氟伐他汀（FLV、Lescol®、Canef®）被認為是一種合成的 3-羥基-3-甲基戊二酰輔酶 A（HMG-CoA）還原酶抑製劑，專為治療高脂血症而設計。儘管已經描述了它對 K+ 電流的影響，但對離子電流的總體作用對電可興奮細胞在很大程度上是不確定的。在這項研究中，FLV 的存在可以有效地抑制垂體腫瘤 (GH3) 細胞中響應階躍超極化的失活和復活 erg 介導的 K+ 電流 (IK(erg)) 的幅度。 FLV 對 IK(erg) 抑製作用的有效 IC50 估計為 3.2μM。在雙脈衝電壓鉗配置中，FLV (3μM) 的存在明顯地將 IK(erg) 激活曲線的中點移動到更小的負電位 10 mV，對門控電荷的修改最小。然而，當細胞暴露於 FLV 時，由長效膜超極化引起的超極化激活陽離子電流 (Ih) 的大小逐漸降低，IC50 值為 8.7μM。在持續存在 evolocumab（一種較新的降脂藥物）的情況下，隨後添加 FLV 未能進一步降低 Ih 幅度。濃度為 30μM 的這種藥物的存在溫和地降低了響應去極化命令而引起的延遲整流器 K+ 電流的幅度。在存在 30μM FLV 的情況下，檢測到電壓門控 Na+ 電流峰值幅度的最小變化。在 HL-1 心房心肌細胞中，FLV 還有效地降低了失活和復活 IK(erg) 的幅度。綜上所述，本研究強調了可靠的證據，以揭示 FLV 具有擾亂電可興奮細胞（例如，GH3 和 HL-1 細胞）中 IK(erg) 和 Ih 的幅度和門控的傾向，假設類似的體內結果出現。

Fluvastatin (FLV, Lescol®, Canef®), is regarded to be a synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase tailored for the management of hyperlipidemia. Although its effects on K+ currents have been described, the overall actions on ionic currents on electrically excitable cells are largely uncertain. In this study, The presence of FLV could effectively inhibit the amplitude of both deactivating and resurgent erg-mediated K+ current (IK(erg)) in response to step hyperpolarization in pituitary tumor (GH3) cells. The effective IC50 of FLV effect on the inhibition of IK(erg) was estimated to be 3.2 μM. With a two-pulse voltage-clamp profile, the presence of FLV (3 μM) distinctly shifted the midpoint in the activation curve of IK(erg) to less negative potential by 10 mV, with minimal modification of the gating charge. However, as cells were exposed to FLV, the magnitude of hyperpolarization-activated cation current (Ih) elicited by long-lasting membrane hyperpolarization was progressively decreased with the IC50 value of 8.7 μM. In continued presence of evolocumab, a newer lipid-lowering drug, subsequent addition of FLV failed to decrease Ih amplitude further. The presence of this drug at a concentration of 30 μM mildly decreased the amplitude of delayed-rectifier K+ currents elicited in response to depolarizing commands. Minimal modification in the peak amplitude of voltage-gated Na+ current was detected in the presence of 30 μM FLV. In HL-1 atrial cardiomyocytes, FLV also effectively decreased the amplitude of deactivating and resurgent IK(erg). Taken together, the present study highlights credible evidence to unveil that FLV has the propensity to perturb the amplitude and gating of IK(erg) and Ih in electrically excitable cells (e.g., GH3 and HL-1 cells), assuming that similar in-vivo results occur.

1. Adams SP, Sekhon SS, Tsang M, Wright JM. Fluvastatin for lowering lipids. Cochrane
Database Syst Rev 2018;3:CD012282.
2. Adhyaru BB, Jacobson TA. Safety and efficacy of statin therapy. Nat Rev Cardiol
2018;15:757-769.
3. Ali N, Begum R, Faisal MS, Khan A, Nabi M, Shehzadi G, Ullah S, Ali W. Current
statins show calcium channel blocking activity through voltage gated channels.
BMC Pharmacol Toxicol 2016;17:43.
4. Banderali U, Belke D, Singh A, Jayanthan A, Giles WR, Narendran A. Curcumin
blocks Kv11.1 (erg) potassium current and slows proliferation in the infant acute
monocytic leukemia cell line THP-1. Cell Physiol Biochem 2011;28:1169-1180.
5. Bauer CK, Meyerhof W, Schwarz JR. An inwardly rectifying K+
current in clonal rat pituitary cells and its modulation by thyrotropin-releasing
hormone. J Physiol 1990;429:169-189.
6. Belardinelli L, Giles WR, West A. Ionic mechanisms of adenosine actions in
pacemaker cells from rabbit heart. J Physiol 1988; 405:615-633.
7. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics
and drug interactions. Circulation 2004;109(23 Suppl 1):III50-7.
8. Biel M, Wahl-Schott C, Michalakis S, Zong X. Hyperpolarization-activated cation
channels: from genes to function. Physiol Rev 2009;89:847-885.
9. Calejo AL, Jorgačevski J, Rituper B, Guček A, Pereira PM, Santos MA, Potokar M,
Vardjan N, Kreft M, Gonçalves PP, Zorec R. Hyperpolarization-activated cyclic
nucleotide-gated channels and cAMP-dependent modulation of exocytosis in
cultured rat lactotrophs. J Neurosci 2014;34:15638-15647.
10. Carretero L, Llavona P, López-Hernández A, Casado P, Cutillas PR, de la Peña P,
Barros F, Domínguez P. ERK and RSK are necessary for TRH-induced inhibition
of r-ERG potassium currents in rat pituitary GH3 cells. Cell Signal 2015;27:1720-
1730.
11. Chang WT, Wu SN. Activation of voltage-gated sodium current and inhibition
of ergmediated potassium current caused by telmisartan, an antagonist of
angiotensin II type-1receptor, in HL-1 atrial cardiomyocytes. Clin Exp
Pharmacol Physiol 2018;45:797-807.
12. Cheng L, Wang X, Liu T, Tse G, Fu H, Li G. Modulation of ion channels in the
superior cervical ganglion neurons by myocardial ischemia and fluvastatin t
reatment. Front Physiol 2018;9:1157
13. Cheng LJ, Li GP, Li J, Chen Y, Wang XH. Effects of fluvastatin on characteristics of
stellate ganglion neurons in a rabbit model of myocardial ischemia. Chin Med J
(Engl) 2016;129:549-556.
14. Cheng L, Wang X, Liu T, Tse G, Fu H, Li G. Modulation of ion channels in the
superior cervical ganglion neurons by myocardial ischemia and fluvastatin
treatment. Front Physiol 2018;9:1157
15. Corsini A. Fluvastatin: effects beyond cholesterol lowering. J Cardiovasc
Pharmacol Ther 2000;5:161-175.
16. Ding C, Fu X, He Z, Chen , Xue L, Li J. Cardioprotective effects of simvastatin on
reversing electrical remodeling induced by myocardial ischemia-reperfusion in
normocholesterolemic rabbits. Chin Med J (Engl) 2008;121:551-556.
17. Fürst O, D’Avanzo N. Isoform dependent regulation of human HCN channels
by cholesterol. Sci Rep 2015;5:14270.
18. Gullo F, Ales E, Rosati B, Lecchi M, Masi A, Guasti L, Cano-Abad MF, Arcangeli A,
Lopez MG, Wanke E. ERG K+channel blockade enhances firing and
epinephrine secretion in rat chromaffin cells: the missing link to LQT2-related
sudden death? FASEB J 2003;17:330-332.
19. Hardman RM, Forsythe ID. Ether-a-go-go-related gene K+ channels contribute
to threshold excitability of mouse auditory brainstem neurons. J Physiol
2009;587:2487-2497.
20. He C, Chen F, Li B, Hu Z. Neurophysiology of HCN channels: from cellular
functions to multiple regulations. Prog Neurobiol 2014;112:1-23.
21. Höpfner M, Baradari V, Huether A, Schöfl C, Scherübl H. The insulin-like growth
factor receptor 1 is a promising target for novel treatment approaches in
neuroendocrine gastrointestinal tumours. Endocr Relat Cancer 2006;13:135-
149
22. Hsiao HT, Liu YC, Liu PY, Wu SN. Concerted suppression of Ih and activation of
IK(M) by ivabradine, and HCN-channel inhibitor, in pituitary cells and
hippocampal neurons. Brain Res Bull 2019;149:11-20.
23. Hsu HT, Lo YC, Wu SN. Characterization of convergent suppression by UCL-
2077 (3-(triphenylmethylaminomethyl)pyridine), known to inhibit slow
afterhyperpolarization, of erg-mediated potassium currents and intermediate-
conductance calcium-activated potassium channels. Int J Mol Sci 2020;21:1441.
24. Hu YF, Chen YC, Cheng CC, Higa S, Chen YJ, Chen SA. Fluvastatin reduces
pulmonary vein spontaneous activity through nitric oxide pathway. J
Cardiovasc Electrophysiol 2009;20:200-206.
25. Irisawa H, Brown HF, Giles W. Cardiac pacemaking in the sinoatrial node.
Physiol Rev 1993;73:197-227.
