The influence of phosphodiesterase inhibitor, rolipram, on plasma tumor necrosis factor-a levels and haemodynamics in lipopolysaccharide-treated rats

Dutta, Prasannajit (2000) The influence of phosphodiesterase inhibitor, rolipram, on plasma tumor necrosis factor-a levels and haemodynamics in lipopolysaccharide-treated rats. Masters thesis, Memorial University of Newfoundland.

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Abstract

Septic shock is the thirteenth most common cause of death in the United States and the leading cause of death of individuals in intensive care units once it progresses to multiple organ dysfunction syndrome (MODS) (Parrillo et al., 1993). Mortility ranges from 20% to 95% (Eidleman et al., 1995; Parrillo et al., 1993; Wiessner et al., 1995). Septic shock is caused most often by gram-negative bacteria and it has increased dramatically in the past 10 years. Even when properly treated with available therapies, it carries a 60% mortality (Wiessner et al., 1995). -- The administration of iipopolysaccharide (LPS) has been reported to produce hypotension and reduced cardiac output. The aim of the present investigation was to (a) examine the influence of type IV phosphodiesterase inhibitor rolipram on haemodynamics, plasma levels of tumor necrosis factor-a (TNF-a) 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 a,-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 anaesthetized with thiobutabarbital. Cardiac output was measured using radioactive labeled microspheres and arterial blood pressure was measured via an intraarterial catheter. Plasma levels of TNF- a were measured by an immunoassay technique, and nitric oxide synthase (inducible & constitutive) activity in lung homogenate was assessed by measuring the conversion of [3H]L-arginine to [3H]L-citrulline. -- Administration of LPS (0.8 mg/kg i.v.) to animals resulted in a significant reduction in cardiac index over time. Changes in arterial resistance, heart rate and blood pressure were insignificant over time in LPS-treated animals. The administration of LPS to rats resulted in a substantial rise in the plasma levels of TNF-a. Furthermore, the injection of LPS resulted in a significant increase in the iNOS activity in lungs. Pre-treatment with rolipram (10 mg/kg) or dexamethasone (5 mg/kg) 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. In contrast, in animals treated with dexamethasone and subsequently LPS, infusion of methoxamine significantly reduced cardiac index and increased blood pressure and arterial resistance. Pre-treatment with rolipram (10 mg/kg) or dexamethasone in animals injected with LPS significantly prevented the rise in TNF-a when compared to respective values in vehicle treated animals. However, pre-treatment with dexamethasone but not rolipram was found to significantly reduce iNOS activity in the lungs of animals injected with LPS. -- The present observations support the view that cardiac index can be maintained in animals treated with LPS independent of iNOS inhibition. Furthermore, our findings seem to support the idea that induction of NOS may occur independently of TNF-a in LPS-treated rats.

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