INHIBITION OF BRONCHOSPASM AND OZONE-INDUCED AIRWAY HYPERRESPONSIVENESS IN THE GUINEA-PIG BY CDP840, A NOVEL PHOSPHODIESTERASE TYPE-4 INHIBITOR

1 The activity of CDP840, a novel, potent and selective cyclic nucleot ide phosphodiesterase type 4 (PDE 4) inhibitor, was evaluated in guine a-pig models (in vitro and in vivo) of bronchospasm, ozone-induced air way hyperresponsiveness (AHR) and non-cholinergic bronchoconstriction. Comparisons were made with (i) other PDE 4 inhibitors: CT1731 (S-enan tiomer of CDP840), rolipram, RP73401 and (ii) the clinically used agen ts salbutamol and theophylline. 2 CDP840 relaxed isolated trachea, und er basal tone (EC(50) 4.5+/-1.1 mu M) being 17 fold less potent than r olipram (EC(50) 0.26+/-0.13 mu M) but attaining the same E(max) (83+/- 6% of the response to 300 mu M papaverine). 3 CDP840 relaxed tracheae pre-contracted with carbachol (IC25 39+/-9 mu M) and histamine (IC25 4 +/-1 mu M) producing monophasic curves. Stereoselectivity was not obse rved with CT1731 against either carbachol (IC25 33+/-11 mu M) or hista mine (IC25 17+/-10 mu M). Aminophylline was 1.6 fold (carbachol) and 1 1 fold (histamine) less potent than CDP840. Rolipram and RP73401 produ ced tri-phasic relaxation curves but were of similar potency (at the I C25 level) to CDP840 against carbachol (rolipram 18+/-5 mu M, RP73401 39+/-1 mu M) whereas against histamine they were approximately 20 fold more potent (rolipram 0.2+/-0.1 mu M, RP73401 0.2+/-0.1 mu M). In pro ducing >30% (carbachol) and >60% (histamine) relaxation these inhibito rs had similar potency and were poor compared to salbutamol. 4 Pre-inc ubation with CDP840 (10 mu M) did not antagonize histamine-induced con traction of isolated trachea; however, it did cause a slight potentiat ion of the subsequent relaxation to salbutamol (IC50 23+/-1 to 15+/-2 nM) 5 Pretreatment (1 h) with either CDP840 (1 mg kg(-1), i.p. or 3 mg kg(-1), i.v.) or rolipram (1 mg kg(-1), i.p.) did not bronchodilate o r antagonize bronchospasm due to inhaled histamine in anaesthetized, v entilated guinea-pigs. Salbutamol (1 mg kg(-1), i.p.) did not bronchod ilate but caused a parallel 7 fold rightward shift in the histamine do se-response curve. 6 Stimulation of the vagus nerve in the presence of atropine resulted in a frequency-related bronchoconstriction. CDP840 and rolipram (i.v.) inhibited the response being similar to equipotent (EC(50) similar to 10 mu g kg(-1)). Neither drug inhibited bronchospa sm to inhaled substance P. 7 CDP840 (1-10 mu g kg(-1) i.p.) dose relat edly inhibited ozone-induced bronchoconstriction. CT1731 (1 mg kg(-1)) , rolipram (1 mg kg(-1)), RP73401 (10 mu g kg(-1)) and aminophylline ( 10 mg kg(-1)) had no effect. Ozone-induced AHR to inhaled histamine wa s inhibited by CDP840 in a dose-related manner, 10 mu g kg(-1) abolish ing the AHR. This effect was stereoselective as CT1731 was similar to 30 fold less potent than CDP840. Rolipram was similar to 100 fold less potent and RP73401 and aminophylline had no effect. CDP840 was orally active being similar to 10 fold less potent compared to i.p. administ ration. 8 CDP840 is a poor spasmolytic and anti-spasmogenic agent in r esponse to exogenous mediators; however, it potently inhibits vagally mediated non-cholinergic bronchoconstriction and ozone-induced AHR to histamine. It is possible that regulation of cyclic AMP by PDE 4 contr ibutes to neuronal sensitivity in the airways. Furthermore, CDP840 may suppress AHR without being an overt bronchodilator. Such a profile of activity may have therapeutic benefit in airways diseases such as ast hma.