U73122

U73122 significantly inhibits aggregation of human platelets induced by a variety of agonists, including collagen, thrombin, ADP, arachidonic acid, with IC50 of 1-5 μM. U-73122 (10 μM) inhibits the production of IP3 and the subsequent rapid increase in cytosolic Ca²⁺ induced by either thrombin or U-46619 through inhibiting hydrolysis of phosphatidyl[³H]inositol and phosphatldyl[³H]inosito1 4,5-bisphosphate catalyzed by a soluble fraction from platelets (K_i=9 and 40 μM, respectively). U-73122 inhibits thromboxane B production induced by collagen through inhibiting receptor-coupled mobilization of arachidonic acid. U73122 inhibits also FMLP-induced aggregation of human polymorphonuclear neutrophils and the associated production of IP3 and diacylglycerol. ^[1]

U-73122 causes a concentration-dependent inhibition of C5a, FMLP, PAF and LTB4-induced MPO and B12-BP release from cyto-chalasin B-treated PMNs. The IC50 values are 60 (FMLP), 110 (LTB4), 115 (C5a) and 120 (PAF) nM for MPO release; and 105 (FMLP), 110 (LTB4), 120 (C5a) and 140 (PAY) nM for B12-BP release. U-73122 is also a potent inhibitor of superoxide anion production by cytochalasin B-treated PMNs activated with either C5a or FMLP with IC50 of 160 and 300 nM, respectively. U-73122 causes suppression of the rise in [Ca²⁺]_i, IP3 production and DAG production in FMLP-stimulated PMNs with IC50 of 500 nM, 2 μM, and 2 μM, respectively. 3 μM U-73122 causes 100% inhibition of FMLP-induced GTPase activity. U-73122 causes a concentration-dependent inhibition of the FMLP-evoked association of PKC with the extractable particulate fraction of PMNs, but not a soluble preparation of PMN PKC. ^[2]

U73122 significantly inhibits recombinant human PLC-β2, with an IC50 of ~6 μM. U73122 has little effect on PLC-β1, PLC-β3, or PLC-β4. U73122 reduces interleukin-8 and leukotriene B4-induced Ca²⁺ flux and chemotaxis in human neutrophils with IC50 of ~6 μM and ~5 μM, respectively. ^[3]

1 μM U73122 blocks bradykinin (BK)-induced increases in the intracellular free Ca²⁺ concentration in undifferentiated NG108-15 cell. The IC50 for a 20-min exposure is approximately 200 nM. 1 μM U73122 produces a small but significant increase in [Ca²⁺]_i which results from Ca ²⁺ release from an intracellular store. In differentiated NG108-15 cells U73122 blocks completely depolarization-induced Ca²⁺ influx. In contrast, in DRG neurons U73122 inhibits only slightly voltage-sensitive Ca²⁺ channels. ^[4]

U73122 is a relatively specific inhibitor of G-protein-mediated phospholipase C activation in pancreatic acini. U73122 inhibits phosphatidylinositol (PI) hydrolysis on stimulation with either cholecystokinin (by 81%) or carbachol (by 73%) at a maximal effect concentration of 10 μM. U73122 (10 μM) inhibits the increases in [Ca²⁺]_i stimulated by high concentrations of secretagogues in fura-2-loaded acini. U73122 also inhibits the [Ca²⁺]_i signal generated by directly stimulating G-proteins with sodium fluoride. U73122 rapidly inhibits the oscillating [Ca²⁺]_i signal elicited by low concentrations of cholecystokinin or carbachol. ^[5]

U73122 increases the activity of hPLCβ3 in a concentration-and time-dependent manner in a cell-free micellar system, with up to an 8-fold increase in enzyme activity and a EC50 of 13.6 μM. Activation of hPLCβ3 by U73122 requires covalent modification of cysteines. U73122 (10 μM) also activates hPLCγ1(>10-fold) and hPLCβ2(~2-fold); PLC δ1 is neither activated nor inhibited. ^[6]

U73122 (30 mg/kg i.p.) blocks swelling of rats hind paw by 65 and 80% at 1 and 3 h postcarrageenan challenge. U73122 (0.1 mg/mL) inhibits carrageenan-induced macrophage and lymphocyte accumulation into subcutaneous chambers in dogs by 65 and 74%, respectively. U73122 (30 mg/kg i.p.) totally inhibits the LPS-induced increase in macrophage and lymphocyte infiltration and prostaglandin E2 production (by 80%) in a mouse peritonitis model, and inhibits and 12- O-tetradecanoyl-phorbol-13-acetate-induced ear edema in mice. ^[3]