Bronchodilatory and anti-inflammatory properties of inhaled selective phosphodiesterase inhibitors in a guinea pig model of allergic asthma.
In a guinea pig model of allergic asthma, we investigated the effects of the selective phosphodiesterase inhibitors rolipram (phosphodiesterase 4-selective), Org 9935 (phosphodiesterase 3-selective) and Org 20241 (dual phosphodiesterase 4/phosphodiesterase 3-selective), administered by aerosol inhalation in approximately equipotent bronchodilatory doses, on allergen-induced early and late asthmatic reactions, airway hyperreactivity and airway inflammation. Using ovalbumin-sensitized non-challenged animals, different nebulizer concentrations of each inhibitor were tested for their protective effects against histamine-induced bronchoconstriction. Inhalation of 2.5 mM rolipram, 100 mM 4,5-dihydro-6-(5,6-dimethoxybenzo[b]thien-2-yl-5-methyl-3(2H)pyridazinone (Org 9935) and 10 and 100 mM N-hydroxy-4-(3,4-dimethoxyphenyl)-thiazole-2-carboximidamide HCl (Org 20241) provided a similar, 1.8-fold (P<0.01), 2.0-fold (P<0.05), and 1.8- and 1.9-fold (P<0.05) protection, respectively. The duration of these bronchoprotective effects were different, the rate of decline being faster with rolipram and the lower Org 20241 concentration than with Org 9935 and the higher concentration of Org 20241. All compounds strongly protected against the immediate allergen-induced bronchoconstriction and significantly (P<0.05) diminished the overall early asthmatic reaction from 0 to 6 h following allergen-provocation. The severity of the late asthmatic reaction was also significantly inhibited by rolipram (P<0.05) and Org 9935 (P<0.05). Allergen-induced airway hyperreactivity to inhaled histamine after the early reaction, at 6 h after ovalbumin challenge, was strongly reduced by rolipram (P<0.05) and completely prevented by the two other phosphodiesterase inhibitors; in addition, airway hyperreactivity after the late asthmatic reaction, at 24 h, was abolished in all treatment groups. Bronchoalveolar lavage performed at 24 h after allergen challenge revealed no inhibition of eosinophil infiltration in the rolipram-treated animals, whereas inhalation of Org 9935 and the higher-but not the lower-concentration of Org 20241 strongly reduced the influx of these cells. Eosinophil peroxidase activity in the lavage fluid tended to be diminished in all treatment groups but significance was not reached with the exception of the lower concentration of Org 20241. Infiltration of lymphocytes and macrophages was significantly inhibited by Org 9935 only (P<0.05 and P<0.01, respectively), whereas neutrophil influx was not significantly affected. The results indicate that inhalation of phosphodiesterase 3-, phosphodiesterase 4- and dual phosphodiesterase 3/phosphodiesterase 4-selective inhibitors afford protection against acute histamine- and allergen-induced bronchoconstriction and prevent the development of airway hyperreactivity both after the early and late asthmatic reaction predominantly through inhibition of phosphodiesterase 4; in contrast, for significant reduction of eosinophil infiltration, both phosphodiesterase 3 and phosphodiesterase 4 inhibition seems to be required.
Santing
R E
RE
Department of Molecular Pharmacology, University Centre for Pharmacy, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
de Boer
J
J
Rohof
A
A
van der Zee
N M
NM
Zaagsma
J
J
D000280:Administration, Inhalation; D000485:Allergens / Q000009:adverse effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*
D000485:Allergens; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001993:Bronchodilator Agents; D010726:Phosphodiesterase Inhibitors; D006632:Histamine; D010047:Ovalbumin