Prostacyclin analogs and PDE 5 inhibitors synergistically stimulate ATP release from human RBCs

Researchers at Saint Louis University School of Medicine have discovered a novel interaction between prostacyclin (PGI2) analogs and phosphodiesterase 5 (PDE5) inhibitors, two groups of drugs used in the treatment of pulmonary arterial hypertension (PAH). They found that, in combination, these drugs stimulate enhanced release of a potent vasodilator adenosine triphosphate (ATP) from human red blood cells (RBCs). Their study appears in the September 2013 issue of Experimental Biology and Medicine.

PAH is a chronic disorder characterized by sustained increases in pulmonary vascular resistance leading to pulmonary hypertension and right ventricular heart failure. Although the pathophysiology of PAH is not fully understood, the condition has a poor prognosis in the absence of pharmacological intervention. The major classes of drugs used to treat severe PAH include both PGI2 analogs and PDE5 inhibitors.

It is widely accepted that in vascular , PGI2 analogs dilate blood vessels by increasing cyclic adenosine 3',5' mono-phosphate (cAMP) while PDE5 increases cyclic guanosine 3',5' mono-phosphate (cGMP) by inhibiting its breakdown. However, human erythrocytes also express functional prostacyclin receptors (IPRs) and possess PDE5. The binding of PGI2 analogs to the erythrocyte IPR activates a well-defined signaling pathway that stimulates increases in cAMP and culminates in the release of the vasoactive molecule, adenosine 3'5' triphosphate (ATP). When released from circulating erythrocytes in the vascular lumen, ATP binds to receptors on the endothelium of pulmonary vessels resulting in the synthesis of vasodilators. Importantly, the levels of cAMP in the erythrocyte IPR signaling pathway are regulated by PDE3, a PDE that is inhibited by cGMP. Levels of cGMP in erythrocytes are regulated by PDE5.

Dr. Randy Sprague, senior author of this article, said "We hypothesized that increases in cGMP resulting from PDE5 inhibition would prevent the breakdown of IPR-mediated increases in cAMP leading to enhanced ATP release. The major finding of this study is that either of two chemically dissimilar inhibitors of PDE5 augment increases in cAMP and ATP release produced by incubation of erythrocytes with an IPR agonist, UT-15C (treprostinil). Dr. Stephanie Knebel, first author, said "Our results demonstrate a new role for both prostacyclin analogs and PDE5 inhibitors in the regulation of IPR-mediated increases in cAMP and ATP release from human erythrocytes." These findings have implications for the development of new therapeutic approaches to the treatment of conditions such as .

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine, said "This intriguing study by Knebel et al has demonstrated that both PDE5 inhibitors and prostacyclin analogs are involved in the prostacyclin receptor dependent release of cAMP and ATP for human RBCs. Their results suggest new therapeutic approaches for the treatment of pulmonary arterial hypertension".

add to favorites email to friend print save as pdf

Related Stories

A possible role for Smurf1 in pulmonary arterial hypertension

Jun 21, 2010

Pulmonary arterial hypertension (PAH) is a progressive disease, marked by shortness of breath and fatigue which can be fatal if untreated. Increased pressure in the pulmonary artery and its branches is associated with dysfunctional ...

New genetic cause of pulmonary hypertension identified

Jul 24, 2013

Columbia University Medical Center (CUMC) scientists have identified new genetic mutations that can cause pulmonary arterial hypertension (PAH), a rare fatal disease characterized by high blood pressure in the lungs. The ...

Recommended for you

Growing a blood vessel in a week

Oct 24, 2014

The technology for creating new tissues from stem cells has taken a giant leap forward. Three tablespoons of blood are all that is needed to grow a brand new blood vessel in just seven days. This is shown ...

Testing time for stem cells

Oct 24, 2014

DefiniGEN is one of the first commercial opportunities to arise from Cambridge's expertise in stem cell research. Here, we look at some of the fundamental research that enables it to supply liver and pancreatic ...

Team finds key signaling pathway in cause of preeclampsia

Oct 23, 2014

A team of researchers led by a Wayne State University School of Medicine associate professor of obstetrics and gynecology has published findings that provide novel insight into the cause of preeclampsia, the leading cause ...

Rapid test to diagnose severe sepsis

Oct 23, 2014

A new test, developed by University of British Columbia researchers, could help physicians predict within an hour if a patient will develop severe sepsis so they can begin treatment immediately.

User comments