Comparison of the effects of selective inhibitors of phosphodiesterase types III and IV in airway smooth muscle with differing β‐adrenoceptor subtypes

Abstract

1 The relaxant properties of the type IV adenosine 3',5'-cyclic monophosphate phosphodiesterase (cyclic AMP PDE) inhibitor, rolipram and the P2-selective and non-selective P-adrenoceptor agonists salbutamol and isoprenaline, were compared on the guinea-pig, bovine, and mouse trachea and porcine bronchus all precontracted with methacholine (EC30).2 Rolipram and both P-agonists produced concentration-dependent reversal of the methacholineinduced tone in the four airway preparations.3 Isoprenaline and salbutamol were similar in potency on the guinea-pig 8.06) and bovine (-loglo IC50:8.52, 8.40) airways. In contrast, salbutamol was much less potent than isoprenaline on the mouse trachea (>1000 fold) and the porcine bronchus (>100 000 fold). 4 The potency of rolipram approached that of isoprenaline on the guinea-pig and bovine trachea (132-adrenoceptors predominate). However, rolipram was significantly less active than isoprenaline on the porcine bronchus (1000 fold) and mouse trachea (>2000 fold) where P2-adrenoceptors predominate.5 Siguazodan, the type III cyclic AMP PDE inhibitor, produced concentration-dependent relaxations of the porcine bronchus and guinea-pig trachea contracted with methacholine. Siquazodan was 100 fold more active than rolipram in pig tissues indicating the type III isoenzyme may be of greater functional significance in this tissue. In contrast, siguazodan was 15 times less potent that rolipram in guinea-pig airways suggesting a greater role for the type IV PDE.6 These findings may reflect a possible relationship between the P2-adrenoceptor subtype and the functional importance of the type IV PDE isoenzyme. A similar relationship may exist between P,-adrenoceptors and the PDE type III isoenzyme.

Effects of rolipram and siguazodan on the human isolated bronchus and their interaction with isoprenaline and sodium nitroprusside

“…Sodium nitroprusside-induced relaxation was not modified by either drug. 5 These results show that rolipram is a potent relaxant of the human isolated bronchus, potentiating the effects of P-adrenoceptor stimulation and suggest that, as previously demonstrated in other species (guinea-pig, cow) (Tomkinson et al, 1993), there may be a connection between the P2-adrenoceptor subtype, which predominate in human airway smooth muscle, and the cyclic AMP phosphodiesterase type IV. …”

“…They also demonstrated that siguazodan was 100 fold more active than rolipram on porcine tissues but 15 times less potent on guinea-pig airways. On the basis of these results, Tomkinson et al (1993) suggested that there might be a connection between the P-adrenoceptor subtype which predominates in a given tissue and the functional importance of the PDE isoenzyme in reducing smooth muscle contractility. They reported that PDE types I, II, IV and V can be isolated by ion-exchange chromatography from human, isolated bronchial muscle.…”

β 2 -Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids

“…In this regard, there is persuasive evidence suggesting that the classical bronchodilatory effects of β-adrenoceptor agonists are mediated via the β 1 , rather than the β 2 , subtype in the mouse (39). Thus, β 2 -adrenoceptor agonists are poor bronchodilators in the mouse, and this explains why nonselective agonists are more effective and potent bronchodilators than β 2 -selective agonists (40). Nevertheless, our data clearly show that β 2 -adrenoceptor agonists induce the expression of Rgs2 and that this leads to a significant nonredundant bronchoprotective effect that is absent in Rgs2 −/− animals.…”

Pulmonary effects of type V cyclic GMP specific phosphodiesterase inhibition in the anaesthetized guinea‐pig

“…More recently, however, interest has focused on the potential of isoenzyme-selective PDE inhibitors as bronchodilator and anti-inflammatory agents. Selective inhibitors of the PDE III and IV isoenzymes are effective relaxants of guinea-pig trachea (Harris et al, 1989;Tomkinson et al, 1993), canine trachealis (Torphy et al, 1988;, bovine trachea (PDE III inhibitors are only weakly active, Shahid et al, 1991) and human bronchus (de Boer et '." Macmillan Press Ltd, 1994Cortijo et al, 1993) in vitro and have bronchodilator activity in the guinea-pig (Harris et al, 1989;Cortijo et al, 1993;Howell et al, 1993) and dog (Heaslip et al, 1991) in vivo.…”