Lack of effect of TNF antibodies on the cardiovascular sequelae of lipopolysaccharide infusion in conscious rats

Abstract

1 The aims of the present study were to determine the profile of tumour necrosis factor (TNF) release, and the effect of monoclonal antibodies to TNF, on the changes in regional haemodynamics and the responses to vasodilator and vasoconstrictor challenges, during a continuous 24 h low dose infusion of lipopolysaccharide (LPS) in conscious rats. 2 Male Long Evans rats were chronically instrumented for measurement of regional haemodynamics (renal, superior mesenteric and hindquarters) and were challenged with 3 min infusions of acetylcholine (22 nmol min-'), methoxamine (120 nmol min-'), salbutamol (0.83 nmol min-') and bradykinin (14.4 nmol min-'). The rats were given either saline, or the TNF antibodies, TN3gl or TN3g2a, 1 h before the start of a continuous infusion of LPS (150 pg kg -' h -') and were subsequently re-tested with the vasodilator and vasoconstrictor challenges 2, 6 and 24 h after the start of the LPS infusion. 3 Prior to infusion of LPS, TNF was not detectable in the plasma. During continuous infusion of LPS there was a transient elevation in plasma TNF levels, reaching a maximum (-2300 pg ml-') after approximately 1 h, and returning to undetectable levels after approximately 3 h of LPS infusion. 4 In the saline pretreated group, after 1-2 h of LPS infusion, there was a small hypotension and a marked renal vasodilatation; 6 h after the start of LPS infusion there was a minor elevation in MAP above control levels, renal vasodilatation was maintained and a hindquarters vasoconstriction occurred; after 24 h of LPS infusion, there was a hypotension and renal and hindquarters vasodilatation. There were significant reductions in the tachycardic and renal vasodilator responses and an enhanced depressor response to acetylcholine after 24 h of LPS infusion. LPS infusion also caused a generalized hyporesponsiveness to the cardiovascular effects of methoxamine and salbutamol. The major changes in response to bradykinin were reduced tachycardic and enhanced depressor responses throughout the LPS infusion, a biphasic decrease and increase in renal conductance and enhanced hindquarters vasodilatation at 24 h. 5 Pretreatment with either TN3gl or TN3g2a antibodies had no major effects on the changes in resting haemodynamics, or on the changes in response to methoxamine, salbutamol or bradykinin challenges during LPS infusion. However, the tachycardic responses to acetylcholine were generally preserved, and its hypotensive effect after 24 h of LPS infusion was not enhanced after TN3gl or TN3g2a pretreatment. Thus, despite substantial, but transient, elevation of plasma TNF levels during continuous LPS infusion, it appears that the majority of cardiovascular changes were dependent on factors other than plasma TNF.

The influence of antibodies to TNF‐α and IL‐1β on haemodynamic responses to the cytokines, and to lipopolysaccharide, in conscious rats

“…In the light of this observation it could be suggested that bolus injection of LPS activates cytokine cascades in a way not seen with LPS infusion. However, we have shown that LPS infusion (as here) causes substantial elevation of plasma TNF‐α levels (Waller et al , 1995). So, another interpretation is that only those effects of LPS infusion that were changed by antibody pretreatment (i.e., the initial hindquarters vasodilatation and the recovery from the initial fall in MAP) involved TNF‐α and/or IL‐1β.…”

A potential role for Akt/FOXO signalling in both protein loss and the impairment of muscle carbohydrate oxidation during sepsis in rodent skeletal muscle

“…The aim of this study was to measure the effects of lipopolysaccharide (LPS)‐induced endotoxaemia on the expression of Akt, FOXO and its downstream targets, to examine the potential dual role of FOXO in both muscle protein loss and impairment of carbohydrate oxidation in vivo during sepsis. To investigate this, conscious, chronically instrumented rats were infused intravenously with a non‐lethal dose of bacterial LPS, as a clinically relevant model of endotoxaemia that results in a systemic inflammatory response syndrome and represents the early stages of clinical sepsis (Waller et al 1995).…”

Temporal changes in the involvement of pyruvate dehydrogenase complex in muscle lactate accumulation during lipopolysaccharide infusion in rats

“…Vary et al utilized an intra‐abdominal abscess model of sepsis, which developed over 3–7 days; they provided no information on changes occurring in the first 24 h of the septic challenge (Vary et al 1998). We have previously assessed the haemodynamic changes produced by continuous infusion of lipopolysaccharide (LPS) in conscious rats, and have shown that in this experimental protocol, the hyperdynamic circulatory state mimics that seen in the early stages of clinical sepsis (Waller et al 1995). Therefore, in the present study, we used the LPS infusion model to examine changes in fast‐twitch muscle, which is known to be highly susceptible to sepsis (Tiao et al 1997; Wray et al 2003).…”