Liposomal Delivery of a Phosphodiesterase 5 Inhibitor Enhances Prostacyclin-Mediated Adenosine Triphosphate Release from Human Red Blood Cells

Abstract

Pulmonary arterial hypertension (PAH) is characterized by high pulmonary vascular resistance (PVR) and right heart failure. Red blood cells (RBCs) of PAH patients fail to release the vasodilator, adenosine triphosphate (ATP), when deformed as would occur when traversing the lung. Such a defect could contribute to increased PVR. However, RBCs of PAH patients do release ATP in response to prostacyclin (PGI2) analogs and this is augmented by phosphodiesterase 5 (PDE5) inhibitors. Current PAH treatment includes PGI2 analogs and PDE5 inhibitors alone or in combination. Unfortunately, these drugs can have untoward side effects. Encapsulation of drugs within liposomes (small lipid-membraned vesicles) that can be targeted to RBCs has been shown to increase effectiveness and tolerability of some medications.The objective of this study was to determine if encapsulation of the PDE5 inhibitor zaprinast (ZAP) within liposomes is an effective means to deliver this class of drugs to human RBCs and if this approach would augment ATP release stimulated by the PGI2 analog UT-15c. Human RBCs were isolated and incubated with either blank liposomes (n=10), liposomes containing ZAP (n=9) or liposomes containing the PDE3 inhibitor, cilosatzol (CILO, n=10). RBCs (20% hematocrit) were then treated with UT-15c (1 µM). ATP release was measured before and 5, 10, and 15 min after the addition of UT-15c. In the presence of empty liposomes, the dose of UT-15c used did not stimulate ATP release. However, UT-15c did stimulate ATP release from RBCs pretreated with ZAP encapsulated by liposomes (P<0.01). The average time for maximal release was 9 ± 1 min. In contrast, when exposed to liposomes containing CILO, there was no ATP release following UT-15c administration.These studies demonstrate that the selective delivery of a PDE5 inhibitor to human RBCs potentiates UT-15c induced ATP release. Moreover the findings are consistent with the hypothesis that directed delivery of this class of drugs to PAH RBCs could be a new and important method to augment PGI2 analog-induced ATP release from these cells. Such an approach could significantly limit side effects of both drugs without compromise of their therapeutic effectiveness in PAH. DisclosuresNo relevant conflicts of interest to declare.