26. Jang HD, Lee SE, Yang J, Lee HC, Shin D, Lee H, Lee J, Jin S, Kim S, Lee SJ, You J,
Park HW, Nam KY, Lee SH, Park SW, Kim JS, Kim SY, Kwon YW, Kwak SH, Yang
HM, Kim HS. Cyclase-associated protein 1 is a binding partner of proprotein
convertase subtilisin/kexin type-9 and is required for the degradation of low-
density lipoprotein receptors by proprotein convertase subtilinisn/kexin type-
9. Eur Heart J 2019;41:239-252.
27. Kretschmannova K, Kucka M, Gonzalez-Iglesias AE, Stojilkovic SS. The
expression and role of hyperpolarization-activated and cyclic nucleotide-gated
channels in endocrine anterior pituitary cells. Mol Endocrinol 2012;26:153-164.
28. Kuo PC, Kao ZH, Lee SW, Wu SN. Effects of sesamin, the major furofuran lignan
of sesame oil, on the amplitude and gating of voltage-gated Na+
and K+currents. Molecules 2020;25:3062.
29. Labro AJ, Priest MF, Lacroix JJ, Snyders DJ, Bezanilla F. Kv3.1 uses a timely
resurgent K+current to secure action potential repolarization. Nat Commun
2015;6:10173.
30. Laszlo R, Schwiebert M, Menzel KA, Eick C, Schreiner B, Schreieck J. Effects of
dexamethasone and atorvastatin on atrial sodium current and its early
tachycardia-induced electrical remodeling in rabbits. Pak J Pharm Sci
2011;24:383-387.
31. Lawrence JM, Reckless JPD. Fluvastatin. Exp Opin Pharmacother 2002;3:1631-
1641.
32. Li DY, Liu HT, Liu XY, Wang HY, Li T, Wang XR, Jia SW, Wang P, Wang YF.
Involvement of hyperpolarization-activated cyclic nucleotide gated channel 3
in oxytocin neuronal activity in lactating rats with pup deprivation. ASN Neuro
2020;12: 1759091420944658.
33. Li L, Matsuoka I, Suzuki Y, Watanabe Y, Ishibashi T, Yokoyama K, Maruyama Y,
Kimura J. Inhibitory effect of fluvastatin on lysophosphatidylcholine-induced
nonselective cation current in guinea pig ventricular myocytes. Mol Pharmacol
2002;62:602-607.
34. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol
2005;45:89-118.
35. Liu YC, Wang YJ, Wu PY, Wu SN. Tramadol-induced block of hyperpolarization-
activated cation current in rat pituitary lactotrophs. Naunyn Schmiedebergs
Arch Pharmacol 2009;379:127-135.
36. Lu TL, Lu TJ, Wu SN. Inhibitory effective perturbations of cilobradine (DK-
AH269), a blocker of HCN channels, on the amplitude and gating of both
hyperpolarization-activated cation and delayed-rectifier potassium currents.
Int J Mol Sci 2020;21:2416.
37.Ma S, Zhao Y, Cao M, Sun C. Human ether-à-go-go-related gene mutation
L539fs/47-hERG leads to cell apoptosis through the endoplasmic reticulum
stress pathway. Int J Mol Med 2019;43:1253-1262.
38. Martinson AS, van Rossum DB, Diatta FH, Layden MJ, Rhodes SA, Martindale
MQ, Jegla T. Functional evolution of Erg potassium channel gating reveals an
ancient origin for IKr. Proc Natl Acad Sci USA 2014;111:5712-5717.
39. Mukai Y, Shimokawa H, Matoba T, Hiroki J, Kunihiro I, Fujiki T, Takeshita A. Acute
vasodilator effects of HMG-CoA reductase inhibitors: involvement of PI3
kinase/Akt pathway and Kv channels. J Cardiovasc Pharmacol 2003;42:118-124.
40. Owczarek J, Jasińska-Stroschein M, Orszulak-Michalak D. Concomitant
administration of different doses of simvastatin with ivabradine influence on
PAI-1 and heart rate in normoand hypercholesterolaemic rats. Scientific World
Journal 2012;2012:976519.
41. Pierno S, Camerino GM, Cippone V, Rolland JF, Desaphy JF, De Luca A,
Liantonio A, Bianco G, Kunic JD, George AL Jr, Conte Camerino D. Statins and
fenofibrate affect skeletal muscle chloride conductance in rats by differently
impairing CIC-1 channel regulation and expression. Br J Pharmacol
2009;156:1206-1215.
42. Raschi E, Vasina V, Poluzzi E, De Pointi F. The hERG K+ channel: target and
antitarget strategies in drug development. Pharmacol Res 2008;57:181-195.
43. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between
an inherited and an acquired cardiac arrthymia: HERG encodes the IKr
potassium channel. Cell 1995;81:290-307.
44. Schachter M. Chemical, pharmacokinetic and pharmacodynamics properties of
statins: an update. Fundam Clin Pharmacol 2004;19:117-125.
