Nitric Oxide Synthesis Inhibition Does Not Improve the Hemodynamic Response to Hemorrhagic Shock in Dehydrated Conscious Swine

Ip, Brown; Rl, Williams; McKirnan,; Ur, Limjoco; Cg, Gray

doi:10.1097/00024382-199504000-00008

Cited by 19 publications

(9 citation statements)

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“…[12][13][14] Evidence suggests that the therapeutic effects of NOS inhibitors may depend on the dose, timing, and the severity and category of diseases.…”

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confidence: 99%

Dose Effects of Chronically Infused Nitric Oxide Synthase Inhibitor NG-Nitro-L-arginine Methyl Ester on Anabolic Response and Arginine Metabolism in Rats with Subacute Peritonitis

Hsiao

Lee

Tsao

et al. 2011

Biological & Pharmaceutical Bulletin

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Patients with peritonitis develop arginine deficiency due to decreased consumption, impaired absorption, and increased utilization of arginine.1,2) Arginine, a precursor for the synthesis of nitric oxide (NO), urea, creatinine, glutamate, proline, and polyamines, is a conditionally essential amino acid in stressed conditions, especially in inflammation. 1,3,4) Green et al. 5) was the first research group to show that nitrate/nitrite concentrations and the severity of infection are closely correlated. Subsequent studies showed that patients with peritonitis have uncontrolled activation of inducible nitric oxide synthase (NOS), which results in NO overproduction and the following sepsis.6) Therefore, inhibition of NOS might be a useful strategy to treat arginine deficiency and inhibit excess NO production. 6,7) In animal and human studies, the results of NOS inhibition in inflammation have been ambiguous. For example, N G -nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor which inhibits both constitutive and inducible NOS, effectively ameliorated the inflammatory lesions in the skin of zinc-deficient rats, 8) improved the myocardial function in sepsis, 9) and attenuated the lipopolysaccharide-induced peritoneal permeability and NO release in mice.10) On the contrary, some studies have shown that L-NAME may cause hypertension, augment the expressions of interferon (IFN)-g and interleukin (IL)-2, and result in markedly severe disease in rats with T cell-dependent autoimmune interstitial nephritis.11) The adverse effects of NOS inhibitors have also been observed in subjects with hemodynamic instability and sepsis. [12][13][14] Evidence suggests that the therapeutic effects of NOS inhibitors may depend on the dose, timing, and the severity and category of diseases.In clinical practice, a number of in hospital patients with subacute peritonitis developed chronic malnutrition and inflammation. Administration of total parenteral nutrition solution is an efficient method to supply all daily nutrition requirements; however, it is associated with occurrence of increased complicated infections.15) Zheng et al. 16) indicated that long-term parenteral nutrition-induced liver steatosis may be attenuated by L-NAME administration. Up to now, only few reports have described the long-term application of L-NAME for subacute peritonitis. Additionally, no study has ever addressed the effects of L-NAME on the inflammatory response and amino acid metabolism in subjects administered parenteral nutrition. In our study, we used a rat model with subacute peritonitis induced by cecal puncture and administered total parenteral nutrition solution to provide adequate nutrition, and we investigated the dose effects of parenterally supplemented L-NAME on the anabolism, inflammatory response, and arginine-derived metabolites such as the intermediates of the urea cycle, circulating profile of amino acids, NO, and cytokines. MATERIALS AND METHODS Animals and Experimental DesignMale Wistar rats (8-9 weeks old), initially weighi...

