Endothelin receptor antagonist attenuates inflammatory response and prolongs the survival time in a neonatal sepsis model

Goto, Tatenobu; Hussein, Mohamed Hamed; Kato, Shin; Daoud, Ghada A; Kato, Tatsuya; Kakita, Hiroki; Mizuno, Haruo; Imai, Masaki; Ito, Tetsuya; Kato, Ineko; Suzuki, Satoshi; Okada, Noriko; Togari, Hajime; Okada, Hidechika

doi:10.1007/s00134-010-2040-0

Cited by 19 publications

(21 citation statements)

References 36 publications

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“…In our sepsis model, we observed an elevation in nitric oxide metabolites levels in the CLP group (19). We have previously reported that ETR-P1/fl inhibits the elevation of nitric oxide metabolites, which may help to maintain mean arterial pressure in the ETR-P1/fl group as compared with that in the CLP group (16). A previous study has similarly indicated that ETR-P1/fl treatment suppresses NO synthesis (35).…”

Section: Discussionsupporting

confidence: 54%

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Endothelin receptor antagonist attenuates oxidative stress in a neonatal sepsis piglet model

et al. 2012

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Background: Oxidative stress (oxidant-antioxidant imbalance) plays an important role in the pathophysiology of neonatal sepsis. This study evaluated whether an antisense peptide endothelin receptor antagonist, eTR-P1/fl, could attenuate oxidative stress in a neonatal sepsis model. Methods: a total of 18 3-d-old piglets were anesthetized and mechanically ventilated. six piglets received cecal ligation and perforation (cLP group) for induction of sepsis. six piglets also received continuous infusion (0.05 mg/kg/h) of eTR-P1/fl 30 min after cLP (eTR-P1/fl group). six piglets received a sham operation. serum total hydroperoxide (Th), biological antioxidant potentials (BaPs), oxidative stress index (OsI, calculated as Th/BaP), interleukin (IL)-6, serum glutamic oxaloacetic transaminase (GOT), and creatinine were measured before cLP and at 1, 3, and 6 h after cLP. results: cLP evoked a state of shock resulting in elevated Th, OsI, and IL-6 levels. eTR-P1/fl administration after cLP resulted in lower serum Th at 1 and 3 h after cLP, OsI at 1 and 3 h after cLP, IL-6 at 1 and 3 h after cLP, and GOT at 3 and 6 h after cLP as compared with the cLP group. conclusion: eTR-P1/fl treatment significantly attenuated the elevation of serum oxidative stress markers (Th and OsI), IL-6, and GOT in a progressive neonatal sepsis cLP model.

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Section: Discussionsupporting

confidence: 54%

“…It also attenuates inflammatory responses during sepsis (15). We have previously suggested that ETR-P1/fl could have a suppressive effect on the release of inflammatory cytokines, including tumor necrosis factor-α and the highly mobile group-1 box protein, and could prolong survival time (16).…”

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confidence: 99%

Endothelin receptor antagonist attenuates oxidative stress in a neonatal sepsis piglet model

et al. 2012

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“…These animals develop rapid hemodynamic changes and microvascular dysfunction that are not the same as in adult rats (Seely et al, 2011;Sims et al, 2014). Neonatal, 3-day-old piglets subjected to CLP show deterioration of cardiac output, pulmonary hypertension, and shock (Goto et al, 2010), consistent with cold shock (low cardiac output with high systemic vascular resistance) frequently observed in newborns and infants with severe sepsis (Wheeler et al, 2011).…”

Section: Animal Modelsmentioning

confidence: 99%

Could Biomarkers Direct Therapy for the Septic Patient?

Sims

Nguyen

Mayeux

2016

Journal of Pharmacology and Experimental Therapeutics

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Sepsis is a serious medical condition caused by a severe systemic inflammatory response to a bacterial, fungal, or viral infection that most commonly affects neonates and the elderly. Advances in understanding the pathophysiology of sepsis have resulted in guidelines for care that have helped reduce the risk of dying from sepsis for both children and older adults. Still, over the past three decades, a large number of clinical trials have been undertaken to evaluate pharmacological agents for sepsis. Unfortunately, all of these trials have failed, with the use of some agents even shown to be harmful. One key issue in these trials was the heterogeneity of the patient population that participated. What has emerged is the need to target therapeutic interventions to the specific patient's underlying pathophysiological processes, rather than looking for a universal therapy that would be effective in a "typical" septic patient, who does not exist. This review supports the concept that identification of the right biomarkers that can direct therapy and provide timely feedback on its effectiveness will enable critical care physicians to decrease mortality of patients with sepsis and improve the quality of life of survivors.

