Inhibition of adenosine uptake and augmentation of ischemia-induced increase of interstitial adenosine by cilostazol, an agent to treat intermittent claudication

Cilostazol (Pletal), a quinolinone derivative with a cyclic nucleotide phos phodiesterase type 3 (PDE3) inhibitory activity, was recently approved by t he Food and Drug Administration for treatment of symptoms of intermittent c laudication (IC). However, the underlying mechanisms of action are not enti rely clear, In this study, we showed that cilostazol inhibited adenosine up take into cardiac ventricular myocytes, coronary artery smooth muscle, and endothelial cells with a median effective concentration (EC50) similar to 1 0 mu M. In vivo, cilostazol increased cardiac interstitial adenosine levels after a 2-min ischemia in rabbit hearts (329 +/- 92% increase vs. 102 +/- 29% ischemia alone). The combination of cilostazol and 2-min ischemia reduc ed infarction from subsequent 30-min regional ischemia and 3 h of reperfusi on (infarct size was 18 +/- 4% vs. 53 +/- 3% in the hearts with 2-min ische mia alone or 48 +/- 2% in the hearts treated with cilostazol alone). In con trast, milrinone had no effect on either adenosine uptake or interstitial a denosine levels. These data show that cilostazol, unlike milrinone, inhibit s adenosine uptake, and thus potentiates adenosine accumulation from a 2-mi n ischemia. Future studies are needed to investigate the role of adenosine in the treatment of IC by cilostazol.