Interaction of nitric oxide and cGMP with signal transduction in activated platelets.
Although nitric oxide (NO), one of the endothelium-derived relaxing factors, prevents formation of platelet aggregates, the mechanism by which this occurs is not fully understood. Accordingly, the effect of NO on signal transduction of gel-filtered human platelets was measured and compared with that of a cell-permeant guanosine 3',5'-cyclic monophosphate (cGMP) analogue, 8-bromo-cGMP (8-BrcGMP). NO inhibited the rise in intracellular Ca2+ concentration ([Ca2+]i), phosphorylation of the 47-kDa substrate (p47) of protein kinase C (PKC), serotonin secretion, and phosphatidic acid production induced by thrombin or the endoperoxide analogue U-46619. Similar effects were seen with 8-BrcGMP, and NO induced a concentration-related rise in cGMP. Neither NO nor 8-BrcGMP inhibited platelet aggregation, [Ca2+]i mobilization, or serotonin secretion induced by the Ca2+ ionophores A23187 or ionomycin or directly activated PKC purified from platelets. However, both NO and 8-BrcGMP enhanced p47 phosphorylation induced by the Ca2+ ionophores without augmenting phosphatidic acid production. Thus, if [Ca2+]i is elevated, a rise in cGMP enhances PKC activation. Both NO and 8-BrcGMP, however, prevent Ca2+ mobilization and platelet aggregation induced by receptor-mediated agonists by interfering with signal transduction at a point proximal to phospholipase C activation.
Nguyen
B L
BL
Charles A. Dana Research Institute, Beth Israel Hospital, Boston, Massachusetts 02215.
Saitoh
M
M
Ware
J A
JA
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001792:Blood Platelets / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D006152:Cyclic GMP / Q000097:blood / Q000494:pharmacology*; D004789:Enzyme Activation; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D010712:Phosphatidic Acids / Q000096:biosynthesis; D010750:Phosphoproteins; D010766:Phosphorylation; D015539:Platelet Activation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012969:Sodium Fluoride / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D001798:Blood Proteins; D010712:Phosphatidic Acids; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; C039077:platelet protein P47; D009569:Nitric Oxide; D000001:Calcimycin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D012969:Sodium Fluoride; D011493:Protein Kinase C; D013917:Thrombin; D006152:Cyclic GMP; D002118:Calcium