Endotoxin priming of thromboxane-related vasoconstrictor responses in perfused rabbit lungs

In prior studies of perfused lungs, endotoxin priming markedly enhanced thromboxane (Tx) generation and Tx-mediated vasoconstriction in response to secondarily applied bacterial exotoxins. The present study addressed this aspect in more detail by employing precursor and intermediates of prostanoid synthesis and performing functional testing of vasoreactivity and measurement of product formation. Rabbit lungs were buffer perfused in the absence or presence of 10 ng/ml endotoxin. Repetitive intravascular bolus applications of free arachidonic acid provoked constant pulmonary arterial presser responses and constant release reactions of TxA(2) and prostaglandin (PG) I-2 in nonprimed lungs. Within 60-90 min of endotoxin recirculation, which provoked progressive liberation of tumor necrosis factor-alpha but did not effect any hemodynamic changes by itself, both presser responses and prostanoid release markedly increased, and both events were fully blocked by cyclooxygenase (Cycle) inhibition with acetylsalicylic acid (ASA). The unstable intermediate PGG(2) provoked moderate presser responses, again enhanced by preceding endotoxin priming and fully suppressed by ASA. Vasoconstriction also occurred in response to the direct Cycle product PGH(2), again amplified after endotoxin pretreatment, together with markedly enhanced liberation of TxA(2) and PGI(2). In the presence of ASA, the priming-related increase in presser responses and the prostanoid formation were blocked, but baseline vasoconstrictor responses corresponding to those in nonprimed lungs were maintained. Presser responses to the stable 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 profound effects on the lung vascular prostanoid metabolism, increasing the readiness to react with Tx-mediated vasoconstrictor responses to various stimuli, suggesting that enhanced Cycle activity is an important underlying event.