Pharmacologic Targeting of Endothelial Ca-activated K Channels: A Strategy to Improve Cardiovascular Function

Overview

Journal Channels (Austin)

Specialty Biochemistry

Date 2018 Mar 27

PMID 29577810

Citations 8

Authors

Cini Mathew John

Rayan Khaddaj Mallat

Grace George

Taeyeob Kim

Ramesh C Mishra

Andrew P Braun

Affiliations

Soon will be listed here.

Abstract

Endothelial small and intermediate-conductance, Ca-activated K channels (KCa2.3 and KCa3.1, respectively) play an important role in the regulation of vascular function and systemic blood pressure. Growing evidence indicates that they are intimately involved in agonist-evoked vasodilation of small resistance arteries throughout the circulation. Small molecule activators of KCa2.x and 3.1 channels, such as SKA-31, can acutely inhibit myogenic tone in isolated resistance arteries, induce effective vasodilation in intact vascular beds, such as the coronary circulation, and acutely decrease systemic blood pressure in vivo. The blood pressure-lowering effect of SKA-31, and early indications of improvement in endothelial dysfunction suggest that endothelial KCa channel activators could eventually be developed into a new class of endothelial targeted agents to combat hypertension or atherosclerosis. This review summarises recent insights into the activation of endothelial Ca activated K channels in various vascular beds, and how tools, such as SKA-31, may be beneficial in disease-related conditions.

Citing Articles

Endothelial KCa channels: Novel targets to reduce atherosclerosis-driven vascular dysfunction.

Vera O, Wulff H, Braun A Front Pharmacol. 2023; 14:1151244.

PMID: 37063294 PMC: 10102451. DOI: 10.3389/fphar.2023.1151244.

Crocin Improves Endothelial Mitochondrial Dysfunction GPx1/ROS/KCa3.1 Signal Axis in Diabetes.

Li X, Liu Y, Cao A, Li C, Wang L, Wu Q Front Cell Dev Biol. 2021; 9:651434.

PMID: 33777959 PMC: 7994751. DOI: 10.3389/fcell.2021.651434.

KCa channel activation normalizes endothelial function in Type 2 Diabetic resistance arteries by improving intracellular Ca mobilization.

Mishra R, Kyle B, Kendrick D, Svystonyuk D, Kieser T, Fedak P Metabolism. 2020; 114:154390.

PMID: 33039407 PMC: 7736096. DOI: 10.1016/j.metabol.2020.154390.

Clinical Importance of the Human Umbilical Artery Potassium Channels.

Lorigo M, Oliveira N, Cairrao E Cells. 2020; 9(9).

PMID: 32854241 PMC: 7565333. DOI: 10.3390/cells9091956.

SKA-31, an activator of Ca-activated K channels, improves cardiovascular function in aging.

John C, Khaddaj Mallat R, Mishra R, George G, Singh V, Turnbull J Pharmacol Res. 2019; 151:104539.

PMID: 31707036 PMC: 6956598. DOI: 10.1016/j.phrs.2019.104539.

References

FEIGL E . Coronary physiology. Physiol Rev. 1983; 63(1):1-205. DOI: 10.1152/physrev.1983.63.1.1. View

Faraci F, Heistad D . Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev. 1998; 78(1):53-97. DOI: 10.1152/physrev.1998.78.1.53. View

Fanger C, Neben A, Miller M, Rauer H, Wulff H, Rosa J . Calcium-activated potassium channels sustain calcium signaling in T lymphocytes. Selective blockers and manipulated channel expression levels. J Biol Chem. 2001; 276(15):12249-56. DOI: 10.1074/jbc.M011342200. View

Zhang M, Pascal J, Zhang J . Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca²⁺-sensing and SK channel activation. Proc Natl Acad Sci U S A. 2013; 110(12):4828-33. PMC: 3607015. DOI: 10.1073/pnas.1220253110. View

Mishra R, Wulff H, Hill M, Braun A . Inhibition of Myogenic Tone in Rat Cremaster and Cerebral Arteries by SKA-31, an Activator of Endothelial KCa2.3 and KCa3.1 Channels. J Cardiovasc Pharmacol. 2015; 66(1):118-27. PMC: 4500737. DOI: 10.1097/FJC.0000000000000252. View

Cervantes Gracia K, Llanas-Cornejo D, Husi H . CVD and Oxidative Stress. J Clin Med. 2017; 6(2). PMC: 5332926. DOI: 10.3390/jcm6020022. View

