The effect of selective and non-selective phosphodiesterase inhibitors on allergen- and leukotriene C(4)-induced contractions in passively sensitized human airways.
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 effect on smooth muscle and inhibition of histamine and cysteinyl leukotriene (LT) release from airways. We investigated the effects 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. Macroscopically normal airways from 76 patients were sensitized with IgE-rich sera (>250 u ml(-1)) containing specific antibodies against allergen (Dermatophagoides farinae). Contractile responses of bronchial rings were assessed using standard organ bath techniques. 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 significantly 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 significantly decrease responses to either allergen or LTC(4). We conclude that combined inhibition of PDE3 and PDE4, but not selective inhibition of either isoenzyme or antagonism of adenosine receptors, is effective 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.
Schmidt
D T
DT
Leiden University Medical Centre, Department of Pulmonology, NL-2333 ZA Leiden, The Netherlands. d.schmidt@lumc.nl
Watson
N
N
Dent
G
G
Rühlmann
E
E
Branscheid
D
D
Magnussen
H
H
Rabe
K F
KF
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D039741:Antigens, Dermatophagoides; D001549:Benzamides / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000494:pharmacology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000276:immunology / Q000494:pharmacology*; D006632:Histamine / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D017997:Leukotriene C4 / Q000276:immunology / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000503:physiopathology; D009119:Muscle Contraction / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D039741:Antigens, Dermatophagoides; D001549:Benzamides; D001993:Bronchodilator Agents; D006023:Glycoproteins; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011725:Pyridines; D017997:Leukotriene C4; D006632:Histamine; D013806:Theophylline; C051270:motapizone; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D015056:1-Methyl-3-isobutylxanthine; C066436:zardaverine; C087566:piclamilast