Pharmacological Effect of YC-1 and BAY 41-2272, Soluble Guanylate Cyclase Activators, on β-Hexosaminidase Release in RBL-2H3 Mast Cells
| Autor: | 潘彥霖 |
|---|---|
| Rok vydání: | 2004 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 92 In this study, the effect of soluble guanylate cyclase (sGC) activators, YC-1 [3-(5’-hydroxymethyl-2’-furyl)-1-benzyl indazole] and BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine], on anti-DNP IgE/DNP-BSA- and Ca2+ ionophore A23187- elicited β-hexosaminidase release in rat basophilic leukemia RBL-2H3 cells were investigated, and the underlying mechanisms of action were assessed. YC-1 and BAY 41-2272 produced a concentration-dependent inhibition of β-hexosaminidase release stimulated by anti-DNP IgE/DNP-BSA and Ca2+ ionophore A23187. However, the cGMP analogue dibutyryl-cGMP inhibited anti-DNP IgE/DNP-BSA, but not Ca2+ ionophore A23187, caused β-hexosaminidase release. Further studies suggested that cGMP did not mediate the inhibition of YC-1 and BAY 41-2272, because even at the combination of YC-1 or BAY 41-2272 with nitric oxide donor sodium nitroprusside and PDE5 inhibitor zaprinast neither actived sGC/cGMP pathway nor affected the inhibitory function of YC-1 and BAY 41-2272. Additionally, a role for cAMP in β-hexosaminidase release of RBL-2H3 cells was excluded because (a) PDE3 inhibitor milrinone and non-selective PDE inhibitor 3-isobutyl-1-methylxanthine could elevate cAMP concentrations but not succeed in cellular function, and (b) the cAMP analogue dibutyryl-cAMP did not alter both anti-DNP IgE/DNP-BSA- and calcium ionophore A23187- induced β-hexosaminidase released. Indeed, a role for cAMP in YC-1 caused inhibition of β-hexosaminidase release was also ruled out. Interestingly, both anti-DNP IgE/DNP-BSA- and calcium ionophore A23187- induced phosphorylation of AktSer473, but not phosphorylation of protein tyrosine kinase, were inhibited by YC-1 and BAY 41-2272. In summary, these results indicate that the inhibition by YC-1 and BAY 41-2272 of anti-DNP IgE/DNP-BSA- and Ca2+ ionophore A23187- elicited β-hexosaminidase release in rat basophilic leukemia RBL-2H3 cells can probably be attributed to the blockade of phosphorylation of AktSer473 via cGMP- and cAMP- independent pathways. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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