Xanthine derivative HWA 138 attenuates hemodynamic and oxygen uptake dysfunction secondary to severe endotoxin shock in sheep

Abstract

Continuous E. coli endotoxin infusion in five awake sheep produced hypodynamic shock characterized by decreased cardiac output, increased pulmonary vascular resistance (PVR), leukopenia, high plasma levels of lactate, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha), and a pathological oxygen delivery-consumption relationship, i.e., a dependence of oxygen consumption on oxygen delivery, leading to death within 8-9 hr. Pretreatment with the xanthine derivative HWA 138 in six sheep prevented the endotoxin-induced fall in cardiac output and oxygen delivery, attenuated the increase in PVR and plasma 6-k-PGF1 alpha, and prolonged survival to 13-19 hr in five of the six sheep. The xanthine derivative had no effect on endotoxin-induced leukopenia, nor on the increase of plasma lactate and TXB2 levels. Although in the HWA 138 treated animals oxygen consumption increased significantly (by 59 +/- 17% at 8 hr), this increase was only transient, and at a level that was most probably insufficient to meet the increased metabolic requirements of this model. We conclude that pretreatment with HWA 138 attenuates endotoxin-induced hemodynamic and oxygen uptake disturbances and prolongs survival in this animal model of severe endotoxin shock.