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The Phosphodiesterase 3 (PDE3) Inhibitor, Cilostazol, Rescues Low O2‐induced ATP Release from Erythrocytes (RBCs) of Humans with Type 2 Diabetes (DM2) Restoring Their Ability to Dilate Skeletal Muscle Arterioles
Author(s) -
Sprague Randy S,
Stephenson Alan H,
Bowles Elizabeth A,
Achilleus David,
Ellsworth Mary L
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1023.14
Subject(s) - phosphodiesterase 3 , phosphodiesterase , vasodilation , skeletal muscle , medicine , chemistry , vascular smooth muscle , perfusion , endocrinology , cilostazol , arteriole , microcirculation , microbiology and biotechnology , biology , biochemistry , enzyme , smooth muscle , aspirin
Healthy human (HH) RBCs exposed to low O 2 release ATP via a pathway requiring increases in cAMP levels which are regulated by PDE3. Isolated skeletal muscle arterioles perfused with these cells dilate when exposed to similar decreases in extraluminal O 2. In contrast, DM2 RBCs neither release ATP nor stimulate dilation of arterioles under the same conditions. We investigated the hypothesis that inhibition of PDE3 would rescue low O 2 ‐induced ATP release from DM2 RBCs and permit these cells to stimulate vasodilation. RBCs were exposed to low PO 2 (~10 mmHg) and ATP release was determined in the absence or presence of the PDE3 inhibitor, cilostazol (CZ, 100 μM). In the absence of CZ, ATP release from HH (n=6) and DM2 (n=7) RBCs increased by 126±54 (p<0.05) and 10±17% (NS), respectively. Pretreatment of DM2 RBCs with CZ (n=7) augmented low O 2 ‐induced ATP release (105±46%, P<0.05) and restored the ability of DM2 RBCs to stimulate dilation of perfused arterioles exposed to reduced extraluminal O 2 . These findings are consistent with the hypothesis that decreased ATP release from DM2 RBCs may contribute to peripheral vascular disease due to failure of a control mechanism for the regulation of perfusion distribution to meet tissue O 2 needs. Importantly, these studies suggest that PDE3 inhibitors could improve this defect via a heretofore unrecognized effect on RBCs. [Supported by NIH grant HL‐89094 and a Presidential Grant from SLU].