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      Myosin light chain kinase is necessary for post-shock mesenteric lymph drainage enhancement of vascular reactivity and calcium sensitivity in hemorrhagic-shocked rats

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          Abstract

          Vascular hyporeactivity is an important factor in irreversible shock, and post-shock mesenteric lymph (PSML) blockade improves vascular reactivity after hemorrhagic shock. This study explored the possible involvement of myosin light chain kinase (MLCK) in PSML-mediated vascular hyporeactivity and calcium desensitization. Rats were divided into sham (n=12), shock (n=18), and shock+drainage (n=18) groups. A hemorrhagic shock model (40±2 mmHg, 3 h) was established in the shock and shock+drainage groups. PSML drainage was performed from 1 to 3 h from start of hypotension in shock+drainage rats. Levels of phospho-MLCK (p-MLCK) were determined in superior mesenteric artery (SMA) tissue, and the vascular reactivity to norepinephrine (NE) and sensitivity to Ca 2+ were observed in SMA rings in an isolated organ perfusion system. p-MLCK was significantly decreased in the shock group compared with the sham group, but increased in the shock+drainage group compared with the shock group. Substance P (1 nM), an agonist of MLCK, significantly elevated the decreased contractile response of SMA rings to both NE and Ca 2+ at various concentrations. Maximum contractility (E max) in the shock group increased with NE (from 0.179±0.038 to 0.440±0.177 g/mg, P<0.05) and Ca 2+ (from 0.515±0.043 to 0.646±0.096 g/mg, P<0.05). ML-7 (0.1 nM), an inhibitor of MLCK, reduced the increased vascular response to NE and Ca 2+ at various concentrations in the shock+drainage group (from 0.744±0.187 to 0.570±0.143 g/mg in E max for NE and from 0.729±0.037 to 0.645±0.056 g/mg in E max for Ca 2+, P<0.05). We conclude that MLCK is an important contributor to PSML drainage, enhancing vascular reactivity and calcium sensitivity in rats with hemorrhagic shock.

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          Most cited references 36

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          Fluid resuscitation: past, present, and the future.

          Hemorrhage remains a major cause of preventable death following both civilian and military trauma. The goals of resuscitation in the face of hemorrhagic shock are restoring end-organ perfusion and maintaining tissue oxygenation while attempting definitive control of bleeding. However, if not performed properly, resuscitation can actually exacerbate cellular injury caused by hemorrhagic shock, and the type of fluid used for resuscitation plays an important role in this injury pattern. This article reviews the historical development and scientific underpinnings of modern resuscitation techniques. We summarized data from a number of studies to illustrate the differential effects of commonly used resuscitation fluids, including isotonic crystalloids, natural and artificial colloids, hypertonic and hyperoncotic solutions, and artificial oxygen carriers, on cellular injury and how these relate to clinical practice. The data reveal that a uniformly safe, effective, and practical resuscitation fluid when blood products are unavailable and direct hemorrhage control is delayed has been elusive. Yet, it is logical to prevent this cellular injury through wiser resuscitation strategies than attempting immunomodulation after the damage has already occurred. Thus, we describe how some novel resuscitation strategies aimed at preventing or ameliorating cellular injury may become clinically available in the future.
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            Gut lymph and lymphatics: a source of factors leading to organ injury and dysfunction.

            Major trauma, shock, sepsis, and other conditions can lead to the acute respiratory distress syndrome (ARDS), which may progress to the highly lethal multiple organ dysfunction syndrome (MODS). Although a number of therapeutic strategies have been initiated, their success has been limited largely due to an incomplete understanding of the biology of MODS. However, recent studies indicate that the intestinal lymphatics serve as the primary route for nonbacterial, tissue injurious gut-derived factors, which can induce acute ARDS and MODS. The gut lymph hypothesis of ARDS and MODS thus helps clarify several important issues. First, because the lung is the first organ exposed to mesenteric lymph and not the liver (i.e., mesenteric lymph enters the subclavian vein via the thoracic duct, which, in turn, empties directly into the heart and lungs), it would explain the clinical observation that the lung is generally the first organ to fail. Second, this hypothesis provides new pathophysiologic information, thereby providing a basis for novel therapies. Finally, by studying the composition of lymph, MODS-inducing factors can be isolated and identified. © 2010 New York Academy of Sciences.
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              Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside.

              To delineate some of the characteristics of septic vascular hypotension, to assess the most commonly cited and reported underlying mechanisms of vascular hyporesponsiveness to vasoconstrictors in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents. Nitric oxide (NO) and peroxynitrite are crucial components implicated in vasoplegia and vascular hyporeactivity. Vascular ATP-sensitive and calcium-activated potassium channels are activated during shock and participate in hypotension. In addition, shock state is characterized by inappropriately low plasma glucocorticoid and vasopressin concentrations, a dysfunction and desensitization of alpha-receptors, and an inactivation of catecholamines by oxidation. Numerous other mechanisms have been individualized in animal models, the great majority of which involve NO: MEK1/2-ERK1/2 pathway, H(2)S, hyperglycemia, and cytoskeleton dysregulation associated with decreased actin expression. Many therapeutic approaches have proven their efficiency in animal models, especially therapies directed against one particular compound, but have otherwise failed when used in human shock. Nevertheless, high doses of catecholamines, vasopressin and terlipressin, hydrocortisone, activated protein C, and non-specific shock treatment have demonstrated a partial efficiency in reversing sepsis-induced hypotension.
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                Author and article information

                Affiliations
                Institute of Microcirculation, Hebei North University, Hebei, China
                Author notes
                Correspondence: C.Y. Niu, Institute of Microcirculation, Hebei North University, Diamond South Road 11, Hebei, Zhangjiakou 075000, China. Fax: +86-313-402-9168. E-mail: ncylxf@ 123456126.com
                Journal
                Braz J Med Biol Res
                Braz. J. Med. Biol. Res
                Brazilian Journal of Medical and Biological Research
                Associação Brasileira de Divulgação Científica
                0100-879X
                1414-431X
                10 August 2013
                July 2013
                : 46
                : 7
                : 574-579
                23903684 3859335 10.1590/1414-431X20132900

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Figures: 3, Tables: 2, References: 31, Pages: 1
                Categories
                Biomedical Sciences

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