Molsidomine Increases Endotoxic Survival and Decreases Cytokine Production

Kumins, Norman H.; Hunt, J.; Gamelli, Richard L.; Filkins, James P.

doi:10.1097/00024382-199703000-00008

Cited by 23 publications

(9 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…High levels of NO have been functionally linked to LPS tolerance in various animal species (141,203,227,334,377,411). At least in mice, the phenomenon may have functional redundancy, since mice genetically deficient in iNOS (iNOS knockout [KO] mice) can be made LPS tolerant (447).…”

Section: Homeostatic Functionsmentioning

confidence: 99%

Pathogenesis of Malaria and Clinically Similar Conditions

et al. 2004

View full text Add to dashboard Cite

There is now wide acceptance of the concept that the similarity between many acute infectious diseases, be they viral, bacterial, or parasitic in origin, is caused by the overproduction of inflammatory cytokines initiated when the organism interacts with the innate immune system. This is also true of certain noninfectious states, such as the tissue injury syndromes. This review discusses the historical origins of these ideas, which began with tumor necrosis factor (TNF) and spread from their origins in malaria research to other fields. As well the more established proinflammatory mediators, such as TNF, interleukin-1, and lymphotoxin, the roles of nitric oxide and carbon monoxide, which are chiefly inhibitory, are discussed. The established and potential roles of two more recently recognized contributors, overactivity of the enzyme poly(ADP-ribose) polymerase 1 (PARP-1) and the escape of high-mobility-group box 1 (HMGB1) protein from its normal location into the circulation, are also put in context. The pathogenesis of the disease caused by falciparum malaria is then considered in the light of what has been learned about the roles of these mediators in these other diseases, as well as in malaria itself

show abstract

Section: Homeostatic Functionsmentioning

confidence: 99%

Pathogenesis of Malaria and Clinically Similar Conditions

et al. 2004

View full text Add to dashboard Cite

show abstract

“…One key component in the triggering of the inflammatory response is the activation of nuclear factor κB (NF-κB), a transcription factor that integrates the signaling elicited by various cell stresses and is required for the expression of most genes involved in host defense, among them the NOS-2 gene (4,(17)(18)(19). Indeed, the important role played by NF-κB activation in liver inflammation has been confirmed in animals carrying a degradation-resistant IκBα transgene under the control of a liver-specific promoter (20) and in cultured hepatocytes transduced with adenovirus carrying an IκBα gene that impairs NOS-2 expression (21).In liver cells, expression of NOS-2 leads to the synthesis of large amounts of NO, and genetic and pharmacological data suggest that this molecule exerts a dual role in the course of inflammation: exogenous addition of NO impairs the release of inflammatory mediators (22)(23)(24)(25) and protects against apoptotic death by inhibiting various caspases via nitrosylation of key cysteine residues (26-28). Synthesis of NO after expression of NOS-2 is responsible for an important part of the damage occurring during sepsis (29-31).…”

mentioning

confidence: 99%

“…In liver cells, expression of NOS-2 leads to the synthesis of large amounts of NO, and genetic and pharmacological data suggest that this molecule exerts a dual role in the course of inflammation: exogenous addition of NO impairs the release of inflammatory mediators (22)(23)(24)(25) and protects against apoptotic death by inhibiting various caspases via nitrosylation of key cysteine residues (26)(27)(28). Synthesis of NO after expression of NOS-2 is responsible for an important part of the damage occurring during sepsis (29)(30)(31).…”

mentioning

confidence: 99%

Protection by nitric oxide against liver inflammatory injury in animals carrying a nitric oxide synthase‐2 transgene

Mojena¹,

Hortelano

Castrillo

et al. 2001

FASEB j.

View full text Add to dashboard Cite

The effect of pre-existent hepatic NO synthesis on liver injury induced by lipopolysaccharide was studied in animals carrying a nitric oxide synthase-2 (NOS-2) transgene under the control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter. These animals expressed NOS-2 in liver cells under fasting conditions. Lipopolysaccharide-induced liver injury in D-galactosamine-conditioned mice, which enhanced notably the effect of the endotoxin on the liver, was impaired in animals expressing NOS-2. This protection against inflammatory liver damage was dependent on NO synthesis and was caused by an inhibition of nuclear factor kB (NF-kB) activity and an impairment of the synthesis of the proinflammatory cytokines tumor necrosis factor a and interleukin 1b. These data indicate that intrahepatic synthesis of NO protects liver by inhibiting the release of cascades of proinflammatory mediators and suggest a beneficial role for local delivery of NO in the control of liver injury.

show abstract

“…SIN-1 spontaneously decomposes into NO and the stable metabolite N-3-morpholinoiminoacetonitrile (SIN-1C). Although SIN-1 at high doses may simultaneously generate NO and superoxide anion (17), it is an effective agent in the treatment of coronary artery disease and has effects at least as powerful as nitroglycerin. Also, Pastor et al (25) recently demonstrated that SIN-1 administration in the early phase of endotoxic shock in rabbits can preserve systemic and hepatic perfusion while preventing lactic acidosis.…”

