Therapeutic Potential of NOS Inhibitors in Septic Shock

Vallance, Patrick; Rees, Daryl D.; Moncada, Salvador

doi:10.1007/978-3-642-57077-3_17

Cited by 8 publications

(8 citation statements)

References 35 publications

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“…This is even less than cortisol levels of 3 Á/4 mM observed in septic shock patients during ld HC therapy [45]. In a randomized controlled study, plasma levels of nitrite/ nitrate were 70 Á/80 mM before ld HC application, and 30 Á/40 mg/dl after ld HC application [45], which is in agreement with reported levels in non-septic controls in the order of 30 Á/40 mM, and 60 Á/100 mM in patients with severe septic shock [46], indicating inhibition of iNOS and preservation of eNOS activity by ld HC.…”

Section: Hemodynamic Effects Of Corticosteroidssupporting

confidence: 84%

Current state of corticosteroid therapy in patients with septic shock

Keh

Feldheiser

Ahlers

2005

Clinical Intensive Care

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The human organism reacts to stressors such as sepsis with immune-neuro-endocrine responses to maintain basal and stress-related homeostasis. In this system, the adrenal gland plays the key role by the release of cortisol. Cortisol is recognized to be crucial for both ensuring resistance to infection and protecting the host from overshooting inflammation. Therefore, glucocorticoids have been used to treat infections for decades, with disappointing and encouraging results. Whereas high doses of glucocorticoids failed to improve outcome in patients with severe sepsis or septic shock, prolonged treatment with low doses of hydrocortisone has been effective to resolve shock and to improve survival, especially in patients with septic shock and relative adrenal insufficiency (RAI). However, it is unclear yet how to define RAI in septic shock, whether all patients with septic shock or only patients with high risk of mortality, or only patients with RAI, or even patients without shock should receive low dose hydrocortisone. This review focuses on the role of the HPA axis in the stress response and summarizes recent data on low dose corticosteroid therapy.

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Section: Hemodynamic Effects Of Corticosteroidssupporting

confidence: 84%

Current state of corticosteroid therapy in patients with septic shock

Keh

Feldheiser

Ahlers

2005

Clinical Intensive Care

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“…Inexperimental sepsis models and a recent phase III study with l-arginine analogue N G -monomethyl-l-arginine strongly indideed, plasma NOx correlated significantly only with norepinephrine requirement, an effect that was even more pronounced cate that excessive and nonspecific blocking of nitric oxide synthases (NOSs) is fatal, stressing the importance of cytoprotective during hydrocortisone treatment, indicating that inhibition of nitric oxide formation increased vascular tone. Furthermore, and regulative properties of maintained basal nitric oxide production (35)(36)(37). Therefore, selective inhibition of inducible NOS hydrocortisone treatment seemed to maintain basal nitric oxide synthesis, as NOx concentrations were reduced from 70-80 to might be more effective and targets the "pathologic" nitric oxide while leaving the "physiologic" nitric oxide unaffected (35).…”

Section: Granulocyte Dysfunctionmentioning

confidence: 99%

“…Furthermore, and regulative properties of maintained basal nitric oxide production (35)(36)(37). Therefore, selective inhibition of inducible NOS hydrocortisone treatment seemed to maintain basal nitric oxide synthesis, as NOx concentrations were reduced from 70-80 to might be more effective and targets the "pathologic" nitric oxide while leaving the "physiologic" nitric oxide unaffected (35). In 30-40 M, which is in agreement with reported levels in nonseptic control subjects in the order of 30-40 and 60-100 M in pacontrast to nonspecific competitive inhibitors of nitric oxide synthesis (l-arginine analogues, isothioureas), glucocorticoids intients with severe septic shock (35).…”

Section: Granulocyte Dysfunctionmentioning

confidence: 99%

Immunologic and Hemodynamic Effects of “Low-Dose” Hydrocortisone in Septic Shock

Keh

Boehnke

Weber-Cartens

et al. 2003

Am J Respir Crit Care Med

521

140

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Within the last few years, increasing evidence of relative adrenal insufficiency in septic shock evoked a reassessment of hydrocortisone therapy. To evaluate the effects of hydrocortisone on the balance between proinflammatory and antiinflammation, 40 patients with septic shock were randomized in a double-blind crossover study to receive either the first 100 mg of hydrocortisone as a loading dose and 10 mg per hour until Day 3 (n = 20) or placebo (n = 20), followed by the opposite medication until Day 6. Hydrocortisone infusion induced an increase of mean arterial pressure, systemic vascular resistance, and a decline of heart rate, cardiac index, and norepinephrine requirement. A reduction of plasma nitrite/nitrate indicated inhibition of nitric oxide formation and correlated with a reduction of vasopressor support. The inflammatory response (interleukin-6 and interleukin-8), endothelial (soluble E-selectin) and neutrophil activation (expression of CD11b, CD64), and antiinflammatory response (soluble tumor necrosis factor receptors I and II and interleukin-10) were attenuated. In peripheral blood monocytes, human leukocyte antigen-DR expression was only slightly depressed, whereas in vitro phagocytosis and the monocyte-activating cytokine interleukin-12 increased. Hydrocortisone withdrawal induced hemodynamic and immunologic rebound effects. In conclusion, hydrocortisone therapy restored hemodynamic stability and differentially modulated the immunologic response to stress in a way of antiinflammation rather than immunosuppression.

