Abstract
Septic shock is characterized by a decrease in systemic vascular resistance. Nevertheless, regional increases in vascular resistance can occur that may predispose mammals to organ dysfunction, including the acute respiratory distress syndrome. In the host infected by endotoxin (lipopolysaccharide, LPS), the expression and release of proinflammatory tumor necrosis factor-alpha (TNFalpha) rapidly increases, and this cytokine production is regulated by agents elevating cyclic AMP. In this report, we present evidence that terbutaline, a beta2-agonist, inhibits TNFalpha production and enhances interleukin-10 (IL-10) release in the anesthetized rat treated with LPS. In addition, an overproduction of nitric oxide (NO, examined by its metabolites nitrite/nitrate) by inducible NO synthase (iNOS, examined by western blot analysis) is attenuated by pretreatment of LPS rats with terbutaline. Overall, pretreatment of rats with terbutaline attenuates the delayed hypotension and prevents vascular hyporeactivity to norepinephrine. In addition, pretreatment of mice with terbutaline also improves the survival in a model of severe endotoxemia. The infiltration of polymorphonuclear neutrophils into organs (e.g., lung and liver) from the surviving LPS mice treated with terbutaline was reduced almost to that seen in the normal controls. These findings suggest that the inhibition of TNFalpha and NO (via iNOS) production as well as the increment of IL-10 production contribute to the beneficial effect of terbutaline in animals with endotoxic shock.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholine / pharmacology
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Adrenergic beta-Agonists / pharmacology
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Adrenergic beta-Agonists / therapeutic use*
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Animals
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Aorta, Thoracic / drug effects
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Aorta, Thoracic / physiopathology
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Blood Pressure / drug effects
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Drug Interactions
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Endotoxemia / blood
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Endotoxemia / drug therapy*
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Endotoxemia / physiopathology
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Enzyme Induction / drug effects
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Enzyme Inhibitors / pharmacology
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Hemodynamics / drug effects*
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Interleukin-10 / biosynthesis
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Interleukin-10 / blood
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Lipopolysaccharides / toxicity
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Liver / pathology
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Lung / enzymology
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Lung / pathology
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Male
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Mice
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Mice, Inbred ICR
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Muscle Contraction / drug effects
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / physiopathology
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NG-Nitroarginine Methyl Ester / pharmacology
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Neutrophil Infiltration / drug effects
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Nitrates / blood
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Nitric Oxide / biosynthesis
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / biosynthesis
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Nitric Oxide Synthase Type II
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Norepinephrine / pharmacology
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Rats
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Rats, Inbred WKY
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Shock, Septic / blood
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Shock, Septic / etiology
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Shock, Septic / pathology
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Shock, Septic / prevention & control*
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Terbutaline / pharmacology
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Terbutaline / therapeutic use*
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Tumor Necrosis Factor-alpha / analysis
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Tumor Necrosis Factor-alpha / biosynthesis
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Vascular Resistance / drug effects
Substances
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Adrenergic beta-Agonists
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Enzyme Inhibitors
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Lipopolysaccharides
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Nitrates
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Tumor Necrosis Factor-alpha
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Interleukin-10
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Nitric Oxide
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Nos2 protein, rat
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Terbutaline
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Acetylcholine
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NG-Nitroarginine Methyl Ester
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Norepinephrine