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Isoproterenol‐ and iloprost‐induced ATP release is enhanced by selective phosphodiesterase inhibition in human erythrocytes (RBCs)
Author(s) -
Adderley Shaquria,
DuFaux Eileen,
Sridharan Meera,
Hanson Madelyn,
Bowles Elizabeth,
Stephenson Alan,
Sprague Randy
Publication year - 2009
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.23.1_supplement.767.13
Subject(s) - rolipram , ehna , phosphodiesterase 3 , phosphodiesterase , chemistry , iloprost , zaprinast , phosphodiesterase inhibitor , pharmacology , agonist , milrinone , microbiology and biotechnology , biochemistry , endocrinology , enzyme , receptor , biology , prostacyclin , inotrope , adenosine deaminase
Previously, we reported that the β agonist, isoproternol (ISO), and the PGI 2 analog, iloprost (ILO), stimulate increases in cAMP and ATP release from RBCs and that increases in cAMP are a requisite for this ATP release. Accumulation of cAMP depends on a balance between its synthesis and hydrolysis by phosphodiesterases (PDEs). Recently, we reported that PDE3B is present in human RBC membranes and that PDE3 inhibitors potentiate ILO‐induced increases in cAMP. In contrast, PDEs 2 and 4 regulate ISO‐induced increases in cAMP in human RBCs. Here we hypothesized that, based upon their effects on cAMP accumulation, PDE3 inhibitors will augment ILO‐induced ATP release while inhibitors of PDEs 2 and 4 will augment ISO‐induced ATP release from human RBCs. Pretreatment of RBCs with the PDE3 inhibitor, cilostazol (10 μM), augmented ILO (10 nM)‐induced ATP release (n=9, P <0.05). On the contrary, pretreatment of RBCs with either the selective PDE2 inhibitor, EHNA (30µM), or the PDE4 inhibitor, rolipram (20 μM), alone had no effect on ISO (1µM)‐induced ATP release. However, the combination of EHNA and rolipram potentiated the ISO‐induced ATP release (n=11, P <0.05). These results provide strong support for the hypothesis that increases in cAMP and ATP release produced by ILO and ISO are regulated by different PDEs that are specific to each signaling pathway. Supported by NIH grants HL‐64180 and HL‐89094 and ADA grant RA‐133.