Endothelium-Dependent Hyperpolarization (EDH) in Hypertension: The Role of Endothelial Ion Channels

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2018 Jan 25

PMID 29361737

Citations 31

Authors

Kenichi Goto

Toshio Ohtsubo

Takanari Kitazono

Affiliations

Soon will be listed here.

Abstract

Upon stimulation with agonists and shear stress, the vascular endothelium of different vessels selectively releases several vasodilator factors such as nitric oxide and prostacyclin. In addition, vascular endothelial cells of many vessels regulate the contractility of the vascular smooth muscle cells through the generation of endothelium-dependent hyperpolarization (EDH). There is a general consensus that the opening of small- and intermediate-conductance Ca-activated K⁺ channels (SK and IK) is the initial mechanistic step for the generation of EDH. In animal models and humans, EDH and EDH-mediated relaxations are impaired during hypertension, and anti-hypertensive treatments restore such impairments. However, the underlying mechanisms of reduced EDH and its improvement by lowering blood pressure are poorly understood. Emerging evidence suggests that alterations of endothelial ion channels such as SK channels, inward rectifier K⁺ channels, Ca-activated Cl channels, and transient receptor potential vanilloid type 4 channels contribute to the impaired EDH during hypertension. In this review, we attempt to summarize the accumulating evidence regarding the pathophysiological role of endothelial ion channels, focusing on their relationship with EDH during hypertension.

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References

Taylor M, Bonev A, Gross T, Eckman D, Brayden J, Bond C . Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure. Circ Res. 2003; 93(2):124-31. DOI: 10.1161/01.RES.0000081980.63146.69. View

Lu C, McMahon D . Modulation of hybrid bass retinal gap junctional channel gating by nitric oxide. J Physiol. 1997; 499 ( Pt 3):689-99. PMC: 1159287. DOI: 10.1113/jphysiol.1997.sp021961. View

Kitazono T, Heistad D, Faraci F . ATP-sensitive potassium channels in the basilar artery during chronic hypertension. Hypertension. 1993; 22(5):677-81. DOI: 10.1161/01.hyp.22.5.677. View

Longden T, Nelson M . Vascular inward rectifier K+ channels as external K+ sensors in the control of cerebral blood flow. Microcirculation. 2015; 22(3):183-96. PMC: 4404517. DOI: 10.1111/micc.12190. View

Haddy F, Vanhoutte P, Feletou M . Role of potassium in regulating blood flow and blood pressure. Am J Physiol Regul Integr Comp Physiol. 2006; 290(3):R546-52. DOI: 10.1152/ajpregu.00491.2005. View

Waldron G, Ding H, Lovren F, Kubes P, Triggle C . Acetylcholine-induced relaxation of peripheral arteries isolated from mice lacking endothelial nitric oxide synthase. Br J Pharmacol. 1999; 128(3):653-8. PMC: 1571697. DOI: 10.1038/sj.bjp.0702858. View

Minami K, Hirata Y, Tokumura A, Nakaya Y, Fukuzawa K . Protein kinase C-independent inhibition of the Ca(2+)-activated K+ channel by angiotensin II and endothelin-1. Biochem Pharmacol. 1995; 49(8):1051-6. DOI: 10.1016/0006-2952(95)98500-9. View

Sunano S, Watanabe H, Tanaka S, Sekiguchi F, Shimamura K . Endothelium-derived relaxing, contracting and hyperpolarizing factors of mesenteric arteries of hypertensive and normotensive rats. Br J Pharmacol. 1999; 126(3):709-16. PMC: 1565861. DOI: 10.1038/sj.bjp.0702355. View

Giachini F, Carneiro F, Lima V, Carneiro Z, Dorrance A, Webb R . Upregulation of intermediate calcium-activated potassium channels counterbalance the impaired endothelium-dependent vasodilation in stroke-prone spontaneously hypertensive rats. Transl Res. 2009; 154(4):183-93. PMC: 2779552. DOI: 10.1016/j.trsl.2009.07.003. View

10.

Sandow S, Tare M, Coleman H, Hill C, Parkington H . Involvement of myoendothelial gap junctions in the actions of endothelium-derived hyperpolarizing factor. Circ Res. 2002; 90(10):1108-13. DOI: 10.1161/01.res.0000019756.88731.83. View

11.

Edwards G, Dora K, Gardener M, Garland C, Weston A . K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature. 1998; 396(6708):269-72. DOI: 10.1038/24388. View

12.

Yamamoto Y, Suzuki H . Dependency of endothelial cell function on vascular smooth muscle cells in guinea-pig mesenteric arteries and arterioles. J Smooth Muscle Res. 2005; 41(2):77-85. DOI: 10.1540/jsmr.41.77. View

13.

Hill C, Phillips J, Sandow S . Heterogeneous control of blood flow amongst different vascular beds. Med Res Rev. 2001; 21(1):1-60. DOI: 10.1002/1098-1128(200101)21:1<1::aid-med1>3.0.co;2-6. View

14.

Sandow S, Hill C . Incidence of myoendothelial gap junctions in the proximal and distal mesenteric arteries of the rat is suggestive of a role in endothelium-derived hyperpolarizing factor-mediated responses. Circ Res. 2000; 86(3):341-6. DOI: 10.1161/01.res.86.3.341. View

15.

Weston A, Porter E, Harno E, Edwards G . Impairment of endothelial SK(Ca) channels and of downstream hyperpolarizing pathways in mesenteric arteries from spontaneously hypertensive rats. Br J Pharmacol. 2010; 160(4):836-43. PMC: 2935991. DOI: 10.1111/j.1476-5381.2010.00657.x. View

16.

Dora K, Sandow S, Gallagher N, Takano H, Rummery N, Hill C . Myoendothelial gap junctions may provide the pathway for EDHF in mouse mesenteric artery. J Vasc Res. 2003; 40(5):480-90. DOI: 10.1159/000074549. View

17.

More A, Mishra J, Hankins G, Yallampalli C, Sathishkumar K . Enalapril Normalizes Endothelium-Derived Hyperpolarizing Factor-Mediated Relaxation in Mesenteric Artery of Adult Hypertensive Rats Prenatally Exposed to Testosterone. Biol Reprod. 2015; 92(6):155. PMC: 4652613. DOI: 10.1095/biolreprod.115.130468. View

18.

Adeagbo A, Joshua I, Falkner C, Matheson P . Tempol, an antioxidant, restores endothelium-derived hyperpolarizing factor-mediated vasodilation during hypertension. Eur J Pharmacol. 2003; 481(1):91-100. DOI: 10.1016/j.ejphar.2003.09.005. View

19.

Gao Y, Zhang Y, Hirota S, Janssen L, Lee R . Vascular relaxation response to hydrogen peroxide is impaired in hypertension. Br J Pharmacol. 2004; 142(1):143-9. PMC: 1574920. DOI: 10.1038/sj.bjp.0705727. View

20.

Jackson W . K channels and the regulation of vascular smooth muscle tone. Microcirculation. 2017; 25(1). PMC: 5760307. DOI: 10.1111/micc.12421. View