Alterations in nitric oxide production in various forms of circulatory shock

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Abstract

The free radical nitric oxide (NO·) is synthesized from the guanidino group of L-arginine by a family of enzymes termed NO· synthase (NOS). In the earlier phases of shock, activation of the endothelial, constitutive NOS (ecNOS) occurs, which, in the case of endotoxic shock, is triggered by endotoxin-induced, acute release of platelet-activating factor (PAF) and also other potential mediators. This early overproduction of NO· results in reduced contractile responsiveness to norepinephrine and contributes to the acute decrease in blood pressure afforded by endotoxin. In the delayed phase of endotoxic shock, a distinct isoform of NOS (iNOS) is induced in various organs and in the vessel wall. The induction of iNOS is mediated by the release of endogenous tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and PAF by endotoxin. These mediators, in turn, act in parallel, or in synergy to induce iNOS. Induction of iNOS contributes to delayed vascular hyporeactivity in vivo and ex vivo, and to the delayed decrease in blood pressure in rats with endotoxic shock. As endotoxic shock, hemorrhagic shock also leads to an early activation of ecNOS, which is responsible for the early vascular hyporeactivity, and a delayed induction of iNOS that contributes to delayed circulatory failure (vascular decompensation and hyporeactivity). The induction of iNOS in hemorrhagic shock is unlikely to be mediated by endogenous release of endotoxin, e.g., due to intestinal ischemia. Endogenous circulating glucocorticoids exert a tonic suppression of the induction of iNOS, as well as the cardiovascular failure in response to endotoxin. Endotoxin tolerance is associated with increased plasma levels of glucocorticoids, which may account for the blunted cardiovascular response and reduced induction of iNOS in these animals. A wide variety of drugs that exert protective effects in various models of circulatory shock also inhibit the induction of iNOS, and this effect is likely to contribute to their protective actions. These drugs include glucocorticoids, TNF-α antibodies, IL-1 receptor blockers/antibodies, PAF antagonists, dihydropyridine calcium-channel antagonists, tyrosine kinase inhibitors, and the experimental drug cloricromene. Various forms of shock can also lead to an inhibition of NO· production by the calcium-dependent ecNOS. Inhibition of ecNOS may then lead to maldistribution of blood flow, which results in coronary, renal, and cerebral ischemia. Additionally, inhibition of ecNOS may enhance the adhesion of neutrophils and platelets to endothelial surfaces. Reduced production of NO· has been demonstrated in various models of traumatic shock, whereas there is experimental evidence for an overproduction of NO· in anaphylactic shock. Modulation of local NO· levels by selective application of NO· to certain vascular beds, selective inhibition of the iNOS, or a combination of these approaches, may improve the outcome of circulatory shock of various etiologies.

Original languageEnglish (US)
Pages (from-to)2-32
Number of pages31
JournalNew Horizons: Science and Practice of Acute Medicine
Volume3
Issue number1
StatePublished - 1995
Externally publishedYes

Fingerprint

Shock
Nitric Oxide
Protein Isoforms
Endotoxins
Septic Shock
Blood Vessels
Platelet Activating Factor
Nitric Oxide Synthase
Glucocorticoids
Hemorrhagic Shock
Tumor Necrosis Factor-alpha
Traumatic Shock
Blood Pressure
Protective Agents
Interleukin-1 Receptors
Antibodies
Calcium Channel Blockers
Anaphylaxis
Brain Ischemia
Interleukin-1

Keywords

  • blood flow
  • cytokines
  • endotoxic shock
  • glucocorticoids
  • hemorrhagic shock
  • inducible nitric oxide synthase
  • inflammation
  • nitric oxide synthase
  • sepsis
  • shock
  • steroids
  • vascular reactivity

