title: Phosphodiesterase 5 inhibitors augment UT-15C-stimulated ATP release from erythrocytes of humans with pulmonary arterial hypertension.
abstract: Both prostacyclin analogs and phosphodiesterase 5 (PDE5) inhibitors are effective treatments for pulmonary arterial hypertension (PAH). In addition to direct effects on vascular smooth muscle, prostacyclin analogs increase cAMP levels and ATP release from healthy human erythrocytes. We hypothesized that UT-15C, an orally available form of the prostacyclin analog, treprostinil, would stimulate ATP release from erythrocytes of humans with PAH and that this release would be augmented by PDE5 inhibitors. Erythrocytes were isolated and the effect of UT-15C on cAMP levels and ATP release were measured in the presence and absence of the PDE5 inhibitors, zaprinast or tadalafil. In addition, the ability of a soluble guanylyl cyclase inhibitor to prevent the effects of tadalafil was determined. Erythrocytes of healthy humans and humans with PAH respond to UT-15C with increases in cAMP levels and ATP release. In both groups, UT-15C-induced ATP release was potentiated by zaprinast and tadalafil. The effect of tadalafil was prevented by pre-treatment with an inhibitor of soluble guanylyl cyclase in healthy human erythrocytes. Importantly, UT-15C-induced ATP release was greater in PAH erythrocytes than in healthy human erythrocytes in both the presence and the absence of PDE5 inhibitors. The finding that prostacyclin analogs and PDE5 inhibitors work synergistically to enhance release of the potent vasodilator ATP from PAH erythrocytes provides a new rationale for the co-administration of these drugs in this disease. Moreover, these results suggest that the erythrocyte is a novel target for future drug development for the treatment of PAH.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University, St Louis, MO 63104, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Bowles
authors.affiliation: Department of Internal Medicine, Saint Louis University, St Louis, MO 63104, USA.
authors.forename: Gina N
authors.initials: GN
authors.lastname: Moody
authors.affiliation: Department of Internal Medicine, Saint Louis University, St Louis, MO 63104, USA.
authors.forename: Yashaswini
authors.initials: Y
authors.lastname: Yeragunta
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University, St Louis, MO 63104, USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Stephenson
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University, St Louis, MO 63104, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Ellsworth
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University, St Louis, MO 63104, USA spraguer@slu.edu.
authors.forename: Randy S
authors.initials: RS
authors.lastname: Sprague
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis; D004357:Drug Synergism; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004912:Erythrocytes / Q000737:chemistry / Q000187:drug effects*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D011688:Purinones / Q000494:pharmacology; D000068581:Tadalafil; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D011688:Purinones; D000068581:Tadalafil; D000255:Adenosine Triphosphate; D011464:Epoprostenol; D000242:Cyclic AMP; C011145:zaprinast; C427248:treprostinil
keywords: Tadalafil; cAMP; cGMP; red blood cell; treprostinil; zaprinast