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“…After induction by inflammatory and immunologic stimuli, including a diversity of infectious agents, the Ev and EE, like most cell types such as macrophages, cardiac myocytes, vascular smooth muscle cells, glial cells (to name only a few), express also another NOS isoform, the 'inducible' NOS (iNOS), whose hallmark is the high-output path of NO production. The increased generation of NO has the potential to cause tissue and organ damage through a variety of mechanisms (see review by Vallance et al 2000). In salmonids, the presence of the L-arginine/ NO pathway and iNOS activity have been demonstrated by biochemical, immunohistochemical and immunoblotting evidence (Barroso et al 2000), while the iNOS transcript expression has been detected in the gills after injection challenge with the Gram-positive pathogen Renibacterium salmoninarum (CamposPerez et al 2000).…”

Section: Resale or Republication Not Permitted Without Written Consenmentioning

confidence: 99%

“…This appears similar to therapeutic strategies adopted in animal models and in humans with septic shock. In such models the induction of iNOS, following endothelial damage (Binko et al 1999), in vivo endotoxin injection (Kelly et al 1996), or activation of pro-inflammatory cytokines (Finkel et al 1992) with consequent generation of large amounts of NO, is responsible for a reversible defect in myocardial function (Vallance et al 2000).…”

Section: Nitric Oxide and The Frank-starling Responsementioning

confidence: 99%

Cardiac performance in Salmo salar with infectious salmon anaemia (ISA): putative role of nitric oxide

Gattuso¹,

Mazza²,

Imbrogno³

et al. 2002

Dis. Aquat. Org.

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Infectious salmon anaemia (ISA) is a viral disease which targets the vascular and endocardial endothelial cells. An in vitro preparation of the spontaneously beating working heart of Salmo salar L. (i.e. able to generate physiological values of output pressure, cardiac output, ventricle work and power) was used to study cardiac performance under basal (i.e. in the absence of stimuli) and loading (i.e. Frank-Starling response) conditions in both control and ISAV-affected fish. In contrast to control fish, the heart preparations of the infected counterparts showed an impairment of the FrankStarling response, particularly evident in fish infected with a higher virus dose. The Frank-Starling response was progressively impaired with the progression of the viral disease from the time of the virus administration until the 20th day. The potential involvement of nitric oxide (NO) in cardiac dysfunction was investigated by using the authentic nitric oxide synthase (NOS) substrate L-arginine and the NOS inhibitors L-NMMA and L-NIL. In contrast to control fish, infected hearts were particularly sensitive to the inducible nitric oxide synthase (iNOS) inhibitor L-NIL and insensitive to L-arginine. While pretreatment with NOS inhibitors reduced the Frank-Starling response in control hearts, it restored this response in infected counterparts. Taken together, the results indicate that cardiac dysfunction and the NO-transduction-pathway can be mechanistically linked in infected salmon.KEY WORDS: ISA virus · Salmon · Heart · Nitric oxide · Myocardial dysfunction Resale or republication not permitted without written consent of the publisherDis Aquat Org 52: [11][12][13][14][15][16][17][18][19][20] 2002 from polymorphonuclear leukocytes shows that these cells may also be target cells . In these cell types, which are metabolically active and capable of phagocytosis, the ISA virus is able to replicate. Indeed, from these cells the virus particles can frequently be observed budding in the lumen of the heart and the blood vessels (Nylund et al. , 1996.The autocrine-paracrine function of the Ev and EE, which involves the synthesis and release of nitric oxide (NO), in addition to endothelin, prostacyclin and other autacoids, is well recognised. In particular, Ev and EE, in addition to cardiomyocytes, blood platelets, and other cell types, represent the predominant source of one of the 3 NOS isoforms, the 'endothelial' NOS (eNOS), so named as it is isolated, purified and cloned from the vascular endothelium (see e.g. Andries et al. 1998, Busse & Fleming 2000. The expression and the activity of this isoform, with the consequent production of NO, plays a major role in controlling various functions of the peripheral vasculature (Busse & Fleming 2000) and the heart (Balligand 2000). After induction by inflammatory and immunologic stimuli, including a diversity of infectious agents, the Ev and EE, like most cell types such as macrophages, cardiac myocytes, vascular smooth muscle cells, glial cells (to name only a few), express al...

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Therapeutic Potential of NOS Inhibitors in Septic Shock

Cited by 8 publications

References 35 publications

Current state of corticosteroid therapy in patients with septic shock

Current state of corticosteroid therapy in patients with septic shock

Immunologic and Hemodynamic Effects of “Low-Dose” Hydrocortisone in Septic Shock

Cardiac performance in Salmo salar with infectious salmon anaemia (ISA): putative role of nitric oxide

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