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“…[12][13][14] Evidence suggests that the therapeutic effects of NOS inhibitors may depend on the dose, timing, and the severity and category of diseases.…”

mentioning

confidence: 99%

Dose Effects of Chronically Infused Nitric Oxide Synthase Inhibitor NG-Nitro-L-arginine Methyl Ester on Anabolic Response and Arginine Metabolism in Rats with Subacute Peritonitis

Hsiao

Lee

Tsao

et al. 2011

Biological & Pharmaceutical Bulletin

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“…Subsequently we applied the model to simulate six other protocols (i.e., model testing) from a total of three published reports (4,5,30) and found that the timing and magnitude of the model's responses generally matched the experimental results. That a model developed to simulate one protocol could also reasonably simulate other, distinct protocols supports that the model successfully captured true physiological behavior.…”

Section: Resultsmentioning

confidence: 99%

“…Fourth, to assess the model's hemodynamic behavior during and after a bleed from a euvolemic versus dehydrated baseline, we implemented the bleed protocol of Brown et al (5), who studied seven splenectomized Hampshire swine dehydrated via 48 h of water deprivation and an additional five euvolemic control swine, all subjected to blood loss of 25 ml/kg over four 15-min intervals (anesthesia not specified). CO was measured by thermodilution.…”

Section: Methodsmentioning

confidence: 99%

“…CO was measured by thermodilution. [Note that we excluded the third experimental group from Brown et al (5), which received a pharmacological intervention that was outside the scope of this modeling investigation.] Fifth, to test whether or not accurate simulation required the inclusion of lymphatic flow, we disabled the lymphatic return circuit, increased the rates of transcapillary fluid shifts.…”

Section: Methodsmentioning

confidence: 99%

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A computational model of hemorrhage and dehydration suggests a pathophysiological mechanism: Starling-mediated protein trapping

Reisner

Heldt

2013

American Journal of Physiology-Heart and Circulatory Physiology

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We sought to understand the degree to which a single computational cardiovascular model could replicate the typical responses of healthy subjects through a breadth of blood loss patterns and whether such a model could illuminate the cause-effect relationships that underlie the observed responses. The model consisted of compartments for the upper body, lower body, viscera, and kidneys as well as a four-chambered heart and a pulmonary compartment. Transcapillary fluid flux was governed by Starling forces, whereas lymphatic flow was driven by hydrostatic tissue pressure and scaled by a lymphatic activation term. We adjusted parameters based on results from one protocol involving moderate continual blood loss in a canine model. Next, we simulated six additional protocols spanning euvolemic and dehydrated subjects and compared in silico behavior with in vivo hemodynamic responses and fluid shifts. The model was able to replicate group-averaged behavior (i.e., within 1 or 2 SEs) of the rate and quantity of vascular refill and the associated cardiac output during slow, moderate, and rapid ongoing blood losses, the restitution after the cessation of blood loss, and the absence of restitution in dehydrated subjects. The model suggested that the earlier phase of restitution, i.e., transcapillary fluid shifts, was antagonistic to the later phase of restitution, i.e., protein return via lymphatics. This phenomenon was termed "interstitial protein trapping." In conclusion, the model appears valid for a range of blood loss patterns and prehydration states. Further investigation into the in vivo relevance of interstitial protein trapping is justified.

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“…The results were not related to pressor effects of NO, and they speculated that the benefit arose from improved microvascular blood flow [19]. Similarly, Brown et al [18] could not demonstrate any hemodynamic benefit of NO inhibition in a swine HEM model.…”

Section: Introductionmentioning

confidence: 95%

Small Intestinal Production of Nitric Oxide Is Decreased Following Resuscitated Hemorrhage

Fruchterman

Spain

Matheson

et al. 1998

Journal of Surgical Research

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Nitric Oxide Synthesis Inhibition Does Not Improve the Hemodynamic Response to Hemorrhagic Shock in Dehydrated Conscious Swine

Cited by 19 publications

References 0 publications

Dose Effects of Chronically Infused Nitric Oxide Synthase Inhibitor NG-Nitro-L-arginine Methyl Ester on Anabolic Response and Arginine Metabolism in Rats with Subacute Peritonitis

Dose Effects of Chronically Infused Nitric Oxide Synthase Inhibitor NG-Nitro-L-arginine Methyl Ester on Anabolic Response and Arginine Metabolism in Rats with Subacute Peritonitis

A computational model of hemorrhage and dehydration suggests a pathophysiological mechanism: Starling-mediated protein trapping

Small Intestinal Production of Nitric Oxide Is Decreased Following Resuscitated Hemorrhage

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