15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and nitrosobis(2-oxopropyl)amine

This study evaluated the mechanism of epinephrine potentiation of platelet secretion induced by thromboxane A(2) (TXA(2)). Dog platelets that do not secrete in response to TXA(2) alone (TXA(2)-) were compared with dog platelets that do secrete (TXA(2)+) and with human platelets. TXA(2)- platelets had impaired TXA(2) receptor (TP receptor)-G protein coupling, indicated by 1) impaired stimulated GTPase activity, 2) elevated basal guanosine 5'-O-(3-thiotriphosphate) binding, and 3) elevated Galpha(q) palmitate turnover that was corrected by preexposure to epinephrine. Kinetic agonist binding studies revealed biphasic dog and human platelet TP receptor association and dissociation. TXA(2)- and TP receptor-desensitized TXA(2)+ dog and human platelets had altered ligand binding parameters compared with untreated TXA(2)+ or human platelets. These parameters were reversed, along with impaired secretion, by epinephrine. Basal phosphorylation of TXA(2)- platelet TP receptors was elevated 60% and was normalized by epinephrine. Epinephrine potentiates platelet secretion stimulated by TXA(2) by reducing basal TP receptor phosphorylation and facilitating TP receptor-G protein coupling in TXA(2)- platelets and, probably, in normal platelets as well.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Amino Acid Sequence; Animals; Blood Platelets; Carbon Radioisotopes; Dogs; Epinephrine; GTP Phosphohydrolases; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Inositol 1,4,5-Trisphosphate; Iodine Radioisotopes; Kinetics; Molecular Sequence Data; Mutagens; Nitrosamines; Palmitates; Phosphorylation; Platelet Activation; Receptors, Thromboxane; Signal Transduction; Sulfur Radioisotopes; Thromboxane A2; Tritium; Vasoconstrictor Agents