Interplay between inhibition of adenosine uptake and phosphodiesterase type 3 on cardiac function by cilostazol, an agent to treat intermittent claudication

The authors have recently shown that cilostazol, a type 3 cyclic nucleotide phosphodiesterase (PDE3) inhibitor, has a much weaker positive inotropic e ffect than milrinone, a PDE3 inhibitor of similar potency. They have also s hown that cilostazol inhibits adenosine uptake, whereas milrinone has no su ch effect. This study investigated the possible cardiac functional signific ance of cilostazot on adenosine uptake inhibition. In isolated rabbit heart s, 10 muM of cilostazol elevated adenosine concentration in interstitial di alysate (0.16 +/- 0.01 muM, or similar to0.81 muM in the interstitial space when adjusted for recovery rate of microdialysis) and coronary effluent (0 .69 +/- 0.03 muM The values are significantly higher than those for 10 muM of milrinone (0.11 +/- 0.1 muM in interstitial dialysate and 0.2 +/- 0.04 m uM in coronary effluent). Although cilostazol increased contractility, hear t rate, and coronary flow in isolated rabbit hearts, the effect on contract ility and heart rate was significantly augmented in the presence of an aden osine A(1) receptor antagonist. Conversely, an adenosine A(1) receptor agon ist or an adenosine uptake inhibitor attenuated the positive inotropic effe ct of milrinone. These results indicate that adenosine uptake inhibition by cilostazol increases interstitial and circulatory adenosine concentration, and antagonizes PDE3 inhibition-induced contractility and heart rate incre ases through an adenosine At receptor-mediated mechanism.