Activation of guanylate cyclase and inhibition of platelet aggregation by endothelium-derived relaxing factor released from cultured cells.
The aggregation of gel-filtered rabbit platelets by 50 microM ADP was inhibited by a labile factor produced by suspensions of cultured bovine pulmonary artery endothelial cells. Inhibition of aggregation occurred when indomethacin-treated endothelial cells (6.10(5) per ml) and rabbit platelets (3.2.10(8) per ml) were incubated together. This anti-aggregatory activity was characterized as similar to endothelium-derived relaxing factor (EDRF) in that it was unstable at neutral pH and by its inhibition by hemoglobin. The activity was unaffected by treatment of the platelets and endothelial cells with the cyclooxygenase inhibitor, indomethacin, and by the lipoxygenase inhibitor, BW755c. In association with the anti-aggregatory activity, the levels of cyclic GMP were elevated 4-fold. The effect of the EDRF-like product on the levels of cyclic nucleotides was mimicked by treatment of platelets with sodium nitroprusside, an activator of soluble guanylate cyclase; sodium nitroprusside had no measurable effect on the levels of cyclic nucleotides of endothelial cells. We conclude that a factor with the properties of EDRF inhibits platelet aggregation, and that this is associated with an activation of guanylate cyclase as in smooth muscle. Thus, EDRF may exert an inhibitory effect on platelets in a manner analogous to its actions on vascular smooth muscle.
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001688:Biological Products / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D006454:Hemoglobins / Q000494:pharmacology; D009569:Nitric Oxide; D009712:Nucleotides, Cyclic / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000378:metabolism
D001688:Biological Products; D006454:Hemoglobins; D009712:Nucleotides, Cyclic; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D013482:Superoxide Dismutase; D006162:Guanylate Cyclase