IBMX is a non-specific inhibitor of phosphodiesterase (PDE) inhibitor that inhibits PDE3, PDE4 and PDE5 with IC50 values of 6.5, 26.3 and 31.7 μm, except PDE8A, PDE8B and PDE9[1,7].
In cardiac H9c2 cells,IBMX reduced loss of δψm caused by H(2)O(2), indicating that inhibition of PDEs can prevent the mPTP opening. However, IBMX could not inhibit the pore opening in cells transfected with the constitutively active GSK-3β (GSK-3β-S9A) mutant, suggesting a critical role of GSK-3β in the action of IBMX. IBMX also reduced reperfusion injury in a GSK-3β dependent manner[5]. Increasing cAMP-signaling with Forskolin or IBMX significantly facilitated neuronal functional maturation. A continuous application of IBMX to the differentiation medium substantially increased the functional expression of voltage-gated Na(+) and K(+) channels, as well as neuronal firing frequency[6].
Chronic exposure to cold caused pulmonary arterial hypertension and increased phosphodiesterase-1C (PDE-1C) expression in pulmonary arteries (PAs) in rats. After 8-week exposure to cold, Treatment with 8-IBMX significantly attenuated the cold-induced increase in right ventricular pressure. Cold exposure also caused right-ventricular hypertrophy, whereas 8-IBMX reversed cold-induced right ventricular hypertrophy. 8-IBMX abolished cold-induced upregulation of PDE-1C in PAs[4]. In hyperglycemic rat, all test compounds decreased blood glucose and the effect of milrinone was potentiated by glybenclamide. Milrinone or IBMX did not change plasma insulin levels, but it was augmented by combination of milrinone and glybenclamide. In both species, liver glycogen storage was decreased by IBMX, mc5, mc6 or MCPIP, increased by mc2 and was not changed in the presence of mc1[3]. ANG II increased ROMK channel activity in CCDs isolated from high-K (HK)-fed but not normal K (NK)-fed rats. Pretreatment of CCDs with IBMX, a broad-spectrum PDE inhibitor, or cilostamide, a PDE3 inhibitor, abolished the stimulatory effect of ANG II on ROMK channels[2].
参考文献:
[1]: Wu BN, Lin RJ, et,al. KMUP-1, a xanthine derivative, induces relaxation of guinea-pig isolated trachea: the role of the epithelium, cyclic nucleotides and K+ channels. Br J Pharmacol. 2004 Aug;142(7):1105-14. doi: 10.1038/sj.bjp.0705791. Epub 2004 Jul 5. PMID: 15237094; PMCID: PMC1575170.
[2]: Wei Y, Liao Y,et,al. Angiotensin II type 2 receptor regulates ROMK-like K? channel activity in the renal cortical collecting duct during high dietary K? adaptation. Am J Physiol Renal Physiol. 2014 Oct 1;307(7):F833-43. doi: 10.1152/ajprenal.00141.2014. Epub 2014 Aug 6. PMID: 25100281; PMCID: PMC4187043.
[3]: Hosseini A, Shafiee-Nick R, et,al. Differential metabolic effects of novel cilostamide analogs, methyl carbostiryl derivatives, on mouse and hyperglycemic rat. Iran J Basic Med Sci. 2012 Jul;15(4):916-25. PMID: 23493150; PMCID: PMC3586914.
[4]: Crosswhite P, Sun Z. Inhibition of phosphodiesterase-1 attenuates cold-induced pulmonary hypertension. Hypertension. 2013 Mar;61(3):585-92. doi: 10.1161/HYPERTENSIONAHA.111.00676. Epub 2013 Jan 14. PMID: 23319544; PMCID: PMC4050371.
[5]: Chanoit G, Zhou J,et,al. Inhibition of phosphodiesterases leads to prevention of the mitochondrial permeability transition pore opening and reperfusion injury in cardiac H9c2 cells. Cardiovasc Drugs Ther. 2011 Aug;25(4):299-306. doi: 10.1007/s10557-011-6310-z. PMID: 21643720.
[6]: Lepski G, Jannes CE, et,al. cAMP promotes the differentiation of neural progenitor cells in vitro via modulation of voltage-gated calcium channels. Front Cell Neurosci. 2013 Sep 19;7:155. doi: 10.3389/fncel.2013.00155. PMID: 24065885; PMCID: PMC3777016.
[7]: Soderling SH, Bayuga SJ, et,al. Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J Biol Chem. 1998 Jun 19;273(25):15553-8. doi: 10.1074/jbc.273.25.15553. PMID: 9624145.
