Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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The effects of lipopolysaccharide (LPS) on the central nervous system, one of the first organs to be affected by sepsis, are still incompletely understood. Rat microglia (BMphi) constitute the main leukocyte-dependent source of reactive oxygen species in the central nervous system. The in vitro effect of LPS on agonist-stimulated superoxide (O2-) generation from BMphi appears controversial. ⋯ Furthermore, stimulation of BMphi with LPS for 17 h resulted in the following concentration-dependent responses: .1-1 ng/mL LPS induced no prior mediator generation but potently enhanced subsequent phorbol-12 myristate 13-acetate-stimulated O2- generation; 3-10 ng/mL LPS caused nitric oxide, tumor necrosis factor-alpha (TNF-alpha), thromboxane B2 and matrix metalloproteinase-9 release although partially inhibiting ensuing phorbol-12 myristate 13-acetate-stimulated O2- generation; 30-100 ng/mL LPS, maximized nitric oxide, TNF-alpha, thromboxane B2, matrix metalloproteinase-9 generation with concomitant lactic dehydrogenase release although strongly deactivating successive phorbol-12 myristate 13-acetate-stimulated O2 production. Our in vitro studies suggest that enhanced release of these four mediators (nitric oxide, TNF-alpha, thromboxane B2, and matrix metalloproteinase-9) during stimulation of BMphi with LPS might play a critical role in the subsequent ability of BMphi to generate O2- in vivo. Potential clinical implications of our findings are suggested by the fact that LPS levels similar to the ones used in this study have been observed in cerebrospinal fluid both in Gram-negative meningitis and sepsis.
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Based on simultaneous power spectral analysis of systemic arterial pressure (SAP) and central venous pressure (CVP) signals in rats anesthetized with pentobarbital sodium, we assessed the hypotheses that subtle changes in the SAP spectrum exist during hemorrhagic shock, and that the CVP spectrum is a feasible index for central blood volume during acute graded blood loss. During Stage I hemorrhagic shock seen after reduction in 10% of total blood volume (TBV), there was a significant increase in the power of both the very low frequency (VLF, 0-.25 Hz) and low frequency (LF, .25-.8 Hz) components, along with a moderate decrease in the very high frequency (VHF, 5-9 Hz) component, of SAP signals. Substantial reduction in VLF, LF, and VHF components in the SAP spectrum occurred after a blood loss of 25% of TBV (Stage II), which persisted during Stage III hemorrhagic shock when the withdrawn blood reached 50% of TBV and the mean SAP maintained at 40 mm Hg. ⋯ The power of the high-frequency (HF, .8-2.4 Hz) component of SAP signals increased discernibly only during Stage III, became significant on spontaneous recovery, and declined during retransfusion. Although CVP and CVP-VHF component progressively declined, the power of the CVP-HF component manifested a gradual increase that was significantly and reversely correlated with the reduction in TBV. We conclude that differential changes in individual components of the SAP spectrum occur during hemorrhagic shock, and that the CVP-HF component may be a reliable indicator for central blood volume during acute graded blood loss.
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Both altered Ca2+ homeostasis and injury by oxygen-free radicals (OFR) are pivotal mechanisms of cellular dysfunction. The purpose of this study was to evaluate the role of OFR and xanthine oxidase in hepatocellular Ca2+ dysregulation following hemorrhagic shock and resuscitation. Anesthetized rats were bled to a mean arterial blood pressure of 40 mm Hg for 60 min and then resuscitated with 60% of shed blood and 3-fold the shed blood volume as lactated Ringer's for another 60 min. ⋯ Continuous administration of superoxide dismutase or catalase (60,000 IU/kg body weight) during resuscitation substantially decreased Ca2+(up), Ca2+(in), Ca2+(flux), and oxidant injury. Pretreatment with allopurinol (50 mg/kg/day for 2 days) significantly inhibited enhanced plasma xanthine oxidase activity and hepatocyte glutathione oxidation, however, it did not prevent hepatocellular Ca2+ dysregulation. These data suggested a significant role of oxyradicals in ischemia/reperfusion-induced Ca2+ overload, however, xanthine oxidase activation seemed not to be a main source of these radicals.
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The renin angiotensin system is highly activated in shock states and has been suggested to be involved in the pathophysiology of the markedly deteriorated splanchnic circulation seen in septic shock. The purpose of the present study was to elucidate the capability of losartan, a nonpeptide angiotensin II type 1 (AT1) receptor antagonist, to attenuate splanchnic blood flow disturbances and counteract intestinal mucosal acidosis in endotoxin shock. A total of 20 pigs were anesthetized and catheterized. ⋯ Also the mucosal-portal venous PCO2gap, used as a monitor of the mucosa in relation to the gut as a whole (including the spleen and pancreas), was greatly increased by endotoxemia but unaffected by losartan administration. In summary, although the angiotensin II type 1 receptor antagonist losartan improved gut oxygen delivery and reduced pulmonary hypertension during established endotoxin shock, it had no effect on intestinal mucosal acidosis. These findings suggest contribution of the angiotensin II type 1 receptor to perfusion disturbances, but not to deterioration of intestinal mucosal homeostasis seen during endotoxemia.