PLATELET RECEPTOR DESENSITIZATION INDUCED BY ELEVATED PROSTACYCLIN LEVELS CAUSES PLATELET-ENDOTHELIAL CELL-ADHESION

Objectives. 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 H-3 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 de sensitization 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.