Regulation of calcium mobilization and entry in human platelets by endothelium-derived factors.
Stimulation of Ca2+ mobilization and entry by agonists such as ADP, thrombin, and thromboxane is an early step of platelet activation. Here, we compared the effects of adenosine 3',5'-cyclic monophosphate (cAMP)-elevating prostaglandins, guanosine 3',5'-cyclic monophosphate (cGMP)-elevating nitrovasodilators, membrane-permeant selective activators of cAMP- or cGMP-dependent protein kinases, and physiological endothelium-derived factors on the agonist-evoked Ca2+ mobilization and entry in human platelets. Prostaglandin E1, the prostacyclin analogue Iloprost, the nitric oxide (NO) donor 3-morpholinosydnonimine hydrochloride, and selective activators of cGMP- or cAMP-dependent protein kinase strongly inhibited the agonist-evoked Ca2+ mobilization from intracellular stores and associated late Ca2+ entry but had little effects on the rapid (1st) phase of ADP-evoked Ca2+ entry. During coincubation of platelets with endothelial cells, endothelium-derived factors that were released strongly inhibited platelet agonist-evoked Ca2+ mobilization and only moderately affected the rapid phase of ADP-evoked Ca2+ entry. These effects were partially prevented when endothelial cells were preincubated with cyclooxygenase and/or NO synthase inhibitors. Endothelial cells therefore produce sufficient quantities of labile platelet inhibitors whose effects on the platelet Ca2+ response resemble those observed with selective cAMP- and cGMP-dependent protein kinase activators.
Geiger
J
J
Medizinische Universitätsklinik, Klinische Forschergruppe, Universität Würzburg, Germany.
Nolte
C
C
Walter
U
U
D001692:Biological Transport; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D009574:Nitro Compounds / Q000494:pharmacology; D009712:Nucleotides, Cyclic / Q000378:metabolism; D011453:Prostaglandins / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D009574:Nitro Compounds; D009712:Nucleotides, Cyclic; D011453:Prostaglandins; D014665:Vasodilator Agents; D009569:Nitric Oxide; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D006152:Cyclic GMP; D002118:Calcium