Delayed Treatment with Sodium Hydrosulfide Improves Regional Blood Flow and Alleviates Cecal Ligation and Puncture (CLP)-Induced Septic Shock

Dobutamine has been used in septic shock for many years as an only inotrope, but its benefit has been questioned. We weighed the effects of dobutamine and milrinone as inotropes in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. CLP-induced septic mice exhibited significant cardiac inflammation, as indicated by greatly increased mRNAs of proinflammatory cytokines and robust infiltration of inflammatory cells in the ventricular myocardium. Elevations of plasma cardiac troponin-I showed cardiac injury in CLP mice. Noninvasive echocardiographic assessment of cardiac function revealed that despite preserved left ventricular function in the presence of fluid replacement, the dobutamine inotropic response was significantly impaired in CLP mice compared with sham-operated controls. By contrast, milrinone exerted inotropic effects in sham-operated and CLP mice in an equally effective manner. Surface expression levels of β1-adrenoceptors and α-subunits of three main G protein families in the myocardium were unaffected by CLP-induced sepsis. Plasma cAMP levels were significantly elevated in both sham-operated and CLP mice in response to milrinone but only in sham-operated controls in response to dobutamine. Of phosphodiesterase (PDE) isoforms, PDE4D, but not PDE3A, both of which are responsible for cardiac cAMP hydrolysis, was significantly upregulated in CLP mouse myocardium. We define a novel mechanism for the impaired responsiveness to dobutamine as an inotrope in sepsis, and understanding the role of PDE4D in modulating cardiac functional responsiveness in sepsis may open the potential of a PDE4D-targeted therapeutic option in septic patients with low cardiac output who have a need for inotropic support. NEW & NOTEWORTHY Advisability of the usefulness of dobutamine in septic shock management is limited. Here, we reveal that the effect of dobutamine as a positive inotrope is impaired in mice with cecal ligation and puncture-induced sepsis without changes in cardiac β1-adrenoceptor signaling as a result of cAMP breakdown achieved by upregulated phosphodiesterase 4D.

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STAT1-DEFICIENT MICE ARE RESISTANT TO CECAL LIGATION AND PUNCTURE–INDUCED SEPTIC SHOCK

Shock ◽

10.1097/shk.0b013e318265a2ab ◽

2012 ◽

Vol 38 (4) ◽

pp. 395-402 ◽

Cited By ~ 24

Author(s):

Daniela Herzig ◽

Geping Fang ◽

Tracy E. Toliver-Kinsky ◽

Yin Guo ◽

Julia Bohannon ◽

...

Keyword(s):

Septic Shock ◽

Cecal Ligation ◽

Cecal Ligation And Puncture ◽

Deficient Mice

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CEFTAZIDIME IMPROVES PANCREATIC REGIONAL BLOOD FLOW IN OVINE SEPTIC SHOCK RESULTING FROM PSEUDOMONAS SEPSIS AND SMOKE INHALATION INJURY.

Critical Care Medicine ◽

10.1097/00003246-200512002-00194 ◽

2005 ◽

Vol 33 ◽

pp. A53

Author(s):

Dirk M Maybauer ◽

M O Maybauer ◽

J F Fraser ◽

M Westphal ◽

P Enkhbaatar ◽

...

Keyword(s):

Septic Shock ◽

Blood Flow ◽

Regional Blood Flow ◽

Inhalation Injury ◽

Smoke Inhalation ◽

Smoke Inhalation Injury

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Endothelial Dysfunction Is a Potential Contributor to Multiple Organ Failure and Mortality in Aged Mice Subjected to Septic Shock: Preclinical Studies in a Murine Model of Cecal Ligation and Puncture

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2014.10.464 ◽

2014 ◽

Vol 76 ◽

pp. S38-S39

Author(s):

Csaba Szabo ◽

Ciro Coletta ◽

Katalin Modis ◽

Gabor Olah ◽

Attila Brunyanszki ◽

...

Keyword(s):

Septic Shock ◽

Endothelial Dysfunction ◽

Multiple Organ Failure ◽

Organ Failure ◽

Murine Model ◽

Cecal Ligation ◽

Multiple Organ ◽

Preclinical Studies ◽

Cecal Ligation And Puncture ◽

Potential Contributor

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Time course of liver nitric oxide concentration in early septic shock by cecal ligation and puncture in rats

Nitric Oxide ◽

10.1016/j.niox.2010.06.002 ◽

2010 ◽

Vol 23 (3) ◽

pp. 194-198 ◽

Cited By ~ 5

Author(s):

P. Eyenga ◽

F. Lhuillier ◽

J. Morel ◽

D. Roussel ◽

B. Sibille ◽

...

