Human endothelial cells inhibit platelet aggregation by separately stimulating platelet cyclic AMP and cyclic GMP.
Thrombin-induced platelet aggregation was monitored in a mixture of washed human platelets and cultured human endothelial cells on microcarrier beads. Endothelial cells completely inhibited platelet aggregation and enhanced the content of both cyclic AMP and cyclic GMP in the platelets. Inhibition of endothelial prostacyclin synthesis with indomethacin abolished the cyclic AMP increase in the platelets, whereas the cyclic GMP increase was unimpaired. A significant component of the endothelial anti-aggregatory effect persisted in the presence of indomethacin. This anti-aggregatory component and the elevation of cyclic GMP were blocked by the inhibitors of endothelium-derived relaxing factor (EDRF), gossypol, haemoglobin and methylene blue. These inhibitors did not affect the endothelium-induced increases in cyclic AMP or the cyclic AMP-mediated anti-aggregatory effects. Exogenous prostacyclin stimulated only platelet cyclic AMP, whereas sodium nitroprusside selectively enhanced cyclic GMP. These data suggest that the endothelium can inhibit platelet aggregation by two completely separate mechanisms, one mediated by prostacyclin and cyclic AMP, and the other by EDRF and cyclic GMP.
Alheid
U
U
Department of Clinical Pharmacology, Hannover Medical School, F.R.G.
Reichwehr
I
I
Förstermann
U
U
D001685:Biological Factors / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000097:blood*; D006152:Cyclic GMP / Q000097:blood*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D011464:Epoprostenol / Q000096:biosynthesis; D006072:Gossypol / Q000494:pharmacology; D006454:Hemoglobins / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009569:Nitric Oxide; D010974:Platelet Aggregation / Q000187:drug effects*
D001685:Biological Factors; D006454:Hemoglobins; D009569:Nitric Oxide; D011464:Epoprostenol; D000242:Cyclic AMP; D006152:Cyclic GMP; D006072:Gossypol; D008751:Methylene Blue; D007213:Indomethacin