Potassium channel blocker

Tetraethylammonium is a commonly used potassium channel blocker

Potassium channel blockers are agents which interfere with conduction through potassium channels.

Medical uses

Arrhythmia

Effect of class III antiarrhythmic agent on cardiac action potential.

Potassium channel blockers used in the treatment of cardiac arrhythmia are classified as class III antiarrhythmic agents. Atrial cardiomyocytes contain a specific subset of potassium ion channels which are absent in the ventricles.^[1] Safety and efficacy of anti-arrhythmic potassium channel blockers will be improved by discovery of blockers specific to atria or ventricle.^[1]

Mechanism

Class III agents predominantly block the potassium channels, thereby prolonging repolarization.^[2] More specifically, their primary effect is on I_Kr.^[3]

Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. (The re-entrant rhythm is less likely to interact with tissue that has become refractory).

Examples and uses

• Amiodarone is indicated for the treatment of refractory VT or VF, particularly in the setting of acute ischemia. Amiodarone is also safe to use in individuals with cardiomyopathy and atrial fibrillation, to maintain normal sinus rhythm. Amiodarone prolongation of the action potential is uniform over a wide range of heart rates, so this drug does not have reverse use-dependent action. Amiodarone was the first agent described in this class.^[4] Amiodarone should only be used to treat adults with life-threatening ventricular arrhythmias when other treatments are ineffective or have not been tolerated.^[5]
• Dofetilide blocks only the rapid K channels; this means that at higher heart rates, when there is increased involvement of the slow K channels, dofetilide has less of an action potential-prolonging effect.
• Sotalol is indicated for the treatment of atrial or ventricular tachyarrhythmias, and AV re-entrant arrhythmias.
• Ibutilide is the only antiarrhythmic agent currently approved by the Food and Drug Administration for acute conversion of atrial fibrillation to sinus rhythm.
• Azimilide
• Bretylium
• Clofilium
• E-4031
• Nifekalant^[6]
• Tedisamil
• Sematilide

Side effects

These agents include a risk of torsades de pointes.^[7]

Anti-diabetics

Sulfonylureas, such as gliclazide, are ATP-sensitive potassium channel blockers.

Other uses

Dalfampridine, A potassium channel blocker has also been approved for use in the treatment of multiple sclerosis.^[8]

A study appears to indicate that topical spray of a selective Tandem pore Acid-Sensitive K+ (TASK 1/3 K+) (potassium antagonist) increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and obstructive sleep apnoea (OSA). ^{[9] [10]}

Reverse use dependence

Potassium channel blockers exhibit reverse use-dependent prolongation of the action potential duration. Reverse use dependence is the effect where the efficacy of the drug is reduced after repeated use of the tissue.^[11] This contrasts with (ordinary) use dependence, where the efficacy of the drug is increased after repeated use of the tissue.

Reverse use dependence is relevant for potassium channel blockers used as class III antiarrhythmics. Reverse use dependent drugs that slow heart rate (such as quinidine) can be less effective at high heart rates.^[11] The refractoriness of the ventricular myocyte increases at lower heart rates.^{[citation needed]} This increases the susceptibility of the myocardium to early Afterdepolarizations (EADs) at low heart rates.^{[citation needed]} Antiarrhythmic agents that exhibit reverse use-dependence (such as quinidine) are more efficacious at preventing a tachyarrhythmia than converting someone into normal sinus rhythm.^{[citation needed]} Because of the reverse use-dependence of class III agents, at low heart rates class III antiarrhythmic agents may paradoxically be more arrhythmogenic.

Drugs such as quinidine may be both reverse use dependent and use dependent.^[11]

Calcium-activated potassium channel blockers

Examples of calcium-activated potassium channel blockers include:

• Charybdotoxin^{[12][13][14][15]}
• Iberiotoxin^[16]
• Apamin^[17][15]

• Kaliotoxin,^[18][19]

• Lolitrem,^[20]

• BK_Ca-specific
  • GAL-021^[21]
  • Ethanol (alcohol)^[22]

Inwardly rectifying channel blockers

Examples of inwardly rectifying channel blockers include:

ROMK (K_ir1.1)

Nonselective: Ba²⁺,^[23] Cs^+[24]

GPCR regulated (K_ir3.x)

