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

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.

Prevention of the onset and progression of collagen‐induced arthritis in rats by the potent p38 mitogen‐activated protein kinase inhibitor FR167653

“…In our in vivo study, we found no adverse events caused by 32 mg/kg/day of FR167653, a dosage that was used in another inflammation model and found to be safe and effective (64). Although most of the in vivo investigations found no adverse effects, one study demonstrated increased plasma creatine levels and lactate dehydrogenase levels in rats (65). The toxicity of FR167653 should be studied extensively.…”

Haemodynamic effects of the bacterial quorum sensing signal molecule, N‐(3‐oxododecanoyl)‐L‐homoserine lactone, in conscious, normal and endotoxaemic rats

“…From previous experiments, we know that administration of antibodies to TNF‐α alone, or antibodies to TNF‐α together with antibodies to IL‐1β, do not greatly influence the haemodynamic effects of LPS in this model of endotoxaemia ( Waller et al ., 1995 ; Gardiner et al ., 1998 ). However, we have also shown that inhibition of TNFα and IL‐1β production, with FR 167653, does affect the early hypotensive effects of LPS ( Gardiner et al ., 1999 ). Thus, if 3‐oxo‐C12‐HSL had inhibited cytokine production, we might have expected to see a similar inhibitory effect on the early fall in blood pressure, but that was not the case.…”

“…In this context, the first objective of the present work was to assess the regional haemodynamic effects of 3‐oxo‐C12‐HSL in conscious rats. Our second objective was to determine whether or not 3‐oxo‐C12‐HSL influenced the cardiovascular changes associated with experimental endotoxaemia, achieved by infusion of LPS in conscious rats, since, in this model, we have evidence that cytokines, such as TNF‐α, may contribute to the haemodynamic sequelae ( Gardiner et al ., 1999 ). An unexpected finding in our initial studies was a striking effect of 3‐oxo‐C12‐HSL on heart rate.…”

P38 Mitogen-Activated Protein Kinase Inhibitor, FR167653, Inhibits Parathyroid Hormone Related Protein-Induced Osteoclastogenesis and Bone Resorption

“…In the present study, we also found that there is no significant side effects when twice daily treatment with 30 mg/kg FR167653 for about 1 week. Long-term injection of FR167653 may lead to toxic events; indeed, one study demonstrated that FR167653 treatment increased plasma creatine and lactate dehydrogenase levels in rats [37]. Clearly, the potentially adverse effects of FR167653, including its modulation of calcium homeostasis, need to be studied extensively.…”