Cipolla M, Smith J, Kohlmeyer M, Godfrey J . SKCa and IKCa Channels, myogenic tone, and vasodilator responses in middle cerebral arteries and parenchymal arterioles: effect of ischemia and reperfusion. Stroke. 2009; 40(4):1451-7. PMC: 2755234. DOI: 10.1161/STROKEAHA.108.535435. View

Ishii T, Silvia C, HIRSCHBERG B, Bond C, Adelman J, Maylie J . A human intermediate conductance calcium-activated potassium channel. Proc Natl Acad Sci U S A. 1997; 94(21):11651-6. PMC: 23567. DOI: 10.1073/pnas.94.21.11651. View

Kohler R, Hoyer J . The endothelium-derived hyperpolarizing factor: insights from genetic animal models. Kidney Int. 2007; 72(2):145-50. DOI: 10.1038/sj.ki.5002303. View

10.

Ungvari Z, Kaley G, de Cabo R, Sonntag W, Csiszar A . Mechanisms of vascular aging: new perspectives. J Gerontol A Biol Sci Med Sci. 2010; 65(10):1028-41. PMC: 2950814. DOI: 10.1093/gerona/glq113. View

11.

Steinberg H, Chaker H, LEAMING R, Johnson A, Brechtel G, Baron A . Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest. 1996; 97(11):2601-10. PMC: 507347. DOI: 10.1172/JCI118709. View

12.

Bradding P, Wulff H . The K+ channels K(Ca)3.1 and K(v)1.3 as novel targets for asthma therapy. Br J Pharmacol. 2009; 157(8):1330-9. PMC: 2765317. DOI: 10.1111/j.1476-5381.2009.00362.x. View

13.

Arkin J, Alsdorf R, Bigornia S, Palmisano J, Beal R, Istfan N . Relation of cumulative weight burden to vascular endothelial dysfunction in obesity. Am J Cardiol. 2007; 101(1):98-101. PMC: 2199378. DOI: 10.1016/j.amjcard.2007.07.055. View

14.

Hasenau A, Nielsen G, Morisseau C, Hammock B, Wulff H, Kohler R . Improvement of endothelium-dependent vasodilations by SKA-31 and SKA-20, activators of small- and intermediate-conductance Ca2+ -activated K+ -channels. Acta Physiol (Oxf). 2011; 203(1):117-26. PMC: 3139805. DOI: 10.1111/j.1748-1716.2010.02240.x. View

15.

Fliser D, Wiecek A, Suleymanlar G, Ortiz A, Massy Z, Lindholm B . The dysfunctional endothelium in CKD and in cardiovascular disease: mapping the origin(s) of cardiovascular problems in CKD and of kidney disease in cardiovascular conditions for a research agenda. Kidney Int Suppl (2011). 2014; 1(1):6-9. PMC: 4089605. DOI: 10.1038/kisup.2011.6. View

16.

Donato A, Morgan R, Walker A, Lesniewski L . Cellular and molecular biology of aging endothelial cells. J Mol Cell Cardiol. 2015; 89(Pt B):122-35. PMC: 4522407. DOI: 10.1016/j.yjmcc.2015.01.021. View

17.

Sandoo A, Veldhuijzen van Zanten J, Metsios G, Carroll D, Kitas G . The endothelium and its role in regulating vascular tone. Open Cardiovasc Med J. 2011; 4:302-12. PMC: 3040999. DOI: 10.2174/1874192401004010302. View

18.

Cahalan M, Chandy K . The functional network of ion channels in T lymphocytes. Immunol Rev. 2009; 231(1):59-87. PMC: 3133616. DOI: 10.1111/j.1600-065X.2009.00816.x. View

19.

Miller J, Aronis K, Chrispin J, Patil K, Marine J, Martin S . Obesity, Exercise, Obstructive Sleep Apnea, and Modifiable Atherosclerotic Cardiovascular Disease Risk Factors in Atrial Fibrillation. J Am Coll Cardiol. 2016; 66(25):2899-2906. DOI: 10.1016/j.jacc.2015.10.047. View

20.

Kurian M, Berwick Z, Tune J . Contribution of IKCa channels to the control of coronary blood flow. Exp Biol Med (Maywood). 2011; 236(5):621-7. DOI: 10.1258/ebm.2011.010351. View