• GPCR antagonists^{[example needed]}
• Ifenprodil^[25]
• Caramiphen ^{[citation needed]}
• Cloperastine^[26][27][28]
• Clozapine ^{[citation needed]}
• Dextromethorphan ^{[citation needed]}
• Ethosuximide ^{[citation needed]}
• Tertiapin^[29][15]
• Tipepidine^[30]
• CGP-7930^[31]
• Ba^2+[23]

ATP-sensitive (K_ir6.x)

Meglitinides (Non-Sulfonylureas) Mitiglinide Nateglinide Repaglinide Sulfonylureas Acetohexamide ^[citation needed] Carbutamide ^[citation needed] Chlorpropamide ^[citation needed] Glycyclamide Metahexamide

Sulfonylureas (continued) Tolazamide Tolbutamide Glibornuride ^[citation needed] Glisoxepide Glyclopyramide Gliclazide[32] Glibenclamide (glyburide)[33][15] Glipizide ^[citation needed] Glimepiride ^[citation needed] Glicaramide ^[citation needed]

Tandem pore domain channel blockers

Examples of tandem pore domain channel blockers include:

• Bupivacaine^{[34][35][36][37]}
• Quinidine^{[35][38][39][40][41]}
• Fluoxetine^[42]
• Seproxetine (Norfluoxetine)^[42]
• 12-O-tetradecanoylphorbol-13-acetate (TPA) (phorbol 12-myristate 13-acetate).^[43]

Voltage-gated channel blockers

Examples of voltage-gated channel blockers include:

Some types of dendrotoxins[15] 3,4-Diaminopyridine (amifampridine)[44] 4-Aminopyridine (fampridine/dalfampridine)[45] Adekalant^[citation needed] Almokalant^[citation needed] Amiodarone[NB 1][46][47] Azimilide^[citation needed] Bretylium[48] Bunaftine Charybdotoxin

Clamikalant Conotoxins, such as κ-conotoxin,[49] Dalazatide Dofetilide[NB 2][50] Dronedarone,[51] E-4031[NB 3][52] Guangxitoxin[NB 4][53][54] Hanatoxin HgeTx1 HsTx1[NB 5][55]

Ibutilide,[56] Inakalant Kaliotoxin Linopirdine Lolitrem B Maurotoxin Nifekalant Notoxin Parabutoxin[57] Paxilline Pinokalant

Quinidine ShK-186 Sotalol Tedisamil Terikalant Tetraethylammonium[58][59] Verapamil[47] Vernakalant

hERG (KCNH2, K_v11.1)-specific

Ajmaline Amiodarone AmmTX3 Astemizole Azaspiracid AZD1305 Azimilide Bedaquiline BeKm-1

BmTx3 BRL-32872 Chlorpromazine Cisapride Clarithromycin Darifenacin Dextropropoxyphene Diallyl trisulfide Domperidone

E-4031 Ergtoxins Erythromycin Gigactonine Haloperidol Ketoconazole Norpropoxyphene Orphenadrine Pimozide

PNU-282,987 Promethazine Quinidine Ranolazine Roxithromycin Sertindole Solifenacin Tamulotoxin Terodiline Terfenadine

Thioridazine Tolterodine Vanoxerine Vernakalant

KCNQ (K_v7)-specific

• Linopirdine
• XE-991
• Spooky toxin (SsTx)

See also

• Potassium channel
• Potassium channel opener

Notes

1. Amiodarone also blocks CACNA2D2-containing voltage gated calcium channels
2. works by selectively blocking the rapid component of the delayed rectifier outward potassium current (I_Kr)
3. blocks potassium channels of the hERG-type
4. Primarily inhibits outward voltage-gated K_v2.1 potassium channel currents.
5. a very potent inhibitor of the rat Kv1.3 voltage-gated potassium channel