Keyword(s):

Nitric Oxide ◽

Septic Shock ◽

Time Course ◽

Cecal Ligation ◽

Cecal Ligation And Puncture ◽

Oxide Concentration ◽

Nitric Oxide Concentration

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Gastrointestinal Perfusion in Septic Shock

Anaesthesia and Intensive Care ◽

10.1177/0310057x0703500505 ◽

2007 ◽

Vol 35 (5) ◽

pp. 679-694 ◽

Cited By ~ 34

Author(s):

F. M. P. van Haren ◽

J. W. Sleigh ◽

R Pickkers ◽

J. G. Van Der Hoeven

Keyword(s):

Septic Shock ◽

Blood Flow ◽

Near Infrared ◽

Clinical Decision Making ◽

Regional Blood Flow ◽

Treatment Strategies ◽

Ease Of Use ◽

Gastric Tonometry ◽

Doppler Flowmetry ◽

Gut Barrier Function

Septic shock is characterised by vasodilation, myocardial depression and impaired microcirculatory blood flow, resulting in redistribution of regional blood flow. Animal and human studies have shown that gastrointestinal mucosal blood flow is impaired in septic shock. This is consistent with abnormalities found in many other microcirculatory vascular beds. Gastrointestinal mucosal microcirculatory perfusion deficits have been associated with gut injury and a decrease in gut barrier function, possibly causing augmentation of systemic inflammation and distant organ dysfunction. A range of techniques have been developed and used to quantify these gastrointestinal perfusion abnormalities. The following techniques have been used to study gastrointestinal perfusion in humans: tonometry, laser Doppler flowmetry reflectance spectrophotometry, near-infrared spectroscopy, orthogonal polarisation spectral imaging, indocyanine green clearance, hepatic vein catheterisation and measurements of plasma D-lactate. Although these methods share the ability to predict outcome in septic shock patients, it is important to emphasise that the measurement results are not interchangeable. Different techniques measure different elements of gastrointestinal perfusion. Gastric tonometry is currently the most widely used technique because of its non-invasiveness and ease of use. Despite all the recent advances, the usefulness of gastrointestinal perfusion parameters in clinical decision-making is still limited. Treatment strategies specifically aimed at improving gastrointestinal perfusion have failed to actually correct mucosal perfusion abnormalities and hence not shown to improve important clinical endpoints. Current and future treatment strategies for septic shock should be tested for their effects on gastrointestinal perfusion; to further clarify its exact role in patient management, and to prevent therapies detrimental to gastrointestinal perfusion being implemented.

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Hydrogen sulfide ameliorates cardiovascular dysfunction induced by cecal ligation and puncture in rats

Human & Experimental Toxicology ◽

10.1177/0960327114564794 ◽

2015 ◽

Vol 34 (10) ◽

pp. 953-964 ◽

Cited By ~ 4

Author(s):

RS Abdelrahman ◽

MS El-Awady ◽

MA Nader ◽

EM Ammar

Keyword(s):

Hydrogen Sulfide ◽

Vascular Reactivity ◽

Troponin I ◽

Histopathological Examination ◽

Vascular Dysfunction ◽

Cecal Ligation ◽

Cecal Ligation And Puncture ◽

Cardiovascular Dysfunction ◽

Sodium Hydrosulfide ◽

Creatine Kinase Mb

Hydrogen sulfide (H2S) is an endogenously produced gaseous messenger that participates in regulation of cardiovascular functions. This study evaluates the possible protective effect of H2S in cardiovascular dysfunction induced by cecal ligation and puncture (CLP) in rats. After 24 h of induction of CLP, heart rate (HR), mortality, cardiac and inflammation biomarkers (creatine kinase-MB (CK-MB) isozyme, cardiac troponin I (cTnI), C-reactive protein (CRP), and lactate dehydrogenase (LDH)), in vitro vascular reactivity, histopathological examination, and oxidative biomarkers (malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD)) were determined. CLP induced elevations in HR, mortality, serum CK-MB, cTnI, CRP, and LDH, in addition to impaired aortic contraction to potassium chloride and phenylephrine and relaxation to acetylcholine without affecting sodium nitroprusside responses. Moreover, CLP increased cardiac and aortic MDA and decreased SOD, without affecting GSH and caused a marked subserosal and interstitial inflammation in endocardium. Sodium hydrosulfide, but not the irreversible inhibitor of H2S synthesis dl-propargyl glycine, protected against CLP-induced changes in HR, mortality, cardiac and inflammatory biomarkers, oxidative stress, and myocardium histopathological changes without affecting vascular dysfunction. Our results confirm that H2S can attenuate CLP-induced cardiac, but not vascular, dysfunction possibly through its anti-inflammatory and antioxidant effects.

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