Navigation Links
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 smooth muscle cells, 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 pulmonary arterial hypertension.

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".


Contact: Stephanie M. Knebel
Society for Experimental Biology and Medicine

Related medicine news :

1. Possible predictive biomarker for patients who may respond to autophagy inhibitors
2. Agios research demonstrates the effects of mutant IDH1 and IDH2 inhibitors in primary tumor models
3. Cisplatin-resistant cancer cells sensitive to experimental anticancer drugs, PARP inhibitors
4. Biomarker may identify neuroblastomas with sensitivity to BET bromodomain inhibitors
5. Researchers use new molecular inhibitors to successfully hit difficult cancer target
6. New mechanism of action for PARP inhibitors discovered
7. PARP inhibitors may have clinical utility in HER2-positive breast cancers
8. Preclinical data support ongoing clinical trials testing IDO inhibitors as a treatment for cancer
9. Inhibitors of shuttle molecule show promise in acute leukemia
10. Fountain Valley, CA Gum Disease Treatment with Dr. Robert Mokbel Now Utilizes the FDA-cleared Laser to Stimulate Bone Growth and Can Prevent Tooth Loss
11. Fort Worth Dental Now Offers Laser Gum Disease Treatment to Stimulate Bone Regrowth and Possibly Save Natural Teeth
Post Your Comments:
(Date:11/30/2015)... , ... November 30, 2015 , ... RoamRight, a leading ... with Public Television’s Travel With Kids to promote family vacations around ... family as they explore international destinations and educate families about the people and places ...
(Date:11/30/2015)... ... November 30, 2015 , ... Advocare Orthopedic ... orthopedic care. Led by John Vitolo, M.D., the center offers their patients ... team at Advocare Orthopedic & Sports Medicine is ready to help their patients ...
(Date:11/30/2015)... ... November 30, 2015 , ... International telepathology consultations ... and KingMed Diagnostics researchers. Their review of more than 1,500 ... UPMC pathologists resulted in significantly altered treatment plans for more than half of ...
(Date:11/30/2015)... ... November 30, 2015 , ... The American Society for Clinical Pathology (ASCP) announced ... Day 2015. On Nov. 30, ASCP shared its “Give a minute. Get tested. Find ... and the importance of getting tested for HIV. , ASCP has asked members to ...
(Date:11/30/2015)... ... ... An inventor from Charlottesville, Va., is concerned about the need for peace and ... due to loud noises," she said, "so I decided that there needs to be ... radio waves and microwaves." , The baby BABY MUFF prevents loud noises, radio waves ...
Breaking Medicine News(10 mins):
(Date:11/30/2015)... Texas , Nov. 30, 2015  Hanger, Inc. ... amendment and restatement of the terms of its previously ... Solicitation") relating to its $200,000,000 aggregate principal amount 7⅛% ... other things, (i) the consent fees payable pursuant to ... on the Notes and (iii) the expiration date of ...
(Date:11/30/2015)... NAMUR , Belgium , Nov. 30, ... life sciences company focused on developing blood-based diagnostic tests for ... announced the Company will present at the LD Micro Conference, ... Los Angeles, CA. Attending from VolitionRx will ... and Scott Powell , Vice President of Investor Relations. ...
(Date:11/30/2015)... , November 30, 2015 PFE ... at up to 10 G protein-coupled receptor (GPCR) targets ... to research and develop potential new medicines directed at ... multiple therapeutic areas. --> Heptares Therapeutics ("Heptares"), ... and wholly-owned subsidiary of Sosei Group Corporation ("Sosei"; TSE ...
Breaking Medicine Technology: