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 p latelet prostacyclin receptor desensitization in platelet-endothelial cell adhesion. Background. Platelet-endothelial cell adhesion is regul ated by endothelial cell-derived mediators, such as prostacyclin and e ndothelium-derived relaxing factor. Prostacyclin activates platelet ad enylate cyclase and augments cyclic adenosine monophosphate formation by way of specific membrane receptors. Platelet exposure to prostacycl in or chemically stable analogs results in a time and dose-dependent p rostacyclin receptor desensitization as it occurs during infusion ther apy with prostacyclin analogs or in pathophysiologic situations such a s acute myocardial infarction. Methods. Adhesion of washed and radiola beled human platelets stimulated with thrombin to cultured umbilical v ein endothelial cells was measured under control conditions and under conditions of platelet prostacyclin receptor desensitization induced b y incubation with the prostacyclin analog iloprost (10 to 100 nmol/lit er) for 3 h. Results. Thrombin (0.08 to 0.2 U/ml) increased platelet a dhesion 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-dep endent 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 pr ostacyclin receptor-desensitized platelets with endothelial cells resu lted in a marked augmentation of thrombin-induced adhesion up to 28.6 +/- 4.5%. Approximately the same increase in platelet adhesion was see n 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 ind icated a positive correlation. Conclusions. Platelet prostacyclin rece ptor desensitization was observed in humans in vivo during acute myoca rdial infarction or during therapeutic administration of prostacyclin analogs. In vitro platelet prostacyclin receptor desensitization cause d a marked augmentation of platelet-endothelial cell adhesion. This in crease in adhesion might result in an enhanced tendency toward thrombu s formation in humans.