References

1. Voigt N, Dobrev D (2016). "Atrial-Selective Potassium Channel Blockers". Cardiac Electrophysiology Clinics. 8 (2): 411–421–. doi:10.1016/j.ccep.2016.02.005. PMID 27261831.
2. Lenz TL, Hilleman DE (July 2000). "Dofetilide, a new class III antiarrhythmic agent". Pharmacotherapy. 20 (7): 776–86. doi:10.1592/phco.20.9.776.35208. PMID 10907968. S2CID 19897963.
3. Riera AR, Uchida AH, Ferreira C, et al. (2008). "Relationship among amiodarone, new class III antiarrhythmics, miscellaneous agents and acquired long QT syndrome". Cardiol J. 15 (3): 209–19. PMID 18651412.
4. "Milestones in the Evolution of the Study of Arrhythmias". 16 July 2021.
5. "FDA MedWatch". Food and Drug Administration.
6. Sahara M, Sagara K, Yamashita T, Iinuma H, Fu LT, Watanabe H (August 2003). "Nifekalant hydrochloride, a novel class III antiarrhythmic agent, suppressed postoperative recurrent ventricular tachycardia in a patient undergoing coronary artery bypass grafting and the Dor approach". Circ. J. 67 (8): 712–4. doi:10.1253/circj.67.712. PMID 12890916. S2CID 44536952.
7. "Introduction: Arrhythmias and Conduction Disorders: Merck Manual Professional".
8. Judge SI, Bever CT (July 2006). "Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment". Pharmacol. Ther. 111 (1): 224–59. doi:10.1016/j.pharmthera.2005.10.006. PMID 16472864.
9. Flinders unu,UA:Sleep apnea solution could be right under your nose
10. NIH PubMed:TASK channels: channelopathies, trafficking, and receptor-mediated inhibition
11. Hondeghem, L. M. (1995), Breithardt, Günter; Borggrefe, Martin; Camm, A. John; Shenasa, Mohammad (eds.), "Use Dependence and Reverse Use Dependence of Antiarrhythmic Agents: Pro- and Antiarrhythmic Actions", Antiarrhythmic Drugs: Mechanisms of Antiarrhythmic and Proarrhythmic Actions, Springer Berlin Heidelberg, pp. 92–105, doi:10.1007/978-3-642-85624-2_6, ISBN 9783642856242
12. Thompson J, Begenisich T (May 2000). "Electrostatic interaction between charybdotoxin and a tetrameric mutant of Shaker K(+) channels". Biophysical Journal. 78 (5): 2382–91. Bibcode:2000BpJ....78.2382T. doi:10.1016/S0006-3495(00)76782-8. PMC 1300827. PMID 10777734.
13. Naranjo D, Miller C (January 1996). "A strongly interacting pair of residues on the contact surface of charybdotoxin and a Shaker K+ channel". Neuron. 16 (1): 123–30. doi:10.1016/S0896-6273(00)80029-X. PMID 8562075. S2CID 16794677.
14. Yu M, Liu SL, Sun PB, Pan H, Tian CL, Zhang LH (January 2016). "Peptide toxins and small-molecule blockers of BK channels". Acta Pharmacologica Sinica. 37 (1): 56–66. doi:10.1038/aps.2015.139. PMC 4722972. PMID 26725735.
15. Rang, HP (2015). Pharmacology (8 ed.). Edinburgh: Churchill Livingstone. p. 59. ISBN 978-0-443-07145-4.
16. Candia, S; Garcia, ML; Latorre, R (1992). "Mode of action of iberiotoxin, a potent blocker of the large conductance Ca(2+)-activated K+ channel". Biophysical Journal. 63 (2): 583–90. Bibcode:1992BpJ....63..583C. doi:10.1016/S0006-3495(92)81630-2. PMC 1262182. PMID 1384740.
17. M. Stocker; M. Krause; P. Pedarzani (1999). "An apamin-sentisitive Ca²⁺-activated K⁺ current in hippocampal pyramidal neurons". PNAS. 96 (8): 4662–4667. Bibcode:1999PNAS...96.4662S. doi:10.1073/pnas.96.8.4662. PMC 16389. PMID 10200319.
