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Department of Internal Medicine, Justus-Liebig University, 35385 Giessen; and Department of Anesthesia and Intensive Care Medicine, University Clinic Rudolf Virchow, 13353 Berlin, Germany
Received 14 May 1996; accepted in final form 26 February 1997.
Steudel, Wolfgang, Hans-Joachim Krämer, Daniela
Degner, Simone Rosseau, Hartwig Schütte, Dieter Walmrath, and
Werner Seeger. Endotoxin priming of thromboxane-related
vasoconstrictor responses in perfused rabbit lungs. J. Appl. Physiol. 83(1): 18-24, 1997.
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 pressor responses and constant release reactions of
TxA2 and prostaglandin (PG)
I2 in nonprimed lungs. Within
60-90 min of endotoxin recirculation, which provoked progressive
liberation of tumor necrosis factor-
but did not effect any
hemodynamic changes by itself, both pressor responses and prostanoid
release markedly increased, and both events were fully blocked by
cyclooxygenase (Cyclo) inhibition with acetylsalicylic acid
(ASA). The unstable intermediate
PGG2 provoked moderate pressor
responses, again enhanced by preceding endotoxin priming and fully
suppressed by ASA. Vasoconstriction also occurred in response to the
direct Cyclo product PGH2, again amplified after endotoxin pretreatment, together with markedly enhanced
liberation of TxA2 and
PGI2. In the presence
of ASA, the priming-related increase in pressor responses and the
prostanoid formation were blocked, but baseline vasoconstrictor
responses corresponding to those in nonprimed lungs were maintained.
Pressor responses to the stable Tx analog U-46619 were not
significantly increased by endotoxin pretreatment, but some generation
of TxA2 and
PGI2 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 Cyclo activity is an important underlying
event.
cyclooxygenase; endoperoxides; pulmonary arterial pressure; tumor
necrosis factor-
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