Cross-talk between adenosine and the oxatriazole derivative GEA 3175 in platelets.
We examined the interplay between adenosine and the nitric oxide (NO)-containing oxatriazole derivative GEA 3175 in human platelets. The importance of cyclic guanosine 3'5'-monophosphate (cGMP)-inhibited phosphodiesterases (PDEs) was elucidated by treating the platelets with adenosine combined with either GEA 3175 or the PDE3-inhibitor milrinone. The drug combinations provoked similar cyclic adenosine 3'5'-monophosphate (cAMP) responses. On the contrary, cGMP levels were increased only in GEA 3175-treated platelets. Both drug combinations reduced P-selectin exposure, platelet adhesion and fibrinogen-binding. However, adenosine together with GEA 3175 was more effective in inhibiting platelet aggregation and ATP release. Thrombin-induced rises in cytosolic Ca2+ were suppressed by the two drug combinations. Adenosine administered with GEA 3175 was, however, more effective in reducing Ca2+ influx. In conclusion, the interaction between adenosine and GEA 3175 involves cGMP-mediated inhibition of PDE3. The results also imply that inhibition of Ca2+ influx represent another cGMP-specific mechanism that enhances the effect of adenosine.
Asplund Persson
Anna
A
Department of Medicine and Care, Division of Pharmacology, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden.
Zalavary
Stefan
S
Lindström
Eva
E
Whiss
Per A
PA
Bengtsson
Torbjörn
T
Grenegård
Magnus
M
D000241:Adenosine / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006801:Humans; D020105:Milrinone / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; C093084:GEA 3175; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011810:Quinoxalines; D014230:Triazoles; D000242:Cyclic AMP; D013917:Thrombin; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D020105:Milrinone; D000241:Adenosine; D002118:Calcium