Failure of drugs that selectively inhibit thromboxane synthesis to modify endotoxin shock in conscious rats

Abstract

1 The effects of two thromboxane synthetase inhibitors (dazoxiben and UK 38485) were investigated on the cardiovascular and metabolic effects of Escherichia coli endotoxin infusion in the conscious, unrestrained rat. 2 Infusion of E. coli endotoxin (41.7 ng kg⁻¹ min⁻¹) for 4 h produced a fall in mean arterial pressure, an increase in heart rate, a transient hyperglycaemia (at 1 h) followed by hypoglycaemia (evident at 6 h), an elevation in plasma lactate and a profound thrombocytopenia. 3 The above changes were accompanied by a marked elevation in plasma thromboxane B₂ concentrations (e.g. endotoxin-treated 935 ± 150 pg ml⁻¹ at 1 h compared with pre-endotoxin values of 125 ± 30 pg ml⁻¹). 4 The administration of either dazoxiben (30 mg kg⁻¹ i.v., given 30 min before starting the endotoxin infusion) or UK 38485 (15 mg kg⁻¹ given 30 min before, and again 4 h after, starting the endotoxin infusion) prevented the rise in plasma thromboxane B₂ concentrations. 5 Neither dazoxiben nor UK 38485 prevented the metabolic, cardiovascular or thrombocytopenic effects of endotoxin and did not modify mortality. 6 These results suggest that, although large amounts of thromboxane are generated in response to endotoxin, they do not play an important role in the major pathophysiological consequences of acute endotoxaemia.