Influence of FR 167653, an Inhibitor of TNF-α and IL-1, on the Cardiovascular Responses to Chronic Infusion of Lipopolysaccharide in Conscious Rats

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Abstract
Conscious, male Long Evans rats (350-450 g) chronically instrumented for the measurement of regional haemodynamics, were infused with FR 167653, a dual inhibitor of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) synthesis (0.32 mg/kg/h) for 24 h, beginning 1 h before coinfusion of saline, or with saline for 24 h beginning 1 h before coinfusion of lipopolysaccharide (150 microg/kg/h), or with FR 167653 beginning 1 h before coinfusion of lipopolysaccharide. Animals infused with FR 167653 and saline showed progressive hindquarters vasoconstriction over the 24-h period, but this was not different from the change seen in animals (n = 3) infused with saline alone. However, plasma analysis at the end of the coinfusion of FR 167653 and saline showed substantial elevation in levels of creatine kinase, lactate dehydrogenase, and potassium, consistent with some tissue damage (heart, liver, or skeletal muscle, or a combination of these). Animals coinfused with saline and lipopolysaccharide showed biphasic decreases in mean arterial blood pressure accompanied by renal hyperaemic vasodilatation, and decreases followed by increases in mesenteric and hindquarters flows and vascular conductances. At the end of the infusion period, plasma analysis showed signs of renal dysfunction (elevated creatinine) and hepatic dysfunction (elevated alkaline phosphatase, gamma-glutamyl transferase, and alanine aminotransferase). In the presence of FR 167653, the hypotensive effects of lipopolysaccharide were abolished, but regional haemodynamics were unchanged, as were signs of organ dysfunction. One explanation of these observations is that FR 167653 causes a relative improvement in cardiac function during infusion of lipopolysaccharide, and this opposes the hypotensive effects of the latter, in spite of its persistent vasodilator effects.