title: Synergistic effects of prostacyclin analogs and phosphodiesterase inhibitors on cyclic adenosine 3',5' monophosphate accumulation and adenosine 3'5' triphosphate release from human erythrocytes.
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.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, MO 63104, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Knebel
authors.forename: Mollisa M
authors.initials: MM
authors.lastname: Elrick
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Bowles
authors.forename: Amber K
authors.initials: AK
authors.lastname: Zdanovec
authors.forename: Alan H
authors.initials: AH
authors.lastname: Stephenson
authors.forename: Mary L
authors.initials: ML
authors.lastname: Ellsworth
authors.forename: Randy S
authors.initials: RS
authors.lastname: Sprague
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D002243:Carbolines / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011688:Purinones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000068581:Tadalafil; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D002243:Carbolines; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D014665:Vasodilator Agents; D000068581:Tadalafil; D000255:Adenosine Triphosphate; D011464:Epoprostenol; D000242:Cyclic AMP; C011145:zaprinast; D016285:Iloprost; C427248:treprostinil
keywords: Phosphodiesterase 5; UT-15C; iloprost; tadalafil; zaprinast