ANTIINFLAMMATORY AND BRONCHODILATOR PROPERTIES OF RP-73401, A NOVEL AND SELECTIVE PHOSPHODIESTERASE TYPE-IV INHIBITOR

1 We have investigated the effects of RP 73401, a novel, potent and hi ghly selective cyclic nucleotide phosphodiesterase (PDE) type IV inhib itor, in guinea-pig and rat models of bronchoconstriction and allergic inflammation. In some models, the effects of RP 73401 have been compa red with those of the standard PDE type IV inhibitor, rolipram. 2 RP 7 3401 (0.4-400 mu g kg(-1) intratracheally (i.t.) on lactose) inhibited antigen-induced bronchospasm in previously sensitized conscious guine a-pigs (ID50: 7 +/- 1 mu g kg(-1)) and in anaesthetized rats (ID,,: 10 0 +/- 25 mu g kg(-)1). Rolipram inhibited the antigen-induced bronchos pasm in guinea-pigs with an ID50 of 5 +/- 1 mu g kg(-1). In guinea-pig bronchoalveolar lavage (BAL) fluid, total inflammatory cell and eosin ophil numbers were reduced by RP 73401 (ID(50)s: 3.9 +/- 0.8 mu g kg(- 1) and 3.2 +/- 0.7 mu g kg(-1), respectively). In the rat, inflammator y cell numbers are less affected. Only the highest dose of RP 73401 (4 00 mu g kg(-1)) significantly inhibited eosinophil influx (41 +/- 16% inhibition). 3 RP 73401 (0.02-100 mu g kg(-1), i.v.) inhibited PAF-ind uced bronchial hyperreactivity to bombesin in the anaesthetized guinea -pig (ID50: 0.09 +/- 0.03 mu g kg(-1)) and inhibited (0.4-40 mu g kg(- 1), i.t.) histamine-induced airway microvascular leakage in the anaest hetized guinea-pig by approximately 60% at all doses. 4 RP 73401 relax ed guinea-pig isolated trachea under basal tone (EC(50): 9 nM) and whe n precontracted with histamine (IC50: 2 nM), methacholine (IC50: 29 nM ) or leukotriene D-4 (LTD(4), IC50: 4 nM). 5 RP 73401 (0.4-100 mu g kg (-1), i.t.) inhibited bronchospasm induced by histamine (ID50: 34 +/- 6 mu g kg(-1)), methacholine (ID50: 66 +/- 12 mu g kg(-1)) and LTD(4) (ID50: <4 mu g kg(-1)) in the anaesthetized guinea-pig. Against these same bronchoconstrictors, rolipram (i.t.) had ID50 values of 44 +/- 4, 72 +/- 18 and <4 mu g kg(-1) respectively. RP 73401 (4 and 40 mu g kg (-1), i.t.) increased the magnitude and duration of bronchodilatation produced by salbutamol in the anaesthetized guinea-pig. At doses produ cing significant bronchodilatation, RP 73401 was without effect on hea rt rate or blood pressure in the anaesthetized guinea-pig. RP 73401 (0 .01-0.25 mg kg(-1), i.v.) did not affect heart rate and produced only a small fall in blood pressure in the anaesthetized rat. 6 These data demonstrate that RP 73401 and rolipram inhibit antigen- and mediator-i nduced bronchospasm in guinea-pigs with the same potency. Furthermore, RP 73401 administered directly into the airways, protects against all ergic airway inflammation. These results indicate the importance of PD E IV in regulating smooth muscle and inflammatory cell activity. At do ses suppressing the inflammatory response in the lung, RP 73401 had li ttle effect in the cardiovascular system. RP 73401 may have a role as a bronchodilator and, more importantly, as a prophylactic anti-inflamm atory agent in the treatment of asthma.