The influence of phosphodiesterase inhibitor, rolipram, on hemodynamics in lipopolysaccharide-treated rats.
Administration of bacterial endotoxin (lipopolysaccharide, LPS) intravenously has been noted to produce a shock state, which is characterized by hypotension and multi-organ system failure. The aim of the present investigation was to (a) examine the influence of rolipram on hemodynamics, plasma levels of tumor necrosis factor-alpha (TNF-alpha) levels, and production of inducible nitric oxide synthase (iNOS) in the lungs, ex vivo, in LPS-treated rats, and (b) determine the cardiovascular effects of a selective alpha1-adrenoceptor agonist, methoxamine, in the absence or presence of rolipram in rats treated with LPS. Blood pressure, cardiac index, heart rate and arterial resistance were assessed in Long-Evans rats anesthetized with thiobutabarbital. Administration of LPS to animals resulted in a significant reduction in cardiac index over time. The administration of LPS to rats resulted in a substantial rise in the plasma levels of TNF-alpha. Furthermore, the injection of LPS resulted in a significant increase in the iNOS activity in the lungs. Pre-treatment with rolipram prevented the decline in cardiac index in animals that received LPS. Infusion of methoxamine into animals injected with rolipram and pre-treated with LPS did not result in significant changes in cardiac index. Pre-treatment with rolipram or dexamethasone in animals injected with LPS significantly prevented the rise in TNF-alpha when compared to the respective values in vehicle-treated animals. Our present observations support the view that the cardiac index can be maintained in animals treated with LPS independent of iNOS inhibition.
Dutta
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Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
Ryan
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Tabrizchi
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D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000201:enzymology; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D020889:Rolipram / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D018340:Receptors, Adrenergic, alpha-1; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D008729:Methoxamine; D020889:Rolipram