Faculty Collaboration Database

Synergistic effects of prostacyclin analogs and phosphodiesterase inhibitors on cyclic adenosine 3',5' monophosphate accumulation and adenosine 3'5' triphosphate release from human erythrocytes. Exp Biol Med (Maywood) 2013 Sep;238(9):1069-74

Date

08/30/2013

Pubmed ID

23986226

DOI

10.1177/1535370213498981

Scopus ID

2-s2.0-84884265442 (requires institutional sign-in at Scopus site)   18 Citations

Abstract

Prostacyclin (PGI2) and phosphodiesterase 5 (PDE5) inhibitors are potent vasodilators that are used alone and in combination for the treatment of pulmonary arterial hypertension (PAH). Although these vasodilators are known to stimulate relaxation of vascular smooth muscle directly, other cells in circulation, including erythrocytes, express prostacyclin receptor (IPR) and contain PDE5. The binding of PGI2 analogs to the erythrocyte IPR results in activation of a signaling pathway that increases cyclic adenosine 3',5' monophosphate (cAMP), a requirement for adenosine 3'5' triphosphate (ATP) release. Within this pathway, cAMP levels are regulated by phosphodiesterase 3 (PDE3), a PDE that is inhibited by cGMP, a cyclic nucleotide regulated by the activity of PDE5. Since inhibition of PDE3 enhances ATP release in response to PGI2 analogs, we investigated if the selective PDE5 inhibitors, zaprinast (ZAP) and tadalafil (TAD), would similarly increase cAMP and ATP release from human erythrocytes in response to the same stimulus. We determined that pretreatment of erythrocytes with one of two chemically dissimilar PDE5 inhibitors (ZAP or TAD, 10 µM) potentiated increases in cAMP and ATP release in response to incubation of human erythrocytes with the PGI2 analog, UT-15C (100 nM). These results suggest that a heretofore unrecognized synergism exists between IPR agonists and PDE5 inhibitors that could provide a new rationale for the co-administration of these agents as vasodilators in humans with PAH.

Author List

Knebel SM, Elrick MM, Bowles EA, Zdanovec AK, Stephenson AH, Ellsworth ML, Sprague RS

Author

Amber Zdanovec MD Assistant Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Adult
Carbolines
Cyclic AMP
Epoprostenol
Erythrocytes
Female
Humans
Iloprost
Male
Middle Aged
Phosphodiesterase Inhibitors
Purinones
Signal Transduction
Tadalafil
Vasodilator Agents