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“…18 Of note, several of these cytokines (e.g., IL-1β, iNOS) have also been implicated in endotoxin-induced PA dysfunction, 6 and in this context, inhibition of ET-1 signaling has been demonstrated to improve outcomes in experimental sepsis. 19 ET-1 acts via two receptors that are highly expressed in the pulmonary vasculature: endothelin receptor A (ET A R) and endothelin receptor B (ET B R). Both ET A R and ET B R are expressed on PA smooth muscle cells (PASMCs), where they mediate PA vasoconstriction.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, two previous studies demonstrated beneficial effects of selective ET A R inhibitors during endotoxemia. 19,25 However, mechanistic studies investigating the effects of ET A R inhibition on pulmonary vascular tone and proinflammatory markers in the pulmonary vasculature have not yet been performed. We set out to investigate the effects of the selective ET A R antagonist sitaxsentan on hemodynamic and physiologic parameters in a rat model of endotoxemia.…”

Section: Introductionmentioning

confidence: 99%

Selective Endothelin‐A Receptor Blockade Attenuates Endotoxin‐Induced Pulmonary Hypertension and Pulmonary vascular dysfunction

et al. 2014

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Endothelin-1 is a potent mediator of sepsis-induced pulmonary hypertension (PH). The pulmonary vascular effects of selective blockade of endothelin receptor subtype A (ET A R) during endotoxemia remain unknown. We hypothesized that selective ET A R antagonism attenuates endotoxin-induced PH and improves pulmonary artery (PA) vasoreactivity. Adult male Sprague-Dawley rats (250-450 g) received lipopolysaccharide (LPS; Salmonella typhimurium; 20 mg/kg intraperitoneally) or vehicle 6 hours before hemodynamic assessment and tissue harvest. The selective ET A R antagonist sitaxsentan (10 or 20 mg/kg) or vehicle was injected intravenously 3 hours after receipt of LPS. Right ventricular systolic pressure, mean arterial pressure (MAP), cardiac output (CO), oxygenation (P/F ratio), and serum bicarbonate were measured. Bronchoalveolar lavage (BAL) cell differential and lung wet-to-dry ratios were obtained. Endothelium-dependent and endothelium-independent vasorelaxations were determined in isolated PA rings. PA interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) were measured. LPS caused PH, decreased MAP, CO, and serum bicarbonate, and increased PA IL-1β, IL-6, TNF-α, and iNOS mRNA. Sitaxsentan attenuated sepsis-induced PH and increased MAP. The P/F ratio, CO, serum bicarbonate, and BAL neutrophilia were not affected by sitaxsentan. In isolated PA rings, while not affecting phenylephrine-induced vasocontraction or endothelium-dependent relaxation, sitaxsentan dosedependently attenuated LPS-induced alterations in endothelium-independent relaxation. PA cytokine mRNA levels were not significantly attenuated by ET A R blockade. We conclude that ET A R blockade attenuates endotoxin-induced alterations in systemic and PA pressures without negatively affecting oxygenation. This protective effect appears to be mediated not by attenuation of sepsis-induced cardiac dysfunction, acidosis, or alveolar inflammation but rather by improved endothelium-independent vasorelaxation.

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Endothelin receptor antagonist attenuates inflammatory response and prolongs the survival time in a neonatal sepsis model

Abstract: ETR-P1/fl treatment significantly attenuated the elevation of NOx, TNF-α, and HMGB-1, which improved the systemic hypotension, pulmonary hypertension, and blood gases, thereby causing improvement of survival time in a progressive neonatal sepsis CLP model.

Cited by 19 publications

References 36 publications

Endothelin receptor antagonist attenuates oxidative stress in a neonatal sepsis piglet model

Endothelin receptor antagonist attenuates oxidative stress in a neonatal sepsis piglet model

Could Biomarkers Direct Therapy for the Septic Patient?

Selective Endothelin‐A Receptor Blockade Attenuates Endotoxin‐Induced Pulmonary Hypertension and Pulmonary vascular dysfunction

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