Platelet receptor desensitization induced by elevated prostacyclin levels causes platelet-endothelial cell adhesion.
OBJECTIVE
The purpose of this study was to investigate the role of platelet prostacyclin receptor desensitization in platelet-endothelial cell adhesion.


BACKGROUND
Platelet-endothelial cell adhesion is regulated by endothelial cell-derived mediators, such as prostacyclin and endothelium-derived relaxing factor. Prostacyclin activates platelet adenylate cyclase and augments cyclic adenosine monophosphate formation by way of specific membrane receptors. Platelet exposure to prostacyclin or chemically stable analogs results in a time- and dose-dependent prostacyclin receptor desensitization as it occurs during infusion therapy with prostacyclin analogs or in pathophysiologic situations such as acute myocardial infarction.


METHODS
Adhesion of washed and radiolabeled human platelets stimulated with thrombin to cultured umbilical vein endothelial cells was measured under control conditions and under conditions of platelet prostacyclin receptor desensitization induced by incubation with the prostacyclin analog iloprost (10 to 100 nmol/liter) for 3 h.


RESULTS
Thrombin (0.08 to 0.2 U/ml) increased platelet adhesion in a dose-dependent manner from 2.7 +/- 0.3% to 6.4 +/- 0.6% (mean value +/- SEM). Preincubation of platelets resulted in a dose-dependent down-regulation of 3H-iloprost binding up to 58.8 +/- 6.7% of control platelets with 100 nmol/liter of iloprost. Co-incubation of prostacyclin receptor-desensitized platelets with endothelial cells resulted in a marked augmentation of thrombin-induced adhesion up to 28.6 +/- 4.5%. Approximately the same increase in platelet adhesion was seen after complete abrogation of endothelial cell prostacyclin synthesis by pretreatment with aspirin. Comparison of iloprost-induced receptor desensitization and increased platelet-endothelial cell adhesion indicated a positive correlation.


CONCLUSIONS
Platelet prostacyclin receptor desensitization was observed in humans in vivo during acute myocardial infarction or during therapeutic administration of prostacyclin analogs. In vitro platelet prostacyclin receptor desensitization caused a marked augmentation of platelet-endothelial cell adhesion. This increase in adhesion might result in an enhanced tendency toward thrombus formation in humans.
Darius
H
H
Department of Medicine II, Johannes Gutenberg University, Mainz, Germany.
Binz
C
C
Veit
K
K
Fisch
A
A
Meyer
J
J
D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis / Q000494:pharmacology*; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000187:drug effects* / Q000378:metabolism; D012044:Regression Analysis; D018709:Statistics, Nonparametric; D013917:Thrombin / Q000494:pharmacology; D014316:Tritium
D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D014316:Tritium; D011464:Epoprostenol; D000242:Cyclic AMP; D013917:Thrombin; D016285:Iloprost