Phosphodiesterase inhibitors reduce bronchial hyperreactivity and airway inflammation in unrestrained guinea pigs.
A new guinea pig model of allergic asthma was used to investigate the effects of low doses of the phosphodiesterase inhibitors, rolipram (phosphodiesterase IV selective), ORG 20241 (N-hydroxy-4-(3,4-dimethoxyphenyl)-thiazole-2-carboximidamide; dual phosphodiesterase III/IV inhibitor with some selectivity for the phosphodiesterase IV isoenzyme), and of theophylline (non-selective) on allergen-induced early and late phase asthmatic reactions, bronchial hyperreactivity to histamine inhalation, and airway inflammation. Theophylline (25 mg/kg i.p.) and ORG 20241 (5 mg/kg i.p.) did not affect histamine-induced bronchoconstriction, whereas rolipram (75 micrograms/kg i.p.) only slightly reduced the response to histamine at 7 h after administration. However, bronchial hyperreactivity after the early and after the late reaction was significantly reduced by theophylline, rolipram and ORG 20241, while bronchoalveolar lavage studies revealed a selective inhibition of airway inflammation by the phosphodiesterase inhibitors. Theophylline significantly reduced the number of eosinophils, neutrophils and macrophages; rolipram reduced the number of neutrophils and lymphocytes, and ORG 20241, the number of eosinophils and macrophages. None of the compounds at the dosage indicated reduced the early and late reaction when administered i.p. 1 h before allergen exposure to defined dual responding animals. These results indicate that non-bronchodilator doses of these phosphodiesterase inhibitors markedly reduce the allergen-induced development of bronchial hyperreactivity as well as airway inflammation, presumably by selectively inhibiting cellular migration. The results suggest that an orchestrated series of cellular interactions is involved in the development of bronchial hyperreactivity. It is concluded that phosphodiesterase inhibitors may be very useful in the treatment of bronchial asthma.
Santing
R E
RE
Groningen/Utrecht Institute for Drug Exploration, Department of Medicinal Chemistry, University of Groningen, Netherlands.
Olymulder
C G
CG
Van der Molen
K
K
Meurs
H
H
Zaagsma
J
J
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects; D006168:Guinea Pigs; D006632:Histamine / Q000008:administration & dosage / Q000633:toxicity; D006967:Hypersensitivity; D007249:Inflammation / Q000188:drug therapy; D007274:Injections, Intraperitoneal; D007527:Isoenzymes; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D010047:Ovalbumin / Q000008:administration & dosage / Q000633:toxicity; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D020889:Rolipram; D013047:Specific Pathogen-Free Organisms; D013806:Theophylline / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D007527:Isoenzymes; C094013:ORG 20241; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D013844:Thiazoles; D006632:Histamine; D010047:Ovalbumin; D013806:Theophylline; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram