The effect of selective and non‐selective phosphodiesterase inhibitors on allergen‐ and leukotriene C₄‐induced contractions in passively sensitized human airways

Abstract

1 Non-selective inhibitors of cyclic nucleotide phosphodiesterase (PDE) block allergen-induced contraction of passively sensitized human airways in vitro by a dual mechanism involving a direct relaxant eect on smooth muscle and inhibition of histamine and cysteinyl leukotriene (LT) release from airways. We investigated the eects of non-selective PDE inhibitors and selective inhibitors of PDE3 and PDE4 in order to determine the involvement of PDE isoenzymes in the suppression of allergic bronchoconstriction. 2 Macroscopically normal airways from 76 patients were sensitized with IgE-rich sera (4250 u ml 71) containing speci®c antibodies against allergen (Dermatophagoides farinae). Contractile responses of bronchial rings were assessed using standard organ bath techniques. 3 Passive sensitization caused increased contractile responses to allergen, histamine and LTC 4 . Non-selective PDE inhibitors (theophylline, 3-isobutyl-1-methylxanthine [IBMX]), a PDE3-selective inhibitor (motapizone), PDE4-selective inhibitors (RP73401, rolipram, AWD 12-281) and a mixed PDE3/4 inhibitor (zardaverine) all signi®cantly relaxed inherent bronchial tone at resting tension and to a similar degree. Theophylline, IBMX, zardaverine and the combination of motapizone and RP73401 inhibited the contractile responses to allergen and LTC 4 . Pre-treatment with motapizone, RP73401, rolipram or the methylxanthine adenosine receptor antagonist, 8-phenyltheophylline, did not signi®cantly decrease responses to either allergen or LTC 4 . 4 We conclude that combined inhibition of PDE3 and PDE4, but not selective inhibition of either isoenzyme or antagonism of adenosine receptors, is eective in suppressing allergen-induced contractions of passively sensitized human airways. The relationship between allergen-and LTC 4 -induced responses suggests that PDE inhibitors with PDE3 and PDE4 selectivity are likely to act in part through inhibition of mediator release and not simply through direct relaxant actions on airway smooth muscle.

Pharmacology ofN-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline Carboxamide (SCH 351591), a Novel, Orally Active Phosphodiesterase 4 Inhibitor

“…Under in vivo as well as in vitro conditions, allergen-induced contraction of human airways results from the release of mediators such as histamine and cysteinyl leukotrienes (Heaslip et al, 1992). Lung mast cells contain PDE3 and PDE4 (Giembycz, 2000), and complete inhibition of antigen-driven mediator release from these cells and of contraction of passively sensitized human airways occurs only when both PDE3 and PDE4 are inhibited (Giembycz, 2000;Schmidt et al, 2000). It is important to note that SCH 351591 (3 mg/kg p.o.)…”

Anti-Inflammatory Potential of the Selective Phosphodiesterase 4 InhibitorN-(3,5-Dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic Acid Amide (AWD 12-281), in Human Cell Preparations

“…Among the PDEs, PDE4, PDE7, and PDE8 show specificity for cAMP (Conti and Yin, 1999;Soderling and Beavo, 2000). In the search for an anti-inflammatory treatment alternative to corticosteroids, selective PDE4 inhibitors have received considerable attention, because the PDE4 isoenzyme is the major cAMPmetabolizing enzyme in immune and inflammatory cells (Torphy et al, 1992;Schmidt et al, 1999). Selective inhibition of PDE4 has anti-inflammatory effects in patients with inflammatory diseases such as asthma or chronic obstructive pulmonary disease (COPD) (Compton et al, 2001;Leichtl et al, 2002;Barnes, 2003).…”

Cigarette smoke up‐regulates PDE3 and PDE4 to decrease cAMP in airway cells

“…Next to PDE4, PDE3 is the primary PDE in airway smooth muscle cells (Rabe et al ., 1993; Page and Spina, 2012) and PDE3 inhibitors induce ASM relaxation in vitro (Rabe et al ., 1993; Schmidt et al ., 2000) and in vivo (Hirota et al ., 2001). Even though RPL554 is considered as one of the most selective PDE3 inhibitors based on an about 3000× higher IC 50 value for purified human platelet PDE3 compared to neutrophil PDE4 (PDE3: 0.4 nM; PDE4:1479 nM) (Boswell‐Smith et al ., 2006), a growing body of evidence suggest that dual inhibition of PDE3 and PDE4, using higher levels of inhibitor (10 μM or 0.018 mg·kg −1 ), can more effectively induce bronchodilation with potential additive effects of suppressing release of inflammatory mediators (Calzetta et al ., 2013; Franciosi et al ., 2013).…”