Effects of indomethacin on PMA-induced pulmonary endothelial enzyme dysfunction in vivo.
We investigated the effects of phorbol myristate acetate (PMA) on metabolic pulmonary endothelial ectoenzyme dysfunction. Anesthetized rabbits were placed on total heart bypass, and the single-pass transpulmonary metabolism of [3H]benzoyl-Phe-Ala-Pro (BPAP) by endothelial-bound angiotensin-converting enzyme (ACE) and [14C]adenosine 5'-monophosphate (AMP) by 5'-nucleotidase (NCT) was calculated before and after PMA (10 micrograms/kg iv), a dose that does not produce histologically evident endothelial damage. Under conditions of partial microvascular recruitment (blood flow = 400 ml/min through the entire lung), PMA, but not the vehicle, significantly reduced substrate utilization of both BPAP and adenosine 5'-monophosphate (AMP) and increased the apparent Michaelis constant (Km) values of ACE for BPAP, indicative of metabolic dysfunction. These changes were completely prevented by pretreatment with indomethacin. Under conditions of near full microvascular recruitment (blood flow = 640 ml/min through the left lung only), PMA similarly reduced substrate utilization and increased the apparent Km of ACE for BPAP. In this case, however, indomethacin failed to prevent the observed PMA-induced metabolic dysfunction. We conclude that PMA alters endothelial ectoenzyme substrate metabolism independently from changes in pulmonary blood flow; indomethacin appears to antagonize the effects of PMA under conditions of partial microvascular recruitment only, perhaps by diverting flow to previously unperfused, unexposed to PMA, and hence metabolically healthy vessels.
Chen
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Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 30912-2300.
Orfanos
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SE
Catravas
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JD
D015720:5'-Nucleotidase / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D005740:Gases / Q000097:blood; D006439:Hemodynamics; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D009842:Oligopeptides / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects*; D011817:Rabbits; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D005740:Gases; D009842:Oligopeptides; D000249:Adenosine Monophosphate; C029689:benzoylphenylalanyl-alanyl-proline; D015720:5'-Nucleotidase; D007703:Peptidyl-Dipeptidase A; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin