Attenuation of permeability lung injury after phorbol myristate acetate by verapamil and OKY-046.
Phorbol myristate acetate (PMA), which produces an experimental model of acute lung injury similar to the adult respiratory distress syndrome, was studied in isolated dog lung lobes perfused at constant pressure in Zone 3 conditions. The effect of 25 to 50 micrograms PMA on pulmonary vascular permeability and resistance was observed in 4 groups of lungs: Group 1, perfused with a plasma/dextran solution; Group 2, perfused with blood; Group 3, blood-perfused and pretreated with verapamil (a calcium channel blocker); and Group 4, blood-perfused and pretreated with OKY-046 (a thromboxane synthetase inhibitor). Permeability changes were assessed by determining capillary filtration coefficient (Kf), isogravimetric capillary pressure (Pci), and in blood-perfused lungs, the protein reflection coefficient (sigma d). An increase in Kf, a decrease in Pci, and a decrease in sigma d, all indicative of an increase in vascular permeability, occurred 1 h after PMA in blood-perfused but not in plasma/dextran-perfused lungs. An increase in pulmonary vascular resistance occurred in both blood- and plasma/dextran-perfused lungs. Verapamil (2 X 10(-5) M) and OKY-046 (7 X 10(-4) M) pretreatment in blood-perfused lungs essentially blocked the PMA-induced change in permeability and significantly attenuated the increased vascular resistance. Total leukocyte and platelet counts fell in all blood-perfused lungs, whether pretreated or not. We conclude that cellular components of blood (platelets and/or leukocytes) are required to produce the permeability injury but not the pulmonary vasoconstriction and that the injury can be attenuated by either a calcium channel blocker or a specific thromboxane synthetase inhibitor. The left ventricular volume change caused by increasing right ventricular volume was measured at normal and elevated pericardial pressures.
D000179:Acrylates / Q000627:therapeutic use*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D004285:Dogs; D007958:Leukocyte Count; D008168:Lung / Q000098:blood supply / Q000187:drug effects; D008689:Methacrylates / Q000627:therapeutic use*; D010477:Perfusion; D010704:Phorbols; D010976:Platelet Count; D011654:Pulmonary Edema / Q000139:chemically induced / Q000517:prevention & control; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014700:Verapamil / Q000627:therapeutic use*
D000179:Acrylates; D008689:Methacrylates; D010704:Phorbols; D014700:Verapamil; D013930:Thromboxane-A Synthase; C034364:ozagrel; D013755:Tetradecanoylphorbol Acetate