PMA-induced pulmonary edema: mechanisms of the vasoactive response.
We investigated the effect of phorbol myristate acetate (PMA) in isolated guinea pig lungs perfused with phosphate-buffered Ringer solution. Pulmonary arterial pressure (Ppa), pulmonary capillary pressure (Ppc), and change in lung weight were recorded at 0, 10, 25, 40, and 70 min. The capillary filtration coefficient (Kf), an index of vascular permeability, was measured at 10 and 70 min. The perfusion of PMA (0.5 x 10(-7) M) increased Ppa, Ppc, and lung weight at 70 min. The ratio of arterial-to-venous vascular resistance (Ra/Rv) decreased and the Kf did not change with PMA. The perfusion of the lung with 4 alpha-phorbol didecanoate (inactive toward the protein kinase C analogue of PMA) did not affect the lung. The inhibition of TxA2 synthase with dazoxiben inhibited the response to PMA. The inhibition of the 5-lipoxygenase with U-60257 and the SRS-A receptor antagonist FPL 55712 also prevented the response to PMA. The addition of superoxide dismutase (SOD), catalase, or SOD plus catalase (the enzymes that remove O.2 H2O2, and OH., respectively) did not prevent the PMA effect or the release of TxA2; however, dimethylthiourea (DMTU), a scavenger of OH., did prevent the response to PMA. The data indicate that PMA causes a neutrophil-independent increase in lung weight due to increases in Ppc mediated by TxA2 and SRS-A. The protective effect of DMTU may be due to the inhibition of TxA2 generation.
Johnson
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Research Service, Veterans Administration Medical Center, Albany, New York.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D008297:Male; D010208:Papaverine / Q000494:pharmacology; D010477:Perfusion; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000503:physiopathology; D013189:SRS-A / Q000096:biosynthesis*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D013928:Thromboxane A2 / Q000096:biosynthesis*; D014655:Vascular Resistance / Q000187:drug effects
D013189:SRS-A; D013928:Thromboxane A2; C038983:1,3-dimethylthiourea; D010208:Papaverine; D013890:Thiourea; D013755:Tetradecanoylphorbol Acetate