Cilostazol, a PDE3 (phosphodiesterase 3) inhibitor, enhances prostacyclin receptor‐mediated cAMP accumulation and ATP release in erythrocytes (RBCs) of healthy humans (HH) and humans with type 2 diabetes (DM2)

Abstract

Erythrocytes (RBCs) release ATP when exposed to low oxygen tension (O2), thus matching O2 supply with O2 need in skeletal muscle. Activation of a different pathway, the Gs‐coupled prostacyclin receptor (IPR), results in cAMP accumulation and ATP release from RBCs of HH and DM2. DM2 RBCs, however, demonstrate higher levels of cAMP accumulation and ATP release upon incubation with prostacyclin analog, iloprost (ILO 1μM), when compared to HH RBCs. Previously, we established that PDE3 hydrolyzes cAMP in the IPR‐mediated pathway, limiting cAMP accumulation, and therefore, ATP release from RBCs. Here we investigate the hypothesis that PDE3 activity is decreased in DM2 RBCs, which would explain the increased ILO‐induced cAMP accumulation and ATP release. Pretreatment of RBCs with the selective PDE3 inhibitor cilostazol eliminated differences in ILO‐induced cAMP accumulation and ATP release between DM2 and HH RBCs. Similar results were seen using the prostacyclin analog UT15C. These data suggest that decreased PDE3 activity in DM2 RBCs is responsible for increased cAMP levels and ATP release upon IPR activation. Supported by grants from United Therapeutics and American Diabetes Association.