preparation, we found that both canine and human Lzm-S, at concentrations similar to those found in sepsis, produced vasorelaxation. This decrease in force could not be prevented by inhibitors of NO synthase, prostaglandin synthesis, or potassium channel inhibitors and was not dependent on the presence of the vascular endothelium. However, inhibitors of the sGC pathway prevented the vasodilatory activity of Lzm-S. In addition, Aspergillus niger catalase, which breaks down H(2)O(2), as well as hydroxyl radical scavengers, which included hydroquinone and mannitol, prevented the effect of Lzm-S. Electrochemical sensors corroborated that Lzm-S caused H(2)O(2) release from the carotid artery preparation. In conclusion, these results support the notion that when Lzm-S interacts with the arterial vasculature, this interaction results in the formation of H(2)O(2), which, in turn, activates the sGC pathway to cause relaxation. Lzm-S may contribute to the vasodilation that occurs in septic shock.


Assuntos
Artéria Carótida Interna/metabolismo , Peróxido de Hidrogênio/metabolismo , Artéria Mesentérica Superior/metabolismo , Muramidase/metabolismo , Óxido Nítrico/metabolismo , Sepse/metabolismo , Transdução de Sinais , Vasodilatação , Aminoquinolinas/farmacologia , Animais , Artéria Carótida Interna/efeitos dos fármacos , Artéria Carótida Interna/enzimologia , Catalase/metabolismo , GMP Cíclico/análogos & derivados , GMP Cíclico/metabolismo , GMP Cíclico/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Etanol/farmacologia , Depuradores de Radicais Livres/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Guanilato Ciclase/metabolismo , Humanos , Hidroquinonas/farmacologia , Técnicas In Vitro , Indometacina/farmacologia , Manitol/farmacologia , Artéria Mesentérica Superior/efeitos dos fármacos , Artéria Mesentérica Superior/enzimologia , Azul de Metileno/farmacologia , Muramidase/antagonistas & inibidores , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Oxidiazóis/farmacologia , Fenilefrina/farmacologia , Prostaglandinas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Quinoxalinas/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Sepse/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Guanilil Ciclase Solúvel , Tionucleotídeos/farmacologia , Fatores de Tempo , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , ômega-N-Metilarginina/farmacologia
10.
Am J Physiol Heart Circ Physiol ; 293(5): H3140-9, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17766478

RESUMO

We previously showed that lysozyme (Lzm-S), derived from leukocytes, caused myocardial depression in canine sepsis by binding to the endocardial endothelium to release nitric oxide (NO). NO then diffuses to adjacent myocytes to activate the cGMP pathway. In a canine right ventricular trabecular (RVT) preparation, Lzm-S also decreased the inotropic response to field stimulation (FSR) during which the sympathetic and parasympathetic nerves were simulated to measure the adrenergic response. In the present study, we determined whether the pathway by which Lzm-S decreased FSR was different from the pathway by which Lzm-S reduced steady-state (SS) contraction. Furthermore, we determined whether the decrease in FSR was due to a decrease in sympathetic stimulation or enhanced parasympathetic signaling. In the RVT preparation, we found that the inhibitory effect of Lzm-S on FSR was prevented by NO synthase (NOS) inhibitors. A cGMP inhibitor also blocked the depressant activity of Lzm-S. However, in contrast to the Lzm-S-induced decline in SS contraction, chemical removal of the endocardial endothelium by Triton X-100 to eliminate endothelial NO release did not prevent the decrease in FSR. An inhibitory G protein was involved in the effect of Lzm-S, since FSR could be restored by treatment with pertussis toxin. Atropine prevented the Lzm-S-induced decline in FSR, whereas beta(1)- and beta(2)-adrenoceptor function was not impaired by Lzm-S. These results indicate that the Lzm-S-induced decrease in FSR results from a nonendothelial release of NO. NO then acts through inhibitory G protein to enhance parasympathetic signaling.


Assuntos
Proteínas de Ligação ao GTP/metabolismo , Muramidase/metabolismo , Miocardite/metabolismo , Óxido Nítrico/metabolismo , Receptores Adrenérgicos beta/metabolismo , Sepse/metabolismo , Transdução de Sinais , Sistema Nervoso Simpático/fisiopatologia , Animais , Cães , Estimulação Elétrica , Endotélio Vascular/metabolismo
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