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.

The TMEM16A channel as a potential therapeutic target in vascular disease

“…reduced in NKCC1 knockout mice [18], and NKCC1 expression and transport rate in VSMCs are increased in arteries obtained from a range of rat models of systemic hypertension [12]. These observations are consistent with the role of NKCC1 in increasing [Cl À ] i thus contributing to the generation of a depolarizing E Cl in contractile vascular cells.…”

“…Both vascular smooth muscle cells (VSMCs) and pericytes have a high intracellular Cl À concentration ([Cl À ] i ) ($30 to $50 mM), produced by the plasma membrane Na þ -K þ -2Clco-transporter NKCC1 and Cl -/HCO 3 exchanger AE2, while the physiological extracellular Cl À concentration ([Cl À ] e ) is $110 mM [12][13][14][15]. Consequently, E Cl spans from $-35 to À20 mV in these cells compared to a resting membrane potential (V rest ) of $À60 to À40 mV.…”

“…Opening of TMEM16A channels in contractile vascular cells therefore evokes Cl À efflux (Eq. ( 1)) and depolarisation, which leads to activation of voltage-gated Ca 2þ (CaV) channels, Ca 2þ influx and contraction [12][13][14] (Figs. 1 and 2).…”

“…Consistently, TMEM16A expression and function is increased in arterial VSMCs of spontaneous hypertensive rats (SHRs) [ 16 ], including in renal [ 17 ] and coronary [ 4 ] artery VSMCs. Furthermore, vascular reactivity and systemic blood pressure are reduced in NKCC1 knockout mice [ 18 ], and NKCC1 expression and transport rate in VSMCs are increased in arteries obtained from a range of rat models of systemic hypertension [ 12 ]. These observations are consistent with the role of NKCC1 in increasing [Cl − ] i thus contributing to the generation of a depolarizing E Cl in contractile vascular cells.…”

“…The role of TMEM16A in systemic and pulmonary hypertension has been recently reviewed [ 12 , 78 , 79 , 80 ], and some key studies are described above. In general, mean arterial pressure in the long-term (hours to days) is mainly modulated by renal pressure natriuresis and diuresis, and associated modulation of cardiac preload and output.…”