45. Schäfer R, Wulfsen I, Behrens S, Weinsberg F, Bauer CK, Schwarz JR. The erg-
like potassium current in rat lactotrophs. J Physiol 1999;518:401-416.
46. Schledermann W, Wulfsen I, Schwarz JR, Bauer CK. Modulation of rat erg1,
erg2, erg3 and HERG K+currents by thyrotropin-releasing hormone in anterior
pituitary cells via the native signal cascade. J Physiol 2001;532(Pt 1):143-163.
47. Schulman KA, Reed SD. The economics of PCSK-9 inhibitors. Am Heart J
2017;189:200-201.
48. Shen L, Guo Y, Qiu Y, Cheng T, Nie A, Cui C, Fu C, Li T, Li X, Fu L, Wang Y, Ni Q,
Qang Q, Wang W, Feng B. Atovastatin targets the islet mevalonate pathway to
dysregulate mTOR signaling and reduce -cell functional mass. Diabetes
2020;69:48-59.
49. So EC, Foo NP, Ko SY, Wu SN. Bisoprolol, known to be a selective 1-receptor
antagonist, differentially but directly suppresses IK(M) and IK(erg) in pituitary
cells and hippocampal neurons. Int J Mol Sci 2019;20:657.
50. So EC, Hsing CH, Liang CH, Wu SN. The actions of mdivi-1, an inhibitor of
mitochondrial fission, on rapidly activating delayed-rectifier K+
current and membrane potential in HL1 murine atrial cardiomyocytes. Eur J
Pharmacol 2012;683(1-3):1-9.
51. Spector PS, Curran ME, Zou A, Keating MT, Sanguinetti MC. Fast inactivation
causes rectification of the IKr channel. J Gen Physiol 1996;107:611-619.
52. Stawińska-Brych A, Zdzisińska B, Kandefer-Szerszeń M. Fluvastatin inhibits
growth and alters the malignant phenotypes of the C6 glioma cell line.
Pharmacol Rep 2014;66:121-129.
53. Traudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward
rectifier in the voltage-gated potassium channel family. Science 1995;269:92-
95.
54.Tristani-Firouzi M, Sanguinetti MC. Voltage-dependent inactivation of the
human K+channel KvLQT1 is eliminated by association with minimal K+
channel (mink) subunits.J Physiol 1998;510.1:37-45.
55.Wang H, Zhang Y, Cao L, Han H, Wang J, Yang B, Nattel S, Wang Z. HERG K+
channel, a regulator of tumor cell apoptosis and proliferation. Cancer Res
2002;62:4843-4848.
56. Wei F, Wang Q, Han J, Goswamee P, Gupta A, McQuiston AR, Liu Q, Zhou L.
Photodynamic modification of native HCN channels expressed in
thalamocortical neurons. ACS Chem Neurosci 2020;11:851-863.
57. Winters B, Brown L, Coleman I, Nguyen H, Minas TZ, Kollath L, Vasioukhin V,
Nelson P, Corey E, Üren A, Morrisey C. Inhibition of ERG activity in patient-
derived prostate cancer xenografts by YK-4-279. Anticancer Res 2017;37:3385-
3396.
58. Wu SN, Jan CR, Li HF, Chiang HT. Characterization of inhibition by risperidone
of the inwardly rectifying K+current in pituitary GH3 cells.
Neuropsychopharmacology 2000;23:676-689.
59. Wu SN, Yang WH, Yeh CC, Huang HC. The inhibition by di(2-ethylhexyl)-
phthalate oferg-mediated K+current in pituitary tumor (GH3) cells. Arch
Toxicol 2012a;86:713-723.
60. Wu SN, Yeh CC, Huang HC, So EC, Lo YC. Electrophysiological characterization
of sodium-activated potassium channels in NG108-15 and NSC-34 motor
neuron-like cells. Acta Physiol (Oxf) 2012b;206:120-134.
61. Yang C, Li F, Zhang Y, Li Y, Li M, Wang F, Zhang G, Li Y, Li B, Zhao X. Effects of
As2O3 and resveratrol on the proliferation and apoptosis of colon cancer cells
and the hERGmediated potential mechanisms. Curr Pharm Des 2019;25:1385-
1391.
62. Yang L, Liu X, Yao K, Sun Y, Jiang F, Yan H, Mao P, Fan S, Wei X, Liu Y, Yuan W,
Zhang S. HCN channel antagonist ZD7288 ameliorates neuropathic pain and
associated depression. Brain Res 2019;1717:204-213.
63. Zdebik AA. Statins and fibrate target CIC-1 – from side effects to CLC
pharmacology. Br J Pharmacol 2009;156:1204-1205.