Quinolines attenuate PAF-induced pulmonary pressor responses and edema formation.
In the present study we have investigated the mechanisms of pulmonary edema caused by platelet-activating factor (PAF) in isolated rat lungs as well as in mice in vivo. In blood-free perfused and ventilated rat lungs, PAF increased lung weight by 0.59 +/- 0.18 g. The cyclooxygenase inhibitor aspirin (500 microM) blocked this response by one-third, and the quinolines quinine (330 microM), quinidine (100 microM), and chloroquine (100 microM) by two-thirds. Lipoxygenase inhibition (10 microM AA861) alone or in combination with thromboxane receptor antagonism (10 microM SQ29548) had no effect on PAF-induced weight gain. In combination with aspirin, quinine or quinidine completely prevented PAF-induced weight gain and the concomitant increase of the capillary filtration coefficient (K(f,c)). Pretreatment with quinine in vivo prevented not only PAF-, but also endotoxin-induced edema formation as assessed by Evans Blue extravasation. In addition, in vivo quinine prevented the endotoxin-induced release of tumor neurosis factor (TNF). Furthermore, in perfused lungs quinine reduced the PAF-induced increases in airway and vascular resistance, as well as thromboxane release. These findings demonstrate the following anti-inflammatory properties of quinolines: reduction of thromboxane and TNF formation; reduction of PAF-induced vasoconstriction and bronchoconstriction; and attenuation of PAF- and lipopolysaccharide (LPS)-induced edema formation. We conclude that the PAF- induced edema consists of two separate mechanisms, one dependent on an unknown cyclooxygenase metabolite, the other one sensitive to quinolines.
Falk
S
S
Biochemical Pharmacology, University of Konstanz, Konstanz, Germany.
Göggel
R
R
Heydasch
U
U
Brasch
F
F
Müller
K M
KM
Wendel
A
A
Uhlig
S
S
D000403:Airway Resistance; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002199:Capillary Permeability; D002738:Chloroquine / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D005260:Female; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010972:Platelet Activating Factor / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects*
D016227:Benzoquinones; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D015850:Interleukin-6; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D011804:Quinolines; D017482:Receptors, Thromboxane; D014409:Tumor Necrosis Factor-alpha; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D002738:Chloroquine; C045749:SQ 29548; D011803:Quinine; D011802:Quinidine; D001241:Aspirin