ENDOTOXIN PRIMING OF THROMBOXANE-RELATED VASOCONSTRICTOR RESPONSES INPERFUSED RABBIT LUNGS

In prior studies of perfused lungs, endotoxin priming markedly enhance d thromboxane (Tx) generation and Tx-mediated vasoconstriction in resp onse to secondarily applied bacterial exotoxins. The present study add ressed this aspect in more detail by employing precursor and intermedi ates of prostanoid synthesis and performing functional testing of vaso reactivity and measurement of product formation. Rabbit lungs were buf fer perfused in the absence or presence of 10 ng/ml endotoxin. Repetit ive intravascular bolus applications of free arachidonic acid provoked constant pulmonary arterial presser responses and constant release re actions of TxA(2) and prostaglandin (PG) I-2 in nonprimed lungs. Withi n 60-90 min of endotoxin recirculation, which provoked progressive lib eration of tumor necrosis factor-alpha but did not effect any hemodyna mic changes by itself, both presser responses and prostanoid release m arkedly increased, and both events were fully blocked by cyclooxygenas e (Cycle) inhibition with acetylsalicylic acid (ASA). The unstable int ermediate PGG(2) provoked moderate presser responses, again enhanced b y preceding endotoxin priming and fully suppressed by ASA. Vasoconstri ction also occurred in response to the direct Cycle product PGH(2), ag ain amplified after endotoxin pretreatment, together with markedly enh anced liberation of TxA(2) and PGI(2). In the presence of ASA, the pri ming-related increase in presser responses and the prostanoid formatio n were blocked, but baseline vasoconstrictor responses corresponding t o those in nonprimed lungs were maintained. Presser responses to the s table Tx analog U-46619 were not significantly increased by endotoxin pretreatment, but some generation of TxA(2) and PGI(2) was also noted under these conditions. We conclude that endotoxin priming exerts prof ound effects on the lung vascular prostanoid metabolism, increasing th e readiness to react with Tx-mediated vasoconstrictor responses to var ious stimuli, suggesting that enhanced Cycle activity is an important underlying event.