IBMX 是一种非特异性磷酸二酯酶 (PDE) 抑制剂，可抑制 PDE3、PDE4 和 PDE5，IC50 值为 6.5、26.3 和 31.7 μm，但 PDE8A、PDE8B 和 PDE9 除外 [1,7]。
在心脏 H9c2 细胞中，IBMX 减少了由 H(2)O(2) 引起的 δψm 损失，表明抑制 PDE 可以阻止 mPTP 开放。然而，IBMX 不能抑制转染组成型活性 GSK-3β 的细胞的孔隙开放； (GSK-3β-S9A) 突变体，表明 GSK-3β 的关键作用；在 IBMX 的行动中。 IBMX 还减少了 GSK-3β 中的再灌注损伤；依赖方式[5]。使用 Forskolin 或 IBMX 增加 cAMP 信号显着促进神经元功能成熟。将 IBMX 持续应用于分化培养基可显着提高电压门控 Na(+) 和 K(+) 通道的功能表达，以及神经元放电频率[6]。
长期暴露于寒冷导致大鼠肺动脉高压和磷酸二酯酶-1C (PDE-1C) 表达增加。暴露于寒冷 8 周后，用 8-IBMX 治疗显着减弱了寒冷引起的右心室压力增加。冷暴露也会导致右心室肥大，而 8-IBMX 可逆转冷诱导的右心室肥大。 8-IBMX 消除了 PA 中冷诱导的 PDE-1C 上调 [4]。在高血糖大鼠中，所有测试化合物均降低血糖，米力农的作用被格列本脲增强。米力农或 IBMX 不会改变血浆胰岛素水平，但米力农和格列本脲的组合会增加血浆胰岛素水平。在这两个物种中，IBMX、mc5、mc6 或 MCPIP 降低了肝糖原储存，mc2 增加了肝糖原储存，并且在 mc1 [3] 存在的情况下没有改变。 ANG II 增加了 CCD 中的 ROMK 通道活动，这些 CCD 是从高 K (HK) 喂养的大鼠中分离出来的，但不是正常的 K (NK) 喂养的大鼠。用广谱 PDE 抑制剂 IBMX 或 PDE3 抑制剂西洛酰胺预处理 CCD，消除了 ANG II 对 ROMK 通道的刺激作用[2]。
| Kinase experiment [1]: | |
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Preparation Method |
Purified protein containing PDE3, 4 or 5 enzyme was resuspended in 50 mM Tris HCl containing 5 mM MgCl2 (pH 7.5). Subsequently, the enzyme (11.5 mg ml 1, 10 μl) was incubated with Tris HCl (80 μl) and 10 μM cyclic GMP or cyclic AMP substrate (final concentration 1 μM containing 0.1 μCi [3H]-cyclic GMP or [3H]-cyclic AMP) was added. After 20 min at 37 °C, the samples were heated to 100 °C for 2 min. Ophiophagus hannah snake venom (10 mg ml 1, 10 μl) was then added and incubated at 37 °C for 10 min to convert the 5 -GMP and 5 -AMP to the uncharged nucleosides, guanosine and adenosine, respectively. An ion-exchange resin (200 μl) was added to bind all unconverted cyclic GMP or cyclic AMP. IBMX as inhibitor, used to inhibit PDE detection IC50. |
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Reaction Conditions |
IBMX 10 mM in DMSO |
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Applications |
IBMX is a broad-spectrum phosphodiesterase (PDE) inhibitor that inhibits PDE3,PDE4 and PDE5 with IC50 values of 6.5,26.3 and 31.7 μm, respectively. |
| Cell experiment [2]: | |
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Cell lines |
Cortical collecting duct (CCD) |
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Preparation Method |
Cells were grown in 24-well plates with 105 cells per well at confluence, monolayers were washed with phosphate buffer solution (PBS) and incubated with KMUP-1 (0.1-100μM) in the presence of 100uM IBMX for 20 min by adding 10% trichloroacetic acid (TCA) to stop the incubation. |
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Reaction Conditions |
100μM IBMX for 20 minutes |
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Applications |
IBMX (100 μM) activates renal outer medullary K+ (ROMK) channels (n=6, P |
| Animal experiment [3]: | |
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Animal models |
Six groups of male Sprague–Dawley rats were used (150?80 g) |
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Preparation Method |
After 8 weeks of exposure to cold, 3 groups in each temperature condition received continuous intravenous infusion of 8-isobutyl-methylxanthine (8-IBMX) (PDE-1 inhibitor, 8.5 mg/kg per day),apocynin and vehicle. |
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Dosage form |
8.5 mg/kg/day for 1 week |
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Applications |
Treatments with IBMX and Apocynin significantly decrease cold-induced elevation of right ventricular (RV) systolic pressure although they do not decrease RV pressure to the warm control levels. IBMX or Apocynin significantly reduces medial layer thickness and increases lumen diameter of small PAs in cold-exposed rats. |
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参考文献: [1]. Wu BN, Lin RJ,et,al. KMUP-1, a xanthine derivative, induces relaxation of guinea-pig isolated trachea: the role of the epithelium, cyclic nucleotides and K+ channels. Br J Pharmacol. 2004 Aug;142(7):1105-14. doi: 10.1038/sj.bjp.0705791. Epub 2004 Jul 5. PMID: 15237094; PMCID: PMC1575170. [2]. Wei Y, Liao Y,et,al. Angiotensin II type 2 receptor regulates ROMK-like K? channel activity in the renal cortical collecting duct during high dietary K? adaptation. Am J Physiol Renal Physiol. 2014 Oct 1;307(7):F833-43. doi: 10.1152/ajprenal.00141.2014. Epub 2014 Aug 6. PMID: 25100281; PMCID: PMC4187043. [3]. Crosswhite P, Sun Z. Inhibition of phosphodiesterase-1 attenuates cold-induced pulmonary hypertension. Hypertension. 2013 Mar;61(3):585-92. doi: 10.1161/HYPERTENSIONAHA.111.00676. Epub 2013 Jan 14. PMID: 23319544; PMCID: PMC4050371. |
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