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TJ Torphy, BJ Undem, LB Cieslinski, MA Luttmann, ML Reeves and DW Hay
Department of Inflammation & Respiratory Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
In the present study phosphodiesterase (PDE) isozymes in human airway smooth muscle were isolated, identified and characterized, and the functional roles of these isozymes in intact bronchi were evaluated by using isozyme-selective PDE inhibitors. PDE isozymes in human trachealis were isolated by using a combination of DEAE-Sepharose and calmodulin-Sepharose affinity chromatography, and were identified based upon their kinetic characteristics as well as their sensitivity to allosteric modulators and isozyme-selective PDE inhibitors. By using this approach, six distinct isozymes were identified: two calmodulin- stimulated PDEs (PDE I alpha and PDE I beta), cyclic GMP (cGMP)- stimulated PDE (PDE II), cGMP-inhibited PDE (PDE III), cyclic AMP (cAMP)-specific PDE (PDE IV) and cGMP-specific PDE (PDE V). PDEs III and IV were the major cAMP-hydrolyzing enzymes present, whereas PDEs I alpha, I beta and V accounted for most of the cGMP-hydrolytic activity. In carbachol-precontracted small (< 0.5-2 mm diameter) or large (4-15 mm diameter) human bronchus, zaprinast (10 nM-30 microM), the selective PDE V inhibitor, was without marked relaxant activity (< 13%), whereas rolipram (30 microM), the selective PDE IV inhibitor, produced approximately 25% relaxation in both preparations. Siguazodan was a significantly more effective relaxant than zaprinast or rolipram in large bronchus, producing a maximum relaxation of 77 +/- 15% at a concentration of 30 microM, whereas in small bronchus 30 microM siguazodan elicited 20 +/- 6% relaxation. Similar results were obtained in large bronchi contracted with leukotriene (LT) D4 (0.1 microM). The ability of isozyme-selective PDE inhibitors to potentiate agonist- induced relaxation was studied in LTD4-contracted large bronchi. Siguazodan (10 microM), but not rolipram (10 microM) or zaprinast (10 microM), potentiated the relaxant response in LTD4-contracted large bronchus to isoproterenol, a beta adrenoceptor agonist thought to induce relaxation via a cAMP-mediated mechanism. In contrast, zaprinast (10 microM), but not siguazodan (10 microM), potentiated relaxation induced by sodium nitroprusside, a nitrovasodilator that relaxes airway smooth muscle via a cGMP-mediated mechanism. The most striking observation from functional studies was that the combination of rolipram and siguazodan produced a much greater relaxation of small or large human bronchi than either agent alone, indicating an interaction between PDE III and PDE IV inhibitors that was at least additive and, in some cases, synergistic.(ABSTRACT TRUNCATED AT 400 WORDS)
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