Control of ATP Release by Red Blood Cells and Therapeutic Applications Thereof

Abstract

The invention is based upon the discovery that red blood cells contain phosphodiesterase 3B (PDE3B), and that inhibition of that phosphodiesterase allows for an enhanced accumulation of cAMP and subsequent release of ATP. It was further discovered that RBCS treated with insulin accumulate significantly less cAMP and release significantly less ATP than normal RBCS. Likewise, RBCS of patients suffering from type 2 diabetes (hyperinsulinemia) accumulate significantly less cAMP and release significantly less ATP than normal RBCS. It was further discovered that prostaglandin analogues synergistically work with phosphodiesterase 3B inhibitors to improve or increase cAMP accumulation and ATP release RBCS. Thus the invention is directed to compositions and methods for improving ATP release by RBCS, via administering PDE3B inhibitor or a combination of PDE3B inhibitor and prostaglandin analogue.

1 . A therapeutic composition comprising:
 a phosphodiesterase inhibitor, wherein the phosphodiesterase inhibitor is a phosphodiesterase 3 inhibitor;   a prostaglandin, wherein the prostaglandin is selected from the group consisting of iloprost, UT-15C, and prostaglandin I 2 ; and   a pharmaceutically acceptable excipient.   
     
     
         2 . The therapeutic composition of  claim 1 , wherein the phosphodiesterase 3 inhibitor is selected from the group consisting of amrinone, cilostazol, CI-930, enoximone, meribendan, milrinone, pentoxifylline, pimobendane, and 3-isobutyl-1-methylxanthine. 
     
     
         3 . The therapeutic composition of  claim 1 , further comprising a beta-adrenergic receptor agonist. 
     
     
         4 . The therapeutic composition of  claim 2 , wherein the beta-andrenergic agonist is selected from the group consisting of epinephrine and isoproterenol. 
     
     
         5 . A method of treating a disease or a condition, the method comprising: administering a therapeutically effective amount of a phosphodiesterase inhibitor to a subject, wherein the disease or the condition is selected from the group consisting of pulmonary hypertension, cystic fibrosis, hyperinsulinemia, prediabetes, metabolic syndrome, type 1 diabetes, and type 2 diabetes. 
     
     
         6 . The method of  claim 5 , wherein the phosphodiesterase inhibitor is a phosphodiesterase 3 inhibitor. 
     
     
         7 . The method of  claim 5 , wherein the phosphodiesterase inhibitor is selected from the group consisting of amrinone, cilostazol, CI-930, enoximone, meribendan, milrinone, pentoxifylline, pimobendane, and 3-isobutyl-1-methylxanthine. 
     
     
         8 . The method of  claim 5 , wherein blood flow is increased. 
     
     
         9 . The method of  claim 5  further comprising administering at least one of a prostaglandin and a beta-adrenergic receptor agonist. 
     
     
         10 . The method of  claim 9 , wherein the prostaglandin is selected from the group consisting of iloprost, UT-15C, and prostaglandin I 2 . 
     
     
         11 . The method of  claim 9 , wherein the beta-adrenergic receptor agonist is selected from the group consisting of epinephrine and isoproterenol. 
     
     
         12 . The method of  claim 5 , further comprising co-administration with insulin. 
     
     
         13 . A method of stimulating ATP release by a red blood cell in a subject, the method comprising: administering to the subject a therapeutically effective amount of a phosphodiesterase inhibitor. 
     
     
         14 . The method of  claim 13 , wherein the phosphodiesterase inhibitor is a phosphodiesterase isoform 3 inhibitor. 
     
     
         15 . The method of  claim 14 , wherein the phosphodiesterase inhibitor is selected from the group consisting of amrinone, cilostazol, CI-930, enoximone, meribendan, milrinone, pentoxifylline, pimobendane, and 3-isobutyl-1-methylxanthine. 
     
     
         16 . The method of  claim 13 , further comprising administering at least one of a prostaglandin and a beta-adrenergic receptor agonist. 
     
     
         17 . The method of  claim 16 , wherein the prostaglandin is selected from the group consisting of iloprost, UT-15C, and prostaglandin I 2 . 
     
     
         18 . The method of  claim 16 , wherein the beta-adrenergic receptor agonist is selected from the group consisting of epinephrine and isoproterenol. 
     
     
         19 . The method of  claim 13 , further comprising co-administration with insulin. 
     
     
         20 . The method of  claim 13 , wherein blood flow of the subject is increased.