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

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title = "Alterations in nitric oxide production in various forms of circulatory shock",
abstract = "The free radical nitric oxide (NO·) is synthesized from the guanidino group of L-arginine by a family of enzymes termed NO· synthase (NOS). In the earlier phases of shock, activation of the endothelial, constitutive NOS (ecNOS) occurs, which, in the case of endotoxic shock, is triggered by endotoxin-induced, acute release of platelet-activating factor (PAF) and also other potential mediators. This early overproduction of NO· results in reduced contractile responsiveness to norepinephrine and contributes to the acute decrease in blood pressure afforded by endotoxin. In the delayed phase of endotoxic shock, a distinct isoform of NOS (iNOS) is induced in various organs and in the vessel wall. The induction of iNOS is mediated by the release of endogenous tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and PAF by endotoxin. These mediators, in turn, act in parallel, or in synergy to induce iNOS. Induction of iNOS contributes to delayed vascular hyporeactivity in vivo and ex vivo, and to the delayed decrease in blood pressure in rats with endotoxic shock. As endotoxic shock, hemorrhagic shock also leads to an early activation of ecNOS, which is responsible for the early vascular hyporeactivity, and a delayed induction of iNOS that contributes to delayed circulatory failure (vascular decompensation and hyporeactivity). The induction of iNOS in hemorrhagic shock is unlikely to be mediated by endogenous release of endotoxin, e.g., due to intestinal ischemia. Endogenous circulating glucocorticoids exert a tonic suppression of the induction of iNOS, as well as the cardiovascular failure in response to endotoxin. Endotoxin tolerance is associated with increased plasma levels of glucocorticoids, which may account for the blunted cardiovascular response and reduced induction of iNOS in these animals. A wide variety of drugs that exert protective effects in various models of circulatory shock also inhibit the induction of iNOS, and this effect is likely to contribute to their protective actions. These drugs include glucocorticoids, TNF-α antibodies, IL-1 receptor blockers/antibodies, PAF antagonists, dihydropyridine calcium-channel antagonists, tyrosine kinase inhibitors, and the experimental drug cloricromene. Various forms of shock can also lead to an inhibition of NO· production by the calcium-dependent ecNOS. Inhibition of ecNOS may then lead to maldistribution of blood flow, which results in coronary, renal, and cerebral ischemia. Additionally, inhibition of ecNOS may enhance the adhesion of neutrophils and platelets to endothelial surfaces. Reduced production of NO· has been demonstrated in various models of traumatic shock, whereas there is experimental evidence for an overproduction of NO· in anaphylactic shock. Modulation of local NO· levels by selective application of NO· to certain vascular beds, selective inhibition of the iNOS, or a combination of these approaches, may improve the outcome of circulatory shock of various etiologies.",
keywords = "blood flow, cytokines, endotoxic shock, glucocorticoids, hemorrhagic shock, inducible nitric oxide synthase, inflammation, nitric oxide synthase, sepsis, shock, steroids, vascular reactivity",
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T1 - Alterations in nitric oxide production in various forms of circulatory shock

AU - Szabo, Csaba

PY - 1995

Y1 - 1995

N2 - The free radical nitric oxide (NO·) is synthesized from the guanidino group of L-arginine by a family of enzymes termed NO· synthase (NOS). In the earlier phases of shock, activation of the endothelial, constitutive NOS (ecNOS) occurs, which, in the case of endotoxic shock, is triggered by endotoxin-induced, acute release of platelet-activating factor (PAF) and also other potential mediators. This early overproduction of NO· results in reduced contractile responsiveness to norepinephrine and contributes to the acute decrease in blood pressure afforded by endotoxin. In the delayed phase of endotoxic shock, a distinct isoform of NOS (iNOS) is induced in various organs and in the vessel wall. The induction of iNOS is mediated by the release of endogenous tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and PAF by endotoxin. These mediators, in turn, act in parallel, or in synergy to induce iNOS. Induction of iNOS contributes to delayed vascular hyporeactivity in vivo and ex vivo, and to the delayed decrease in blood pressure in rats with endotoxic shock. As endotoxic shock, hemorrhagic shock also leads to an early activation of ecNOS, which is responsible for the early vascular hyporeactivity, and a delayed induction of iNOS that contributes to delayed circulatory failure (vascular decompensation and hyporeactivity). The induction of iNOS in hemorrhagic shock is unlikely to be mediated by endogenous release of endotoxin, e.g., due to intestinal ischemia. Endogenous circulating glucocorticoids exert a tonic suppression of the induction of iNOS, as well as the cardiovascular failure in response to endotoxin. Endotoxin tolerance is associated with increased plasma levels of glucocorticoids, which may account for the blunted cardiovascular response and reduced induction of iNOS in these animals. A wide variety of drugs that exert protective effects in various models of circulatory shock also inhibit the induction of iNOS, and this effect is likely to contribute to their protective actions. These drugs include glucocorticoids, TNF-α antibodies, IL-1 receptor blockers/antibodies, PAF antagonists, dihydropyridine calcium-channel antagonists, tyrosine kinase inhibitors, and the experimental drug cloricromene. Various forms of shock can also lead to an inhibition of NO· production by the calcium-dependent ecNOS. Inhibition of ecNOS may then lead to maldistribution of blood flow, which results in coronary, renal, and cerebral ischemia. Additionally, inhibition of ecNOS may enhance the adhesion of neutrophils and platelets to endothelial surfaces. Reduced production of NO· has been demonstrated in various models of traumatic shock, whereas there is experimental evidence for an overproduction of NO· in anaphylactic shock. Modulation of local NO· levels by selective application of NO· to certain vascular beds, selective inhibition of the iNOS, or a combination of these approaches, may improve the outcome of circulatory shock of various etiologies.

AB - The free radical nitric oxide (NO·) is synthesized from the guanidino group of L-arginine by a family of enzymes termed NO· synthase (NOS). In the earlier phases of shock, activation of the endothelial, constitutive NOS (ecNOS) occurs, which, in the case of endotoxic shock, is triggered by endotoxin-induced, acute release of platelet-activating factor (PAF) and also other potential mediators. This early overproduction of NO· results in reduced contractile responsiveness to norepinephrine and contributes to the acute decrease in blood pressure afforded by endotoxin. In the delayed phase of endotoxic shock, a distinct isoform of NOS (iNOS) is induced in various organs and in the vessel wall. The induction of iNOS is mediated by the release of endogenous tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and PAF by endotoxin. These mediators, in turn, act in parallel, or in synergy to induce iNOS. Induction of iNOS contributes to delayed vascular hyporeactivity in vivo and ex vivo, and to the delayed decrease in blood pressure in rats with endotoxic shock. As endotoxic shock, hemorrhagic shock also leads to an early activation of ecNOS, which is responsible for the early vascular hyporeactivity, and a delayed induction of iNOS that contributes to delayed circulatory failure (vascular decompensation and hyporeactivity). The induction of iNOS in hemorrhagic shock is unlikely to be mediated by endogenous release of endotoxin, e.g., due to intestinal ischemia. Endogenous circulating glucocorticoids exert a tonic suppression of the induction of iNOS, as well as the cardiovascular failure in response to endotoxin. Endotoxin tolerance is associated with increased plasma levels of glucocorticoids, which may account for the blunted cardiovascular response and reduced induction of iNOS in these animals. A wide variety of drugs that exert protective effects in various models of circulatory shock also inhibit the induction of iNOS, and this effect is likely to contribute to their protective actions. These drugs include glucocorticoids, TNF-α antibodies, IL-1 receptor blockers/antibodies, PAF antagonists, dihydropyridine calcium-channel antagonists, tyrosine kinase inhibitors, and the experimental drug cloricromene. Various forms of shock can also lead to an inhibition of NO· production by the calcium-dependent ecNOS. Inhibition of ecNOS may then lead to maldistribution of blood flow, which results in coronary, renal, and cerebral ischemia. Additionally, inhibition of ecNOS may enhance the adhesion of neutrophils and platelets to endothelial surfaces. Reduced production of NO· has been demonstrated in various models of traumatic shock, whereas there is experimental evidence for an overproduction of NO· in anaphylactic shock. Modulation of local NO· levels by selective application of NO· to certain vascular beds, selective inhibition of the iNOS, or a combination of these approaches, may improve the outcome of circulatory shock of various etiologies.

KW - blood flow

KW - cytokines

KW - endotoxic shock

KW - glucocorticoids

KW - hemorrhagic shock

KW - inducible nitric oxide synthase

KW - inflammation

KW - nitric oxide synthase

KW - sepsis

KW - shock

KW - steroids

KW - vascular reactivity

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