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Synergistic effects of prostacyclin analogs and PDE5 inhibitors on ATP release from erythrocytes (RBCs): implications for the treatment of pulmonary hypertension
Author(s) -
Sprague Randy S,
Elrick Mollisa M,
Bowles Elizabeth A,
Zdanovec Amber K,
Stephenson Alan H,
Ellsworth Mary L
Publication year - 2012
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.26.1_supplement.873.6
Subject(s) - prostacyclin , vasodilation , iloprost , agonist , chemistry , pharmacology , pulmonary hypertension , receptor , medicine , biochemistry
Idiopathic pulmonary arterial hypertension (IPAH) is a disease of uncertain etiology that leads to right ventricular failure and death. IPAH treatment includes the vasodilators: prostacyclin (PGI 2 ), other PGI 2 receptor agonists and phosphodiesterase 5 (PDE5) inhibitors. We reported that: 1) RBC‐derived ATP vasodilates isolated‐perfused lungs, 2) RBCs possess PGI 2 receptors and 3) PGI 2 analogs stimulate ATP release from RBCs via a signaling pathway that requires increases in cAMP. Here we investigated the hypothesis that PDE5 inhibitors can enhance PGI 2 agonist‐induced ATP release from human RBCs. ATP release from RBCs was measured in the absence and presence of the PGI 2 agonist, UT‐15C or its vehicle, saline, alone or in combination with the selective PDE5 inhibitor, zapranist (ZAP, 10 μM). Compared to control cells, UT‐15C (1 uM) treated RBCs (n=7) demonstrated an increase in ATP release that was potentiated by ZAP pretreatment (p>0.05). When RBCs were incubated with UT‐15C at 30 (n=7) or 100 nM (n=7), no ATP release was detected. However, when the same cells were pretreated with ZAP, ATP release was stimulated by both concentrations of UT‐15C. These results provide an alternative mechanism by which PGI 2 agonists and PDE5 inhibitors interact to stimulate pulmonary vasodilation making RBCs novel targets for development of new therapies for IPAH. Supported by ADA, NIH and United Therapeutics.