Effect of dazoxiben, a specific inhibitor of thromboxane synthetase, on acute pulmonary responses to E. coli endotoxin in anaesthetized cats.

Abstract

1 The effects of acute pretreatment with the thromboxane synthetase inhibitor dazoxiben 5 mg/kg intravenously (UK 37248-01) were examined on the acute pulmonary responses of pentobarbitone-anaesthetized cats to E. coli endotoxin 2 mg/kg intravenously. 2 E. coli endotoxin in control, untreated, cats resulted in a marked pulmonary hypertension, an increase in intra-tracheal pressure (at a constant pulmonary inflation volume), an increase in both pulmonary arterial and aortic concentrations of thromboxane B2 (TXB2) and a reduction in systematic arterial P02. 3 Dazoxiben prevented, or markedly reduced, the endotoxin-induced pulmonary release ofTXB2, the decrease in systematic arterial P02 and the pulmonary arterial hypertension, but did not modify the increase in intratracheal pressure.4 These results may suggest that TXA2 is responsible for the endotoxin-induced pulmonary arterial hypertension but that some other arachidonic acid derivative (prostaglandin F2a) is responsible for the reduced lung compliance that follows the acute administration of E. coli endotoxin.

Effect of the Thromboxane A₂-Receptor Antagonists, SQ 29,548 and SQ 28,668, on the Pulmonary Hypertensive Response to Endotoxemia in Swine

“…An infusion of at least 30 pg/kg/min SQ 28,668 was required to significantly inhibit both the peak and the overall hypertensive response during the first 60 min after endotoxin ad ministration. These results are in general agreement with the ameliorative actions of TxAi-synthetase inhibitors observed in other species using similar models of septi cemia [2,3,10]. However, the outcome and interpretation of these earlier studies may have been clouded by concurrent changes in the production of other prostanoids.…”

“…These re sponses coincide with augmented produc tion of thomboxane (Tx) A2 and are followed by release of prostacyclin and lipoxygenase metabolites of arachidonic acid [5,9,13]. Since both myospastic responses can be miti gated by inhibitors of cyclooxygenase [7,11] and TxA2-synthetase [2,3,10], TxA2 is con- sidered to be an important mediator of these phenomena. However, the enzymatic inhibi tors employed in these studies can also div ert arachidonic acid metabolism into alter nate pathways and thereby change the con centrations of numerous biologically active products [6,15], This complicates the defin itive identification of a specific eicosanoid as the essential mediator of the pulmonary reactions to septicemia.…”

The release of prostanoids during the acute pulmonary response to E. coli endotoxin in anaesthetized cats

“…This should prevent the formation of TxA2 but still allow generation of PGF2a, perhaps in increased amounts. Preliminary studies (Ball, Parratt & Zeitlin, 1982) indicate that thromboxane may well be the more important mediator of the pulmonary hypertensive effect of endotoxin. In the present study TxA2 and PGF2., were generated by endotoxin in almost equal amounts (Tables 1 and 2) with values around 800pg/ml at 2min and 300 to 500pg/ml at 7min, when there are still pronounced pulmonary effects.…”

Role of Prostaglandins and Related Compounds in the Pathophysiology of Endotoxic and Septic Shock

“…30 In sheep, at least, this early pulmonary hypertensive phase is followed by a later, pro longed period of increased pulmonary vascular permeability. 47,48 Cyclooxygenase inhibi tors 22,37,46,47,49 and thromboxane synthesis in hibitors 30,50 prevent the early hypertensive phase. On the other hand, inhibition of cyclooxygenase activity has relatively little impact on endotoxin-induced changes in pulmonary vascular permeabil ity.…”

“…In cats, endotoxin administra tion causes a marked decrease in lung compli ance. 22,51 Since this phenomenon is blocked by inhibiting cyclooxygenase 22 but not by inhibiting thromboxane synthetase, 50 it is probable that this effect is not mediated by thromboxane, but by some other prostanoid, perhaps PGF 1α .…”