Effects of inhibitors of phosphodiesterase, on antigen-induced bronchial hyperreactivity in conscious sensitized guinea-pigs and airway leukocyte infiltration.
1. The aim of this study was to determine the effects of inhibitors of phosphodiesterase (PDE) on the early and late phase bronchoconstriction in sensitized, conscious guinea-pigs and the subsequent development of acute airway hyperreactivity to the inhaled thromboxane mimetic, U46619, and leukocyte infiltration following ovalbumin (OvA) challenge. 2. Following an inhalation challenge with OvA, there was an early bronchoconstriction which peaked at 15 min with recovery after 3-4 h. A late phase bronchoconstriction occurred between 17 and 24 h after challenge. The PDE 4 inhibitors, Ro 20-1724 (3 mg kg-1, i.p.) and rolipram (1 mg kg-1, i.p.) administered 30 min before and 6 h after antigen challenge (double dosing regimen), did not affect the development of the early or late phase responses. 3. Seventeen to twenty four hours following an acute OvA or saline challenge, a consistently greater bronchoconstrictor response to inhaled U46619 was observed in the OvA challenged group. This increase in responsiveness was significantly attenuated by the administration of Ro 20-1724 and rolipram 30 min before and 6 h after antigen challenge (P < 0.05); this was not attributable to a residual bronchodilator effect of these compounds. There was a trend towards inhibition of the hyperreactivity to U46619 by aminophylline but not by the PDE3 inhibitors, siguazodan or SKF 95654. 4. Aminophylline, rolipram and Ro 20-1724 when administered as the double dose regimen attenuated the rise in macrophages, eosinophils and neutrophils recovered in bronchial lavage fluid 17 to 24 h after antigen challenge. 5. The dose of Ro 20-1724 given at 6 h post challenge was essential for attenuation of airway hyperreactivity and to protect against leukocyte influx. 6. In summary, aminophylline, rolipram and Ro 20-1724 have anti-inflammatory effects against antigen-induced airway leukocyte infiltration. Rolipram and Ro 20-1724 additionally attenuated the development of acute airway hyperreactivity, effects which are probably mediated through inhibition of PDE type 4. A dose of PDE inhibitor 6 h after the antigen challenge appears to be essential to achieve this protection. Inhibitors of PDE type 3 were generally without effect. However, there was no effect of rolipram or Ro 20-1724 on the development of either the early or late phase type responses.
Danahay
H
H
Pharmacology Department, Welsh School of Pharmacy, University of Wales Cardiff.
Broadley
K J
KJ
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000627:therapeutic use; D000628:Aminophylline / Q000627:therapeutic use; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000517:prevention & control*; D006168:Guinea Pigs; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011760:Pyrrolidinones / Q000627:therapeutic use; D020889:Rolipram; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011760:Pyrrolidinones; D000628:Aminophylline; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D010047:Ovalbumin; D020889:Rolipram