Epinephrine correction of impaired platelet thromboxane receptor signaling

Abstract

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.

Mechanisms of Cross-Talk between G-Protein-Coupled Receptors

“…Thus, it might be expected that agents that reduce PKA activity will relieve this inhibition and potentiate thromboxane-mediated responses. Indeed, it has recently been suggested that the ability of adrenaline to potentiate platelet activation [98] may be due to a reduction in PKA activity, via · 2 -adrenoceptors, and a subsequent dephosphorylation of thromboxane A 2 receptors, which are 'hyperphosphorylated' in platelets with impaired thromboxane A 2 signalling [99].…”

The Protective Effect of Poloxamer-188 on Platelet Functions

“…Epinephrine induces platelet aggregation by increasing TxA2 formation via phospholipase A2 activation and by facilitating TXA2-mediated signaling. 17,18 The reason of the observed decreased aggregation with MST-188 may be due to the interactions of MST-188 with membrane phospholipids and its probable effect on TXA2 synthesis. This can be the probable reason of decreased AIA with AA and epinephrine since their receptors are involved in TXA2 signaling system.…”

Anti-platelet and Anti-thrombotic Effects of a Poly-ingredient formulation: In vitro and in vivo experimental evidences

“…22,23 Incubation of adrenaline with PRP in in vitro exhibits a characteristic biphasic aggregation curve, the first phase denoting aggregation mediated through α-adrenoceptors. 24 When adrenaline occupies these receptors present on the platelet membrane, adenylate cyclase activity is inhibited, cAMP production is consequently decreased, and platelets tend to aggregate. 25 The second aggregation phase is mediated entirely through prostaglandin endoperoxides (PGG and PGH) and thromboxane A 2 .…”