Influence of FR 167653, an inhibitor of TNF-alpha and IL-1, on the cardiovascular responses to chronic infusion of lipopolysaccharide in conscious rats

Conscious, male Long Evans rats (350-450 g) chronically instrumented for th e measurement of regional haemodynamics, were infused with FR 167653, a dua l inhibitor of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (I L-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 lipopoly saccharide (150 mu g/kg/h), or with FR 167653 beginning 1 h before coinfusi on of lipopolysaccharide. Animals infused with FR 167653 and saline showed progressive hindquarters vasoconstriction over the 24-h period, but this wa s 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, lacta te dehydrogenase, and potassium, consistent with some tissue damage (heart, liver, or skeletal muscle, or a combination of these). Animals coinfused w ith saline and lipopolysacchnride showed biphasic decreases in mean arteria l blood pressure accompanied by renal hyperaemic vasodilatation, and decrea ses followed by increases in mesenteric and hindquarters flows and vascular conductances. At the end of the infusion period, plasma analysis showed si gns of renal dysfunction (elevated creatinine) and hepatic dysfunction (ele vated alkaline phosphatase, gamma-glutamyl transferase, and alanine aminotr ansferase). In the presence of FR 167653, the hypotensive effects of lipopo lysaccharide were abolished, but regional haemodynamics were unchanged, as were signs of organ dysfunction. One explanation of these observations is t hat FR 167653 causes a relative improvement in cardiac function during infu sion of lipopolysaccharide, and this opposes the hypotensive effects of the latter, in spite of its persistent vasodilator effects.