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 nucleotide phosphodiesterase type 4 (PDE 4) inhibitor, was evaluated in guinea-pig models (in vitro and in vivo) of bronchospasm, ozone-induced airway hyperresponsiveness (AHR) and non-cholinergic bronchoconstriction. Comparisons were made with (i) other PDE 4 inhibitors: CT1731 (S-enantiomer of CDP840), rolipram, RP73401 and (ii) the clinically used agents salbutamol and theophylline. 2 CDP840 relaxed isolated trachea, under basal tone (EC(50) 4.5+/-1.1 mu M) being 17 fold less potent than rolipram (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 observed with CT1731 against either carbachol (IC25 33+/-11 mu M) or histamine (IC25 17+/-10 mu M). Aminophylline was 1.6 fold (carbachol) and 11 fold (histamine) less potent than CDP840. Rolipram and RP73401 produced tri-phasic relaxation curves but were of similar potency (at the IC25 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 producing >30% (carbachol) and >60% (histamine) relaxation these inhibitors had similar potency and were poor compared to salbutamol. 4 Pre-incubation with CDP840 (10 mu M) did not antagonize histamine-induced contraction of isolated trachea; however, it did cause a slight potentiation 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 or antagonize bronchospasm due to inhaled histamine in anaesthetized, ventilated guinea-pigs. Salbutamol (1 mg kg(-1), i.p.) did not bronchodilate but caused a parallel 7 fold rightward shift in the histamine dose-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 bronchospasm to inhaled substance P. 7 CDP840 (1-10 mu g kg(-1) i.p.) dose relatedly 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 was inhibited by CDP840 in a dose-related manner, 10 mu g kg(-1) abolishing 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. administration. 8 CDP840 is a poor spasmolytic and anti-spasmogenic agent in response 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 contributes 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 asthma.