18. Baldus, Marc; Becker, Stefan; Pongs, Olaf; Martin-Eauclaire, Marie-France; Hornig, Sönke; Giller, Karin; Lange, Adam (April 2006). "Toxin-induced conformational changes in a potassium channel revealed by solid-state NMR". Nature. 440 (7086): 959–962. Bibcode:2006Natur.440..959L. doi:10.1038/nature04649. ISSN 1476-4687. PMID 16612389. S2CID 4429604.
19. Martin-Eauclaire, M. F.; Mansuelle, P.; Rochat, H.; Benslimane, A.; Zerrouk, H.; Gola, M.; Jacquet, G.; Crest, M. (1992-01-25). "Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca(2+)-activated K+ channels characterized from Androctonus mauretanicus mauretanicus venom". Journal of Biological Chemistry. 267 (3): 1640–1647. doi:10.1016/S0021-9258(18)45993-5. ISSN 0021-9258. PMID 1730708.
20. Philippe, G (15 February 2016). "Lolitrem B and Indole Diterpene Alkaloids Produced by Endophytic Fungi of the Genus Epichloë and Their Toxic Effects in Livestock". Toxins. 8 (2): 47. doi:10.3390/toxins8020047. PMC 4773800. PMID 26891327.
21. McLeod, JF; Leempoels, JM; Peng, SX; Dax, SL; Myers, LJ; Golder, FJ (November 2014). "GAL-021, a new intravenous BK_Ca-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers". British Journal of Anaesthesia. 113 (5): 875–83. doi:10.1093/bja/aeu182. PMID 24989775.
22. Dopico AM, Bukiya AN, Kuntamallappanavar G, Liu J (2016). "Modulation of BK Channels by Ethanol". International Review of Neurobiology. 128: 239–79. doi:10.1016/bs.irn.2016.03.019. ISBN 9780128036198. PMC 5257281. PMID 27238266.
23. Patnaik, Pradyot (2003). Handbook of inorganic chemicals. McGraw-Hill. pp. 77–78. ISBN 978-0-07-049439-8.
24. Sackin, H; Syn, S; Palmer, L G; Choe, H; Walters, D E (Feb 2001). "Regulation of ROMK by extracellular cations". Biophysical Journal. 80 (2): 683–697. Bibcode:2001BpJ....80..683S. doi:10.1016/S0006-3495(01)76048-1. ISSN 0006-3495. PMC 1301267. PMID 11159436.
25. Kobayashi T, Washiyama K, Ikeda K (March 2006). "Inhibition of G protein-activated inwardly rectifying K+ channels by ifenprodil". Neuropsychopharmacology. 31 (3): 516–24. doi:10.1038/sj.npp.1300844. PMID 16123769. S2CID 10093765.
26. Soeda, Fumio; Fujieda, Yoshiko; Kinoshita, Mizue; Shirasaki, Tetsuya; Takahama, Kazuo (2016). "Centrally acting non-narcotic antitussives prevent hyperactivity in mice: Involvement of GIRK channels". Pharmacology Biochemistry and Behavior. 144: 26–32. doi:10.1016/j.pbb.2016.02.006. ISSN 0091-3057. PMID 26892760. S2CID 30118634.
27. YAMAMOTO, Gen; SOEDA, Fumio; SHIRASAKI, Tetsuya; TAKAHAMA, Kazuo (2011). "Is the GIRK Channel a Possible Target in the Development of a Novel Therapeutic Drug of Urinary Disturbance?". Yakugaku Zasshi. 131 (4): 523–532. doi:10.1248/yakushi.131.523. ISSN 0031-6903. PMID 21467791.
28. KAWAURA, Kazuaki; HONDA, Sokichi; SOEDA, Fumio; SHIRASAKI, Tetsuya; TAKAHAMA, Kazuo (2010). "A Novel Antidepressant-like Action of Drugs Possessing GIRK Channel Blocking Action in Rats". Yakugaku Zasshi. 130 (5): 699–705. doi:10.1248/yakushi.130.699. ISSN 0031-6903. PMID 20460867.
29. Jin, W; Lu, Z (1998). "A novel high affinity inhibitor for inward-rectifier K+ channels". Biochemistry. 37 (38): 13291–13299. doi:10.1021/bi981178p. PMID 9748337.
30. Kawaura, Kazuaki; Ogata, Yukino; Inoue, Masako; Honda, Sokichi; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo (2009). "The centrally acting non-narcotic antitussive tipepidine produces antidepressant-like effect in the forced swimming test in rats" (PDF). Behavioural Brain Research. 205 (1): 315–318. doi:10.1016/j.bbr.2009.07.004. ISSN 0166-4328. PMID 19616036. S2CID 29236491.
