Effects of isoenzyme-selective inhibitors of cyclic nucleotide phosphodiesterase on microvascular leak in guinea pig airways in vivo.
The effects of drugs elevating cyclic nucleotide concentrations or inhibiting cyclic nucleotide phosphodiesterase (PDE) activity on platelet activating factor (PAF)-induced microvascular leak (MVL) was examined in the anesthetized guinea pig. Drugs were dosed as dry powders directly into the tracheobronchial tree and MVL was assessed by using the fluorescent macromolecule fluorescein isothiocyanate-dextran (FITC-dextran, 150 kD). Basal FITC-dextran content was 15 +/- 1 and 23 +/- 4 ng.mg-1 of tracheal and bronchial tissue, respectively, and 0.6 +/- 0.03 micrograms.ml-1 of tracheobronchial lavage fluid. PAF (2-8 nmol, intratracheal (i.t.) administration) produced a dose-dependent increase in MVL; the maximum increase being 100% in tracheal and bronchial tissue and 400% in lavage fluid. PAF (16 nmol) produced acute bronchospasm. The beta-2 adrenoceptor agonist salbutamol (50 or 200 micrograms i.t.) and the nitrovasodilator sodium nitroprusside (200 or 500 micrograms i.t.), which activate adenylyl and guanylyl cyclases, respectively, potently and significantly (P < .05) inhibited PAF-induced MVL in airway tissues and in the airway lumen by 60 to 100%. Sodium nitroprusside (50 micrograms i.t.) only significantly inhibited MVL into the lavage fluid. Inhibition of PDE type IV with rolipram (200 micrograms i.t.) or PDE type V with zaprinast (200 micrograms i.t.) potently (by 70-100%) and significantly (P < .05) reduced MVL into the airways. Lower doses (20 micrograms) were without effect. Neither vinpocetine (PDE type I inhibitor) nor siguazodan (PDE type III inhibitor) inhibited MVL. Theophylline (200 micrograms i.t.) inhibited MVL into lower airway tissues and lavage fluid but was without marked effect in tracheal tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
Raeburn
D
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Rhône-Poulenc Rorer Ltd., Dagenham Research Centre, Essex, England.
Karlsson
J A
JA
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors*; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000098:blood supply* / Q000201:enzymology*; D002199:Capillary Permeability / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006168:Guinea Pigs; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D014132:Trachea / Q000098:blood supply* / Q000201:enzymology*
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010972:Platelet Activating Factor; D009599:Nitroprusside; D000242:Cyclic AMP; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D006152:Cyclic GMP; D000420:Albuterol