Endothelin-3, Ca2+ mobilization and cyclic GMP content in human platelets.
As previously described for endothelin-3, platelet exposure to cyclic GMP-elevating agents such as sodium nitroprusside and M&B-22948 (2-o-propoxyphenyl-8-azapurin-6-one), a cGMP phosphodiesterase inhibitor, lowered Ca2+ mobilization in response to thrombin. Interestingly, when cGMP phosphodiesterases were blocked, endothelin-3 produced a dose-dependent cGMP accumulation (P < 0.001). Since endothelin-3 has been proposed to decrease the activity of Ca2+ accumulating pumps, we examined whether this latter effect could be mediated by a rise in cGMP content. Cyclic GMP decreased in a dose-dependent manner the initial rate and plateau value of the ATP-dependent 45Ca2+ uptake in platelet membrane vesicles (P = 0.006 for each). Furthermore, combined treatment with endothelin-3 and M&B-22948 or a moderate concentration of Na(+)-nitroprusside further reduced the thrombin-evoked Ca2+ discharge (P = 0.004 and 0.01, respectively), suggesting that endothelin-3 pre-exposure had reduced the amount of mobilizable Ca2+. We propose that the depletion of platelet Ca2+ stores and the reduction of Ca2+ release evoked by endothelin-3 could be due, at least in part, to the elevation of cGMP content and to a decrease in Ca2+ accumulating pump activity.
Gagnet
C
C
Department of Pharmacology, CNRS URA 1482, René Descartes University, Necker Medical School, Paris, France.
Brunet
A
A
Pernollet
M G
MG
Devynck
M A
MA
Astarie-Dequeker
C
C
D000704:Analysis of Variance; D001693:Biological Transport, Active / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019334:Endothelin-3 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D019334:Endothelin-3; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D009599:Nitroprusside; D019284:Thapsigargin; D013917:Thrombin; C011145:zaprinast; D006152:Cyclic GMP; D002118:Calcium