31. Hannan SB, Penzinger R, Mikute G, Smart TG (July 2023). "CGP7930 - An allosteric modulator of GABABRs, GABAARs and inwardly-rectifying potassium channels". Neuropharmacology. 109644. doi:10.1016/j.neuropharm.2023.109644. PMC 10951960. PMID 37422181.
32. Lawrence, C. L.; Proks, P.; Rodrigo, G. C.; Jones, P.; Hayabuchi, Y.; Standen, N. B.; Ashcroft, F. M. (2001). "Gliclazide produces high-affinity block of K ATP channels in mouse isolated pancreatic beta cells but not rat heart or arterial smooth muscle cells". Diabetologia. 44 (8): 1019–25. doi:10.1007/s001250100595. PMID 11484080. S2CID 12635381.
33. Serrano-Martín X, Payares G, Mendoza-León A (December 2006). "Glibenclamide, a blocker of K+(ATP) channels, shows antileishmanial activity in experimental murine cutaneous leishmaniasis". Antimicrob. Agents Chemother. 50 (12): 4214–6. doi:10.1128/AAC.00617-06. PMC 1693980. PMID 17015627.
34. Kindler CH, Yost CS, Gray AT (Apr 1999). "Local anesthetic inhibition of baseline potassium channels with two pore domains in tandem". Anesthesiology. 90 (4): 1092–102. doi:10.1097/00000542-199904000-00024. PMID 10201682.
35. Meadows HJ, Randall AD (Mar 2001). "Functional characterisation of human TASK-3, an acid-sensitive two-pore domain potassium channel". Neuropharmacology. 40 (4): 551–9. doi:10.1016/S0028-3908(00)00189-1. PMID 11249964. S2CID 20181576.
36. Kindler CH, Paul M, Zou H, Liu C, Winegar BD, Gray AT, Yost CS (Jul 2003). "Amide local anesthetics potently inhibit the human tandem pore domain background K+ channel TASK-2 (KCNK5)". The Journal of Pharmacology and Experimental Therapeutics. 306 (1): 84–92. doi:10.1124/jpet.103.049809. PMID 12660311. S2CID 1621972.
37. Punke MA, Licher T, Pongs O, Friederich P (Jun 2003). "Inhibition of human TREK-1 channels by bupivacaine". Anesthesia and Analgesia. 96 (6): 1665–73. doi:10.1213/01.ANE.0000062524.90936.1F. PMID 12760993. S2CID 39630495.
38. Lesage F, Guillemare E, Fink M, Duprat F, Lazdunski M, Romey G, Barhanin J (Mar 1996). "TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure". The EMBO Journal. 15 (5): 1004–11. doi:10.1002/j.1460-2075.1996.tb00437.x. PMC 449995. PMID 8605869.
39. Duprat F, Lesage F, Fink M, Reyes R, Heurteaux C, Lazdunski M (Sep 1997). "TASK, a human background K+ channel to sense external pH variations near physiological pH". The EMBO Journal. 16 (17): 5464–71. doi:10.1093/emboj/16.17.5464. PMC 1170177. PMID 9312005.
40. Reyes R, Duprat F, Lesage F, Fink M, Salinas M, Farman N, Lazdunski M (Nov 1998). "Cloning and expression of a novel pH-sensitive two pore domain K+ channel from human kidney". The Journal of Biological Chemistry. 273 (47): 30863–9. doi:10.1074/jbc.273.47.30863. PMID 9812978. S2CID 20414039.
41. Meadows HJ, Benham CD, Cairns W, Gloger I, Jennings C, Medhurst AD, Murdock P, Chapman CG (Apr 2000). "Cloning, localisation and functional expression of the human orthologue of the TREK-1 potassium channel". Pflügers Archiv. 439 (6): 714–22. doi:10.1007/s004240050997. PMID 10784345.
42. Kennard (2005). "Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its metabolite norfluoxetine". British Journal of Pharmacology. 144 (6): 821–9. doi:10.1038/sj.bjp.0706068. PMC 1576064. PMID 15685212.
43. "UniProtKB - Q9NPC2 (KCNK9_HUMAN)". Uniprot. Retrieved 2019-05-29.
