The effect of SK&F 95654, a novel phosphodiesterase inhibitor, on cardiovascular, respiratory and platelet function

Abstract

SK&F 95654 inhibited the guanosine 3′:5′‐cyclic monophosphate (cyclic GMP)‐inhibited phosphodiesterase (cGI‐PDE) with an IC50 value of 0.7 μm. The IC50 values were greater than 100 μm for the other four phosphodiesterase isoenzymes tested. The R‐enantiomer of SK&F 95654 (IC50 = 0.35 μm) was a more potent inhibitor of cGI‐PDE than was the S‐enantiomer (IC50 = 5.3 μm). In the guinea‐pig working heart, SK&F 95654 produced a positive inotropic response without altering heart rate. Oral administration of SK&F 95654 to conscious dogs caused dose‐dependent increases in left ventricular dp/dtmax in the range 10–50 μg kg−1. These positive inotropic responses were maintained for 3 h without simultaneous changes in heart rate or blood pressure. The peak effects on left ventricular dp/dtmax were similar for orally and intravenously administered compound, indicating good oral bioavailability. SK&F 95654 caused a potent inhibition of U46619‐induced aggregation in both a human washed platelet suspension (WPS) (IC50 = 70 nm) and in human platelet‐rich plasma (PRP) (IC50 = 60 nm), indicating that the compound shows negligible plasma binding. The R‐enantiomer of SK&F 95654 was twenty fold more potent as an inhibitor of platelet aggregation than was the S‐enantiomer. The similarity of this ratio to that obtained on the cGI‐PDE suggests that SK&F 95654 inhibits platelet aggregation via its effects on cGI‐PDE. This was also indicated by studies which showed that SK&F 95654 increased adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) levels and activated cyclic AMP‐dependent protein kinase in human platelets. 6 Collagen‐induced aggregation of rat PRP was also inhibited by SK&F 95654 (IC50 = 65 nm). The effects of SK&F 95654, administered intravenously, on ex vivo platelet aggregation were studied in the conscious rat. At 1 mg kg−1, SK&F 95654 inhibited aggregation for at least 4 h post dose and was more potent than the two other cGI‐PDE inhibitors studied (siguazodan and SK&F 94120). 7 In contrast to its potent effects on heart and platelets, SK&F 95654 caused only a modest relaxation of histamine‐ or U46619‐induced bronchoconstriction in the anaesthetized, ventilated guinea‐pig. 8 Taken together, these results indicate that SK&F 95654 may be a suitable agent for the treatment of congestive heart failure. 1992 British Pharmacological Society