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 effect than milrinone, a PDE3 inhibitor of similar potency. They have also shown that cilostazol inhibits adenosine uptake, whereas milrinone has no such effect. This study investigated the possible cardiac functional significance of cilostazol on adenosine uptake inhibition. In isolated rabbit hearts, 10 microM of cilostazol elevated adenosine concentration in interstitial dialysate (0.16 +/- 0.01 microM, or approximately 0.81 microM in the interstitial space when adjusted for recovery rate of microdialysis) and coronary effluent (0.69 +/- 0.03 microM ). The values are significantly higher than those for 10 microM of milrinone (0.11 +/- 0.1 microM in interstitial dialysate and 0.2 +/- 0.04 microM in coronary effluent). Although cilostazol increased contractility, heart rate, and coronary flow in isolated rabbit hearts, the effect on contractility and heart rate was significantly augmented in the presence of an adenosine A 1 receptor antagonist. Conversely, an adenosine A 1 receptor agonist or an adenosine uptake inhibitor attenuated the positive inotropic effect 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 increases through an adenosine A 1 receptor-mediated mechanism.