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The beta-adrenoceptor agonists, isoprenaline, salbutamol and salmeterol, the non-selective phosphodiesterase (PDE) isoenzyme inhibitors, theophylline, trequinsin; the PDE3 isoenzyme inhibitor, milrinone; the PDE3/4 isoenzyme inhibitor, benzafentrine; and the PDE4 isoenzyme inhibitors, denbufylline, nitraquazone, RP 73401, Ro-20-1724, rolipram and tibenelast all induced concentration-dependent reversal of prostaglandin F2α-induced contraction of guinea-pig supervised trachea in vitro . The relaxant response of the non-selective PDE isoenzyme inhibitor trequinsin was slow in onset and demonstrated very slow recovery, similar to that observed with the long-acting beta 2 -adrenoceptor agonist, salmeterol and the PDE4 inhibitor, RP 73401. The relaxant agonists also significantly reversed bombesin-induced bronchospasm in anaesthetised guinea-pigs and there was a highly significant correlation between the ability of drugs to reverse PGF2α-induced contraction of guinea-pig isolated trachea in vitro and bombesin-induced bronchoconstriction in vivo . Furthermore, both salmeterol and trequinsin demonstrated long lasting bronchodilator responses consistent with the in vitro data. These results show that PDE isoenzyme inhibitors demonstrate different pharmacodynamic profiles that is not determined by PDE4 inhibitory potency and indicate that other factors may be important in this regard.

Phosphodiesterases (PDEs) are responsible for the hydrolysis of cAMP and cGMP which act as intracellular second messengers in a variety of cellular functions. In this paper we report that PDE3 and PDE4 were two dominant classes of PDEs expressed in HL60 cells. The influence of specific PDE inhibitors on apoptosis in HL60 cells was studied. The non-specific inhibitor IBMX and PDE3 specific inhibitors (milrinone and trequinsin) did not promote apoptosis. They inhibited apoptosis induced by paclitaxel or thapsigargin. However, PDE4 specific inhibitors (rolipram and RO-20-1724) promoted apoptosis within 5 h. In HL60 cells, other cAMP-eliciting reagents (8-bromo-cAMP, Sp-cAMP and forskolin) also inhibited apoptosis, while cell-permeable cGMP analogs did not affect apoptosis. Therefore, IBMX and PDE3 specific inhibitors may prevent HL60 cells from apoptosis by increasing intracellular cAMP. However, apoptosis induced by PDE4 specific inhibitors is not likely due to increased cAMP level. These results suggest that rolipram and RO-20-1724 promoted apoptosis in HL60 cells through cAMP-independent mechanism.

The new pyrimido-isoquinoline compound HL 725 is an extremely potent inhibitor of the aggregation of human platelets induced in vitro by ADP, collagen, thrombin and epinephrine. The aggregation induced by 0,5 mM arachidonic acid is inhibited about 50 % with 50 pM HL 725. Thus the potency of HL 725 is higher than that of prostacyclin, the most active natural inhibitor of aggregation. We hypothesize that HL 725 inhibits the enzymatic degradation of cyclic adenosine 3′, 5′-monophosphate (cAMP) in the platelets. In accordance with this proposal is the strong inhibitory action on cAMP phosphodiesterase extracted from human platelets. About 250 pM HL 725 inhibited 50 % of the activity of this enzyme at a substrate concentration of 0.5 μM. A marked elevation of cAMP levels in human platelets could be demonstrated after incubation in vitro with 100 nM HL 725.