44. Kirsch GE, Narahashi T (June 1978). "3,4-diaminopyridine. A potent new potassium channel blocker". Biophys J. 22 (3): 507–12. Bibcode:1978BpJ....22..507K. doi:10.1016/s0006-3495(78)85503-9. PMC 1473482. PMID 667299.
45. Judge S, Bever C (2006). "Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment". Pharmacol. Ther. 111 (1): 224–59. doi:10.1016/j.pharmthera.2005.10.006. PMID 16472864.
46. "Amiodarone". Drugbank. Retrieved 2019-05-28.
47. Wang, Shao-Ping; Wang, Jian-An; Luo, Rong-Hua; Cui, Wen-Yu; Wang, Hai (September 2008). "Potassium channel currents in rat mesenchymal stem cells and their possible roles in cell proliferation". Clinical and Experimental Pharmacology & Physiology. 35 (9): 1077–1084. doi:10.1111/j.1440-1681.2008.04964.x. ISSN 1440-1681. PMID 18505444. S2CID 205457755.
48. Tiku, Patience E.; Nowell, Peter T. (1991). "Selective inhibition of K⁺-stimulation of Na,K-ATPase by bretylium". British Journal of Pharmacology. 104 (4): 895–900. doi:10.1111/j.1476-5381.1991.tb12523.x. PMC 1908819. PMID 1667290.
49. Shon KJ, Stocker M, Terlau H, Stühmer W, Jacobsen R, Walker C, Grilley M, Watkins M, Hillyard DR, Gray WR, Olivera BM (1998). "kappa-Conotoxin PVIIA is a peptide inhibiting the shaker K+ channel". J. Biol. Chem. 273 (1): 33–38. doi:10.1074/jbc.273.1.33. PMID 9417043. S2CID 26009966.
50. Roukoz H; Saliba W (January 2007). "Dofetilide: a new class III antiarrhythmic agent". Expert Rev Cardiovasc Ther. 5 (1): 9–19. doi:10.1586/14779072.5.1.9. PMID 17187453. S2CID 11255636.
51. Guillemare E, Marion A, Nisato D, Gautier P, “Inhibitory effects of dronedarone on muscarinic K+ current in guinea pig atrial cells,” in Journal of Cardiovascular Pharmacology, 2000 7
52. Kim I, Boyle KM, Carrol JL (2005) Postnatal development of E-4031-sensitive potassium current in rat carotid chemoreceptor cells. J Appl Physiol 98(4):1469-1477,
53. Herrington J, Zhou YP, Bugianesi RM, Dulski PM, Feng Y, Warren VA, Smith MM, Kohler MG, Garsky VM, Sanchez M, Wagner M, Raphaelli K, Banerjee P, Ahaghotu C, Wunderler D, Priest BT, Mehl JT, Garcia ML, McManus OB, Kaczorowski GJ, Slaughter RS (April 2006). "Blockers of the delayed-rectifier potassium current in pancreatic beta-cells enhance glucose-dependent insulin secretion". Diabetes. 55 (4): 1034–42. doi:10.2337/diabetes.55.04.06.db05-0788. PMID 16567526.
54. Herrington J (February 2007). "Gating modifier peptides as probes of pancreatic beta-cell physiology". Toxicon. 49 (2): 231–8. Bibcode:2007Txcn...49..231H. doi:10.1016/j.toxicon.2006.09.012. PMID 17101164.
55. Lebrun, Bruno (1997). "A four-disulphide-bridged toxin, with high affinity towards voltage-gated K+ channels, isolated from Heterometrus spinnifer (Scorpionidae) venom". Biochemical Journal. 328 (Pt 1): 321–327. doi:10.1042/bj3280321. PMC 1218924. PMID 9359871.
56. Murray, K. T. (10 February 1998). "Ibutilide". Circulation. 97 (5): 493–497. doi:10.1161/01.CIR.97.5.493. PMID 9490245.
57. Huys, I; Olamendi-Portugal, T; Garci-Goméz, BI; Vandenberghe, I (2004). "A subfamily of acidic alpha-K(+) toxins". J Biol Chem. 279 (4): 2781–9. doi:10.1074/jbc.M311029200. PMID 14561751.
58. B. Hille (1967). "The selective inhibition of delayed potassium currents in nerve by tetraethylammonium ions." J. Gen. Physiol. 50 1287-1302.
59. C. M. Armstrong (1971). "Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons." J. Gen. Physiol. 58 413-437.