Amiloride (MK-870)

Amiloride (MK-870) is a selective T-type calcium channel blocker and an inhibitor of epithelial sodium channels (ENaC) and urokinase-type plasminogen activator receptor (uTPA), Ki=7 µM. It is also polycystin-2 (PC2;TRPP2) channel blocker[1-3].

Amiloride(50 mg/L;24h) decreased uPAR expression (due to the presence of lipopolysaccharide) in podocytes[4].

Amiloride is a relatively selective inhibitor of the epithelial sodium channel (ENaC) with an IC50 (the concentration required to reach 50% inhibition of an ion channel) in the concentration range of 0.1 to 0.5 µM. Amiloride is a relatively poor inhibitor of the the Na+/H+ exchanger (NHE) with an IC50 as low as 3 µM in the presence of a low external [Na+] but as high as 1 mM in the presence of a high [Na+][1]. Amiloride(0.1-1mM) together with Bumetanide completely blocked cell transition through G1 and entry into S-phase in BALB/c 3T3 cells ^[5].

Amiloride(10 mg/kg/d;3days;i.g.) might inhibit uPAR expression in podocytes of transient proteinuria induced by lipopolysaccharid in the mouse model[4]. In ApoE(-/-) mice, administration of amiloride(high-fat diets with 0.5% (w/w) amiloride;4 weeks) significantly suppressed LPS-accelerated atherosclerosis and LPS-induced increase of NHE1 activity, and reversed LPS-induced down-regulation of Bcl-2 expression[6]. Amiloride(2mg/kg/d;30days;i.p.) treatment in tumor-bearing mice(The CT26 and LLC cachexia cell models)distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth[7].

References:
[1]. Teiwes J, Toto RD. Epithelial sodium channel inhibition in cardiovascular disease. A potential role for amiloride. Am J Hypertens. 2007 Jan;20(1):109-17. doi: 10.1016/j.amjhyper.2006.05.022. PMID: 17198922.
[2]. Tang CM, Presser F, et,al. Amiloride selectively blocks the low threshold (T) calcium channel. Science. 1988 Apr 8;240(4849):213-5. doi: 10.1126/science.2451291. PMID: 2451291.
[3]. Giamarchi A, Feng S, et,al. A polycystin-2 (TRPP2) dimerization domain essential for the function of heteromeric polycystin complexes. EMBO J. 2010 Apr 7;29(7):1176-91. doi: 10.1038/emboj.2010.18. Epub 2010 Feb 18. PMID: 20168298; PMCID: PMC2857461.
[4]. Xu LB, Chi N, et,al.Amiloride, a urokinase-type plasminogen activator receptor (uTPA) inhibitor, reduces proteinurea in podocytes. Genet Mol Res. 2015 Aug 14;14(3):9518-29. doi: 10.4238/2015.August.14.15. PMID: 26345885.
[5]. Panet R, Snyder D, et,al. Amiloride added together with bumetanide completely blocks mouse 3T3-cell exit from G0/G1-phase and entry into S-phase. Biochem J. 1986 Nov 1;239(3):745-50. doi: 10.1042/bj2390745. PMID: 3548704; PMCID: PMC1147349.
[6]. Cui GM, Zhao YX, et,al.Amiloride attenuates lipopolysaccharide-accelerated atherosclerosis via inhibition of NHE1-dependent endothelial cell apoptosis. Acta Pharmacol Sin. 2013 Feb;34(2):231-8. doi: 10.1038/aps.2012.155. Epub 2012 Dec 31. PMID: 23274414; PMCID: PMC4011619.
[7]. Zhou L, Zhang T, et,al.Amiloride ameliorates muscle wasting in cancer cachexia through inhibiting tumor-derived exosome release. Skelet Muscle. 2021 Jul 6;11(1):17. doi: 10.1186/s13395-021-00274-5. PMID: 34229732; PMCID: PMC8258996.

Amiloride (MK-870)是一种选择性T型钙通道阻滞剂、上皮钠通道(ENaC)和尿激酶型纤溶酶原激活物受体(uTPA)抑制剂,Ki =7 µM。它也是polycystin-2 (PC2;TRPP2)通道阻滞剂[1-3]。

Amiloride (50mg /L;24h)降低足细胞中由于脂多糖的存在而上调的uPAR的表达[4]。Amiloride是一种相对选择性的上皮钠通道(ENaC)抑制剂,其IC50在0.1 ~ 0.5 µM的浓度范围内。Amiloride是一种相对较差的Na+/H+交换剂(NHE)抑制剂,在低外部[Na+]存在时IC50低至3 µM,而在高外部[Na+]存在时IC50高达1 mM[1]。Amiloride (0.1-1mM)联合Bumetanide完全阻断BALB/c 3T3细胞从G0/ G1期退出进入S期的过程[5]。

Amiloride (10 mg/kg/d;3days;i.g.)可能抑制脂多糖诱导的小鼠短暂性蛋白尿足细胞中uPAR的表达[4]。在ApoE(-/-)小鼠中,给予Amiloride (含0.5% (w/w)阿米洛利的高脂饮食;4weeks)可显著抑制LPS加速的动脉粥样硬化和NHE1活性升高,逆转LPS诱导的Bcl-2表达下调[6]。Amiloride(2mg/kg/d;30days;i.p.)治疗荷瘤小鼠(CT26和LLC细胞小鼠模型)明显缓解肌肉萎缩和恶病质相关特征,但不影响肿瘤生长[7]。