Chloride Ions, Vascular Function and Hypertension

Abstract

Blood pressure is determined by cardiac output and systemic vascular resistance, and mediators that induce vasoconstriction will increase systemic vascular resistance and thus elevate blood pressure. While peripheral vascular resistance reflects a complex interaction of multiple factors, vascular ion channels and transporters play important roles in the regulation of vascular tone by modulating the membrane potential of vascular cells. In vascular smooth muscle cells, chloride ions (Cl^-) are a type of anions accumulated by anion exchangers and the anion-proton cotransporter system, and efflux of Cl^- through Cl^- channels depolarizes the membrane and thereby triggers vasoconstriction. Among these Cl^- regulatory pathways, emerging evidence suggests that upregulation of the Ca²⁺-activated Cl^- channel TMEM16A in the vasculature contributes to the increased vascular contractility and elevated blood pressure in hypertension. A robust accumulation of intracellular Cl^- in vascular smooth muscle cells through the increased activity of Na⁺-K⁺-2Cl^- cotransporter 1 (NKCC1) during hypertension has also been reported. Thus, the enhanced activity of both TMEM16A and NKCC1 could act additively and sequentially to increase vascular contractility and hence blood pressure in hypertension. In this review, we discuss recent findings regarding the role of Cl^- in the regulation of vascular tone and arterial blood pressure and its association with hypertension, with a particular focus on TMEM16A and NKCC1.

Keywords: Na+–K+–2Cl− cotransporter 1; TMEM16A; calcium-activated chloride channel; chloride; hypertension; smooth muscle.

Figure 1

Acetylcholine (ACh)-evoked depolarization in mesenteric arteries of spontaneously hypertensive rats (SHRs). (a) A hidden depolarization emerged after blockade of endothelium-dependent hyperpolarization (EDH) with apamin (0.5 μmol/L, a small-conductance Ca²⁺-sensitive K⁺ channel (K_Ca) inhibitor) plus TRAM34 (100 nmol/L, an intermediate-conductance K_Ca inhibitor) in mesenteric arteries of SHRs. All recordings were from the same cell. (b) ACh-evoked depolarization in the presence of apamin (0.5 μmol/L) plus charybdotoxin (60 nmol/L, a large and intermediate-conductance K_Ca inhibitor) was larger in amplitude and faster in time course in SHRs than in Wistar Kyoto (WKY) rats. Each paired recording was from the same preparation. Indomethacin (10 μmol/L) and N^ω-nitro-L-arginine methyl ester (100 μmol/L) were present throughout. Arrows, application of ACh. Modified from Goto et al. [87].

Figure 2

Effects of niflumic acid on acetylcholine-induced, endothelium-dependent hyperpolarization (EDH) in mesenteric arteries of spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats. Niflumic acid (50 μmol/L) improved EDH in SHRs but not in WKY rats. Each paired recording was from the same preparation. Indomethacin (10 μmol/L) and N^ω-nitro-L-arginine methyl ester (100 μmol/L) were present throughout.

Figure 3

Upregulation of endothelial TMEM16A impairs endothelial function in hypertension. In hypertension, the expression and function of vascular endothelial Ca²⁺-activated Cl^— channel TMEM16A are increased. Endothelial stimulation with agonists and shear stress increases the intracellular Ca²⁺concentration, which subsequently activates endothelial small-conductance Ca²⁺-activated K⁺ channels (SK_Cas), intermediate-conductance K_Ca (IK_Ca) and TMEM16A simultaneously. The endothelium-dependent hyperpolarization (EDH) through the activation of both SK_Ca and IK_Ca is reduced by the opposing membrane depolarization evoked by the activation of TMEM16A. In addition, activation of TMEM16A may facilitate the generation of reactive oxygen species (ROS) through Nox2-containing NADPH oxidase, leading to reduced bioavailability of nitic oxide (NO). Impaired EDH and/or NO could be at least partly responsible for the blood pressure rise in hypertension.

Figure 4

Upregulation of smooth muscle Na⁺–K⁺–2Cl⁻ cotransporter 1 (NKCC1) and TMEM16A additively and sequentially increases vascular contractility in hypertension. In hypertension, the intracellular concentration of Cl⁻ is increased in vascular smooth muscle cells because of the increased activity of NKCC1. The increase in the intracellular Cl⁻ concentration then increases the driving force for Cl⁻ efflux via the Ca²⁺-activated Cl⁻ channel TMEM16A when TMEM16A is activated by intracellular Ca²⁺ rise upon stimulation with vasoconstricting agonists, which in turn induces membrane depolarization. TMEM16A might be regulated by a local Ca²⁺ increase that could be generated by IP₃R channels on the sarcoplasmic reticulum (SR) and/or transient receptor potential (TRP) channels. The membrane depolarization would then enhance the open probability of voltage-gated L-type Ca²⁺ channels, leading to an increase in vascular contractility and blood pressure.