Section: Discussionmentioning

confidence: 99%

“…Another recent study, however, showed that NO can increase TNF-␣ production from human neutrophils independently of guanosine 3Ј,5Ј-cyclic monophosphate stimulated by endotoxin in vitro (34). Kumins et al (17) more recently showed that the NO donor molsidomine, which acts only after it is converted by the liver to SIN-1, attenuated TNF-␣, interleukin-1, and interleukin-6 production in endotoxic mice. The higher TNF-␣ release in the L-NMMA group may contribute to the detrimental global and regional hemodynamics.…”

Section: Discussionmentioning

confidence: 99%

Effects of nitric oxide on blood flow distribution and O₂extraction capabilities during endotoxic shock

Zhang

Rogiers

Smaïl

et al. 1997

Journal of Applied Physiology

View full text Add to dashboard Cite

. Effects of nitric oxide on blood flow distribution and O 2 extraction capabilities during endotoxic shock. J. Appl. Physiol. 83(4): 1164-1173.-The effects of the nitric oxide (NO) synthase inhibitor N G -monomethyl-Larginine (L-NMMA) and the NO donor 3-morpholinosydnonimine (SIN-1) were tested in 18 endotoxic dogs. L-NMMA infusion (10 mg · kg Ϫ1 ·h Ϫ1 ) increased arterial and pulmonary artery pressures and systemic and pulmonary vascular resistances but decreased cardiac index, left ventricular stroke work index, and blood flow to the hepatic, portal, mesenteric, and renal beds. SIN-1 infusion (2 µg · kg Ϫ1 · min Ϫ1 ) increased cardiac index; left ventricular stroke work index; and hepatic, portal, and mesenteric blood flow. It did not significantly influence arterial and pulmonary artery pressures but decreased renal blood flow. The critical O 2 delivery was similar in the L-NMMA group and in the control group (13.3 Ϯ 1.6 vs. 12.8 Ϯ 3.3 ml · kg Ϫ1 · min Ϫ1 ) but lower in the SIN-1 group (9.1 Ϯ 1.8 ml · kg Ϫ1 · min Ϫ1 , both P Ͻ 0.05). The critical O 2 extraction ratio was also higher in the SIN-1 group than in the other groups (58.7 Ϯ 10.6 vs. 42.2 Ϯ 7.6% in controls, P Ͻ 0.05; 43.0 Ϯ 15.5% in L-NMMA group, P ϭ not significant). We conclude that NO is not implicated in the alterations in O 2 extraction capabilities observed early after endotoxin administration. cardiac output; hypotension; organ perfusion; oxygen delivery; sepsis; endothelium-derived relaxing factor; nitrite; tumor necrosis factor-␣ SEPTIC SHOCK, a major clinical problem with mortality rates of up to 70%, is characterized by systemic hypotension, vascular hyporeactivity and myocardial depression. Despite the increased cardiac output, cellular O 2 utilization may be inadequate because maldistribution of blood flow can profoundly alter O 2 availability. Regional blood flow to the various organs may also be altered nonuniformly. In particular, the hepatosplanchnic blood flow may decrease more than blood flow to other regions to favor blood supply to vital organs, such as the heart and the brain. Because hepatosplanchnic hypoxia may contribute to the development of multiple organ failure (11), the maintenance of sufficient hepatosplanchnic blood flow may be a fundamental goal in septic shock.Nitric oxide (NO) is a paracrine-acting gas enzymatically synthesized from L-arginine. In basal conditions, the release of NO via calcium-dependent constitutive NO synthase (cNOS) plays an essential role in the maintenance of capillary flow and O 2 availability to the tissues. The greater release of NO via a calciumindependent inducible form of NO synthase (iNOS) has been implicated in the pathophysiological alterations of severe sepsis and septic shock. The resulting overproduction of NO may induce deleterious effects, including arterial hypotension (6), vascular hyporeactivity, and myocardial depression (5). The induction of iNOS in various cells, including macrophages, endothelial cells, vascular smooth muscle cells, or even myocardial cells, requires seve...

show abstract

Molsidomine Increases Endotoxic Survival and Decreases Cytokine Production

Cited by 23 publications

References 0 publications

Pathogenesis of Malaria and Clinically Similar Conditions

Pathogenesis of Malaria and Clinically Similar Conditions

Protection by nitric oxide against liver inflammatory injury in animals carrying a nitric oxide synthase‐2 transgene

Effects of nitric oxide on blood flow distribution and O₂extraction capabilities during endotoxic shock

Contact Info

Product

Resources

About

Molsidomine Increases Endotoxic Survival and Decreases Cytokine Production

Cited by 23 publications

References 0 publications

Pathogenesis of Malaria and Clinically Similar Conditions

Pathogenesis of Malaria and Clinically Similar Conditions

Protection by nitric oxide against liver inflammatory injury in animals carrying a nitric oxide synthase‐2 transgene

Effects of nitric oxide on blood flow distribution and O2extraction capabilities during endotoxic shock

Contact Info

Product

Resources

About

Effects of nitric oxide on blood flow distribution and O₂extraction capabilities during endotoxic shock