Anti‐inflammatory and bronchodilator properties of RP 73401, a novel and selective phosphodiesterase type IV inhibitor

• Published in: British journal of pharmacology Vol. 113; no. 4; pp. 1423 - 1431
• Main Authors: Raeburn, David, Underwood, Stephen L., Lewis, Susan A., Woodman, Valerie R., Battram, Cliff H., Tomkinson, Adrian, Sharma, Steven, Jordan, Roy, Souness, John E., Webber, Stephen E., Karlsson, Jan‐Anders
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-1994; Nature Publishing
• Subjects: Albuterol - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; antiasthmatic; anti‐inflammatory; Benzamides - pharmacology; Biological and medical sciences; Bronchial Hyperreactivity - physiopathology; Bronchial Spasm - drug therapy; Bronchial Spasm - physiopathology; bronchodilator; Bronchodilator Agents - pharmacology; bronchospasm; Capillary Permeability - drug effects; Guinea Pigs; Hemodynamics - drug effects; Histamine - pharmacology; inflammation; Inflammation - pathology; Male; Medical sciences; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Pharmacology. Drug treatments; Phosphodiesterase inhibitor; Phosphodiesterase Inhibitors - pharmacology; Platelet Activating Factor - antagonists & inhibitors; Platelet Activating Factor - pharmacology; Pyridines - pharmacology; Pyrrolidinones - pharmacology; Rats; Rats, Sprague-Dawley; Respiratory system; rolipam; Rolipram; RP 73401; salbutamol; 3',5'-Cyclic-nucleotide phosphodiesterase; Rat; Enzyme; Isozyme; Rodentia; Antiinflammatory agent; Enzyme inhibitor; Smooth muscle; Esterases; Phosphoric diester hydrolases; Muscular relaxation; Vertebrata; Mammalia; Guinea pig; Animal; Hydrolases; Comparative study
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1994.tb17156.x

1
We have investigated the effects of RP 73401, a novel, potent and highly selective cyclic nucleotide phosphodiesterase (PDE) type IV inhibitor, in guinea‐pig and rat models of bronchoconstriction and allergic inflammation. In some models, the effects of RP 73401 have been compared with those of the standard PDE type IV inhibitor, rolipram.
2
RP 73401 (0.4–400 μg kg−1, intratracheally (i.t.) on lactose) inhibited antigen‐induced bronchospasm in previously sensitized conscious guinea‐pigs (ID50: 7 ± 1 μg kg−1) and in anaesthetized rats (ID50: 100 ± 25 μg kg−1). Rolipram inhibited the antigen‐induced bronchospasm in guinea‐pigs with an ID50 of 5 ± 1 μg kg−1. In guinea‐pig bronchoalveolar lavage (BAL) fluid, total inflammatory cell and eosinophil numbers were reduced by RP 73401 (ID50s: 3.9 ± 0.8 μg kg−1 and 3.2 ± 0.7 μg kg−1, respectively). In the rat, inflammatory cell numbers are less affected. Only the highest dose of RP 73401 (400 μg kg−1) significantly inhibited eosinophil influx (41 ± 16% inhibition).
3
RP 73401 (0.02–100 μg kg−1, i.v.) inhibited PAF‐induced bronchial hyperreactivity to bombesin in the anaesthetized guinea‐pig (ID50: 0.09 ± 0.03 μg kg−1) and inhibited (0.4–40 μg kg−1, i.t.) histamine‐induced airway microvascular leakage in the anaesthetized guinea‐pig by approximately 60% at all doses.
4
RP 73401 relaxed guinea‐pig isolated trachea under basal tone (EC50: 9 nm) and when precontracted with histamine (IC50: 2 nm), methacholine (IC50: 29 nm) or leukotriene D4 (LTD4, IC50: 4 nm).
5
RP 73401 (0.4–100 μg kg−1, i.t.) inhibited bronchospasm induced by histamine (ID50: 34 ± 6 μg kg−1), methacholine (ID50: 66 ± 12 μg kg−1) and LTD4 (ID50: < 4 μg kg−1) in the anaesthetized guinea‐pig. Against these same bronchoconstrictors, rolipram (i.t.) had ID50 values of 44 ± 4, 72 ± 18 and < 4 μg kg−1 respectively. RP 73401 (4 and 40 μg kg−1, i.t.) increased the magnitude and duration of bronchodilatation produced by salbutamol in the anaesthetized guinea‐pig. At doses producing significant bronchodilatation, RP 73401 was without effect on heart 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‐induced bronchospasm in guinea‐pigs with the same potency. Furthermore, RP 73401 administered directly into the airways, protects against allergic airway inflammation. These results indicate the importance of PDE IV in regulating smooth muscle and inflammatory cell activity. At doses suppressing the inflammatory response in the lung, RP 73401 had little effect in the cardiovascular system. RP 73401 may have a role as a bronchodilator and, more importantly, as a prophylactic anti‐inflammatory agent in the treatment of asthma.