title: Resolution of impaired pulmonary function and pulmonary hypertension after phorbol ester administration in rabbits.
abstract: To assess metabolic functions of the pulmonary circulation during lung injury and subsequent recovery from injury, we measured angiotensin-converting enzyme (ACE) activity by means of benzoyl-phenylalanyl-alanyl-proline (BPAP) hydrolysis and 5-hydroxytryptamine (5-HT) removal in vivo in three groups of anesthetized rabbits. One group was treated with 30 micrograms/kg/day phorbol myristate acetate (PMA) intravenously 10 times over 14 days (PMA group). A second group received the same PMA treatment but was not studied until 14 days after the last treatment (PMA/recovery group). A third group was treated with vehicle alone. At the end of PMA treatment, rabbits had an elevated pulmonary artery pressure and depressed ACE activity, expressed as the ratio Vmax/Km. Decreased Vmax/Km for ACE was due to a significant reduction in apparent Vmax for BPAP (control = 235 +/- 37, PMA = 139 +/- 12 nmol/s). Km was unchanged (control = 25 +/- 4, PMA = 31 +/- 7 microM). Uptake of 5-HT was unaffected by PMA treatment. After 2 wk of recovery (PMA/recovery group), pulmonary hypertension had resolved. In this group, Vmax for BPAP hydrolysis was not significantly different from control (280 +/- 18 nmol/s), but Km was significantly increased (48 +/- 5 microM). We conclude that repeated exposure of rabbits to PMA results in lung injury manifested as depressed pulmonary ACE activity and pulmonary artery hypertension. Although much of these alterations were reversible within 2 wk after discontinuing PMA, an increase in apparent Km of ACE may be a more persistent alteration in vascular endothelial cell dysfunction.
authors.affiliation: Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: A M
authors.initials: AM
authors.lastname: Havill
authors.forename: D
authors.initials: D
authors.lastname: Riggs
authors.forename: B R
authors.initials: BR
authors.lastname: Pitt
authors.forename: C N
authors.initials: CN
authors.lastname: Gillis
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000493:pharmacokinetics; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011651:Pulmonary Artery / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects*; D011817:Rabbits; D012701:Serotonin / Q000493:pharmacokinetics; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
chemical_list: D009842:Oligopeptides; D012701:Serotonin; C029689:benzoylphenylalanyl-alanyl-proline; D007703:Peptidyl-Dipeptidase A; D013755:Tetradecanoylphorbol Acetate