Vascular KCa-channels as therapeutic targets in hypertension and restenosis disease

Abstract

Importance of the field: Cardiovascular disease is a leading cause of death in modern societies. Hyperpolarizing Ca(2+)-activated K(+) channels (K(Ca)) are important membrane proteins in the control of arterial tone and pathological vascular remodelling and thus could serve as new drug targets.

Areas covered in this review: We summarize recent advances in the field of vascular K(Ca) and their roles in cardiovascular pathologies such as hypertension and restenosis disease and draw attention to novel small-molecule channel modulators and their possible therapeutic utility. This review focuses on literature from the last four to five years.

What the reader will gain: Pharmacological opening of endothelial KCa3.1/KCa2.3 channels stimulates endothelium-derived-hyperpolarizing-factor-mediated arteriolar dilation and lowers blood pressure. Inhibition of smooth muscle KCa3.1 channels has beneficial effects in restenosis disease and atherosclerosis. We consider the therapeutic potential of KCa3.1/KCa2.3 openers as novel endothelium-specific antihypertensive drugs as well as of KCa3.1-blockers for the treatment of pathological vascular remodelling and discuss advantages and disadvantages of the pharmacotherapeutic approaches.

Take home message: Pharmacological manipulation of vascular K(Ca) channels by novel small-molecule modulators offers new venues for alternative treatments of hypertension, restenosis and atherosclerosis. Additional efforts are required to optimize these compounds and to validate them as cardiovascular-protective drugs.

Figure 1

EDHF-signaling pathways involving endothelial and smooth muscle ion channel functions. AA, arachidonic acid; ACh, acetylcholine, KCa1.1, large-conductance Ca²⁺-activated K⁺ channel; CYP, cytochrome P450 epoxygenase; EC, endothelial cell; VSMC, vascular smooth muscle cell; EETs, epoxyeicosatrienoic acids; ER, endoplasmic reticulum; GPCR, G-protein coupled receptor, KCa3.1, intermediate-conductance Ca²⁺-activated K⁺ channel; K_ir, inwardly-rectifying K⁺ channel; KCa2.3, small-conductance Ca²⁺-activated K⁺ channel subtype 3; GJ, myoendothelial gap-junction; SR, sarcoplasmic reticulum; RyR, ryanodine receptor; VDCC, voltage-dependent Ca²⁺ channel. Note, that this figure is an adapted version of a figure in a recent review by our group [20].

Figure 2

Molecular and pharmacological characteristics of KCa3.1, KCa2.X, and KCa1.1 channels. A: Activators of KCa3.1 and KCa2.1–3 channels. B: Openers of the KCa1.1 channel. Molar concentrations above structures are the reported EC₅₀s. 1-EBIO, 1-ethyl-2-benzimidazolinone; BMS-204352, ([3S]-[+]-[5-chloro-2-methoxyphenyl]-1,3-dihydro-3-fluoro-6-[trifluoromethyl]-2H-indol-2-one); CyPPA, cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine; DC-EBIO, 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazole-2-one; DHS-1, dehydrosoyasaponin-1; NS11021 1-(3,5-bis-trifluoromethyl-phenyl)-3-[4-bromo-2-(1H-tetrazol-5-yl)-phenyl]-thiourea; NS1608 (N-(3-trifluoromethyl)phenyl) N′-(2-hydroxy-5-chlorophenyl) urea; NS1619, 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one; NS309, 3-oxime-6,7-dichloro-1H-indole-2,3-dione; SKA-31, naphtho[1,2-d]thiazol-2-amine.

Figure 3

Modulation of endothelial KCa3.1 and KCa2.3 channel alters systemic blood pressure. A: Schematic illustration of the deleterious impact of KCa3.1/KCa2.3-deficiency on EDHF-dilations and blood pressure. B: Schematic illustration of the proposed blood pressure lowering effects of enhanced mRNA-expression of KCa2.3 or of pharmacological potentiation of KCa3.1 by SKA-31.

Figure 3

Modulation of endothelial KCa3.1 and KCa2.3 channel alters systemic blood pressure. A: Schematic illustration of the deleterious impact of KCa3.1/KCa2.3-deficiency on EDHF-dilations and blood pressure. B: Schematic illustration of the proposed blood pressure lowering effects of enhanced mRNA-expression of KCa2.3 or of pharmacological potentiation of KCa3.1 by SKA-31.