Nitric oxide donors induce extrusion of cyclic GMP from isolated human blood platelets by a mechanism which may be modulated by prostaglandins.
In the presence of 3-isobutyl-methylxanthine (IBMX), induction of cyclic 3',5'-guanosine monophosphate (GMP) production in human washed platelets (HWP) by nitric oxide donors (NOD) is followed by its accumulation in the surrounding medium in a time- and concentration-dependent manner. Thirty minutes incubation of HWP with 3-morpholino-sydonimine (SIN-1, 10 microM) at 37 degrees C resulted in a 4.6-fold increase of cyclic GMP in platelets, whereas in the extracellular medium the increase was 17.6-fold. Similar results were obtained when other NOD such as S-nitroso-N-acetylpenicyllamine (SNAP) and 3-(2-methoxy-5-chlorophenyl)oxatriazol-5-imine (GEA 3184) and the selective phosphodiesterase inhibitor, zaprinast (M&B 22948, 10 microM), were used. Probenecid (1-300 microM), an inhibitor of organic anion transport, or ouabain (1-300 microM), an inhibitor of Na+/K+ adenine triphosphate (ATP)-ase had no effect on cyclic GMP production or extrusion after stimulation with SIN-1. Significantly prostaglandin A1 (PGA1) and prostaglandin D2 (PGD2) inhibited the efflux of cyclic GMP from platelets induced by SNAP (10 microM) in a concentration-dependent fashion, with an IC50 of 63 +/- 16 and 143 +/- 17 microM, respectively. These studies suggest that the extrusion of cyclic GMP from human platelets after activation of soluble guanylate cyclase by NOD may contribute to the control of cyclic GMP levels in platelets with potential physiological and therapeutic consequences.
Radziszewski
W
W
Department of Pharmacology, UCLA School of Medicine 90024-1735, USA.
Chopra
M
M
Zembowicz
A
A
Gryglewski
R
R
Ignarro
L J
LJ
Chaudhuri
G
G
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology*; D002478:Cells, Cultured; D003470:Culture Media; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000201:enzymology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D010042:Ouabain / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011339:Probenecid / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology*; D011454:Prostaglandins A / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology
C098220:3-(2-methoxy-5-chlorophenyl)oxatriazol-5-imine; D003470:Culture Media; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011453:Prostaglandins; D011454:Prostaglandins A; D011688:Purinones; D014230:Triazoles; D009569:Nitric Oxide; D010042:Ouabain; C002385:linsidomine; D026423:S-Nitroso-N-Acetylpenicillamine; D008981:Molsidomine; D006162:Guanylate Cyclase; D000254:Sodium-Potassium-Exchanging ATPase; D010396:Penicillamine; C011145:zaprinast; D006152:Cyclic GMP; D011339:Probenecid; D015230:Prostaglandin D2; D015056:1-Methyl-3-isobutylxanthine; C100573:prostaglandin A1