Prostanoids And Endotoxaemia In The Mini-Pig

Abstract

Infusion (iv) of endotoxin (E coli 0111 B4) at a cone, of 1, 10, 100 or lOOOng/kg/min into mini-pigs with sampling every 20 mins produced a dose related fall in WBC, platelets, blood pressure (BP) and early large increases in plasma thromboxane (Tx) B2 with only minor changes in plasma 6-oxo-PGF1α conc. In 5 pigs endotoxin infusion at 100 ng/kg/min for 40 min produced elevated plasma levels of TxB2 from pre-infusion value of 40±5 to 750±50pg/ml, while WBC, platelets and BP expressed as % of pre-infusion value were 40±8, 81±6 and 105±5% respectively. At the end of the endotoxin infusion (100 min) plasma TxB2 had decreased to 120±10pg/ml; WBC, platelets and BP were 22±4, 62±4, 63±5% of pre-infusion value. In 5 other pigs receiving saline only, no significant changes in any of the above parameters were observed.Thus there is an excess of thromboxane production compared to PGI2 in endotoxaemia. We attempted to determine the contribution of this prostanoid imbalance to endotoxaemia, by treating groups of 5 to 9 mini-pigs with either PGI2 (125 ng/kg/min, continuously), or a potent and selective Tx synthesis inhibitor, UK, 37, 248 (7.5mg/kg as a bolus 10 min before) or lignocaine (20mg/kg as bolus 10 mins before followed by an infusion of 2mg/min) prior to endotoxin infusion. Both PGI2 and lignocaine maintained the BP at pre-endotoxin values, but did not have a significant effect on the leucopenia and thrombocytopaenia or on the elevation of plasma TxB2 While the Tx synthesis inhibitor produced a significant (p<0.05) but not a maximum inhibition of the drop in BP, a marked inhibition of plasma TxB2 formation, but with no effect on the leucopenia or thrombocytopaenia induced by the endotoxin infusion.Although Tx formation is a sensitive indicator of endotoxaemia and precedes the development of hypotension, it is not contributory to the thrombocytopaenia or the leucopenia. How ever both PGI2 and the Tx synthesis inhibitor by correcting the prostanoid balance appear to be therapeutically useful in endotoxaemia.