| Summary: | 碩士 === 長庚大學 === 天然藥物研究所 === 95 === BAY 41-2272 (5-Cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-4-ylamine), a novel nitric oxide (NO)-independent direct stimulator of soluble guanylyl cyclase (sGC), is a useful tool for investigating the signaling of guanosine 3’,5’-cyclic monophosphate (cGMP) and may offer a new approach for treating cardiovascular diseases. Mitogen-activated protein kinases (MAPKs) play an important role in modulating human neutrophil functions, including chemotaxis, respiratory burst, exocytosis, cytokine synthesis and apoptosis. However, the precise role of cGMP in regulating activation of MAPKs is still controversial. In the present study, the effects of BAY 41-2272 on activation of p38, ERK1/2 and JNK MAPKs were studied in human neutrophils. In particular, several pharmacological agonists and inhibitors as well as the synergistic action of BAY 41-2272 and NO were used to elucidate the action mechanisms in greater detail. BAY 41-2272 not only directly promoted sGC activity and cGMP formation but also dramatically potentiated sodium nitroprusside (SNP)-induced sGC activity and cGMP formation in human neutrophils. Treatment of neutrophils with BAY 41-2272 (1, 3 and 10 μM) resulted in a rapid and significant phosphorylation of MAPKs in a concentration-dependent manner. Surprisingly, SNP did not alter phosphorylation of MAPKs, and it failed to enhance the effects of BAY 41-2272. These data indicated that the synergistic increases in cGMP levels were not consistent with the MAPKs activation. Furthermore, dibutyryl cGMP, a membrane permeant cGMP analogue, didn’t elicit significant effects on MAPKs activation. In addition, ODQ, a sGC inhibitor, failed to inhibit BAY 41-2272-induced phosphorylation of MAPKs in human neutrophils. In summary, our data demonstrate that BAY 41-2272 activates MAPKs in human neutrophils by a cGMP-independent pathway. Caution thus needs to be used in attributing the BAY 41-2272-mediated response to the activation of sGC.
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