Quantitative assessment of increased airway microvascular permeability to 125I-labelled plasma fibrinogen induced by platelet activating factor and bradykinin.
1. We have used 125I-labelled fibrinogen (I-FN) in experiments monitoring plasma extravasation from vessels within guinea-pig trachea and peripheral lung tissue in response to platelet activating factor (PAF) and bradykinin (BK). Retained tissue radioactivity derived from I-FN was detected by direct measurement and by autoradiography. 2. Both PAF and BK caused concentration-dependent increases in radioactivity in trachea and peripheral lung, with PAF being approximately 1000 times more potent than BK at both sites. On a wet weight basis, mean tracheal leakage responses to PAF and BK were approximately 6 times and 2 times greater respectively than those in peripheral lung. Furthermore, in trachea, the maximal response to PAF was nearly twice that to BK, although they were approximately equiactive in peripheral lung. The dipeptidyl carboxypeptidase inhibitor, enalapril (1 mg kg-1, i.v.), increased the potency of BK by approximately 40 fold. 3. In trachea, PAF (50 ng kg-1, i.v.)-induced leakage was selectively inhibited by the PAF receptor antagonist, WEB 2086 (5-50 micrograms kg-1), while responses to BK (50 micrograms kg-1, i.v.) were selectively inhibited by the BK2 receptor antagonist NPC 349 (0.5-1 mg kg-1). Neither PAF nor BK-induced leakage were significantly altered by pretreatment with the histamine H1-receptor antagonists mepyramine (10 micrograms kg-1) or ketotifen (50 micrograms kg-1) or the leukotriene receptor antagonist SKF 104353. These data indicate that both agonists caused direct, specific receptor operated increases in tracheal vascular permeability to plasma macromolecules.The alpha/beta1-adrenoceptor agonist adrenaline (100 pgkg-1) caused modest inhibition of leakage induced by BK, but not of the leakage response to PAF.4. Peripheral airway leakage responses to both PAF and BK were also detected by light microscopic autoradiography in paraffin-embedded tissue sections. This was possible since a significant amount of extravasated I-FN was apparently precipitated and fixed in the extravascular space as 125-labelled fibrin. Autoradiograms showed that both agonists caused increases in peripheral bronchial circulation microvascular permeability to I-FN. No evidence for leakage in alveolar wall capillaries or in pulmonary blood vessels was observed. Quantitation of such autoradiographic data will allow a comprehensive evaluation of the effects of putative asthma mediators on microvascular permeability throughout the respiratory tree.
Pedersen
K E
KE
Department of Pharmacology, University of Western Australia, Perth, Nedlands.
Rigby
P J
PJ
Goldie
R G
RG
D000818:Animals; D001345:Autoradiography; D001381:Azepines / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D005340:Fibrinogen / Q000378:metabolism*; D006168:Guinea Pigs; D007457:Iodine Radioisotopes; D008168:Lung / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016612:Paraffin Embedding; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins; D011652:Pulmonary Circulation / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled; D014132:Trachea / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D007457:Iodine Radioisotopes; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086; D005340:Fibrinogen; D001920:Bradykinin