Salt-Sensitive Hypertension, Na+/Ca2+ Exchanger, and Vascular Smooth Muscle

doi:10.1016/j.tcm.2005.08.004

Trends in Cardiovascular Medicine

Volume 15, Issue 8, November 2005, Pages 273-277

https://doi.org/10.1016/j.tcm.2005.08.004 Get rights and content

Hypertension is the most common chronic disease and is the leading risk factor for death caused by stroke, myocardial infarction, and end-stage renal failure. The critical importance of excess salt intake in the pathogenesis of hypertension is widely recognized. However, the molecular mechanisms underlying salt-sensitive hypertension remain obscure. Recent studies using selective Na⁺/Ca²⁺ exchanger (NCX) inhibitors and genetically engineered mice provide compelling evidence that salt-sensitive hypertension is triggered by Ca²⁺ entry through NCX type 1 (NCX1) in arterial smooth muscle. Cardiotonic steroids, such as endogenous ouabain, which may contribute to the pathogenesis of salt-sensitive hypertension, seem to be necessary for NCX1-mediated hypertension. These findings have enabled us to explain how high salt intake leads to hypertension and further to describe the potential of vascular NCX1 as a new therapeutic or diagnostic target for salt-sensitive hypertension.

Section snippets

A Link Between Dietary Salt Intake and Blood Pressure

Hypertension is the most common chronic disease in the adult population, which, if untreated, can result in disability and death caused by stroke, myocardial infarction, or end-stage renal failure. High salt (sodium) intake is well documented as a major risk factor for hypertension (Haddy and Pamnani, 1995, Meneton et al. 2005, Weinberger, 1996), although both genetic and environmental factors are involved in “essential hypertension.” Large-scale epidemiological studies, such as INTERSALT (

Early Studies on the Role of Cardiotonic Steroids in Salt-Sensitive Hypertension

The critical importance of sodium retention, resulting from excess salt intake or reduced renal salt excretion, in the pathogenesis of hypertension is widely recognized, but the mechanism by which dietary salt elevates blood pressure is not fully understood. Recently discovered cardiotonic steroids (CTSs), such as endogenous ouabain and other steroids, including marinobufagenin, proscillaridin A, and bufalin, have been proposed as candidate intermediaries in the pathogenesis of salt-sensitive

Early Studies on the Role of NCX in VSM

NCX is a PM ion transporter, which transports Ca²⁺ either out of cells (the forward mode) or into cells (the reverse mode) in exchange for 3Na⁺ (Blaustein and Lederer, 1999, Shigekawa and Iwamoto, 2001, Quednau et al. 2004). This transporter is controlled by membrane potential and transmembrane gradients of Na⁺ and Ca²⁺. NCX forms a multigene family comprising NCX1, NCX2, and NCX3 (Quednau et al. 2004). NCX1 is widely expressed in the heart, kidney, brain, arteries, and other organs, whereas

Critical Role of Vascular NCX1 in Salt-Sensitive Hypertension

What is the role of NCX in the pathogenesis of salt-sensitive hypertension? It is conceivable that the answer to this critical question lies in the process described previously, but so far, it has not been clearly addressed. To explore this issue, we examined the effects of SEA0400, a specific NCX inhibitor (Matsuda et al. 2001), on various hypertensive models. As shown in Figure 1, SEA0400 lowered dose-dependently arterial blood pressure in salt-dependent hypertensive rat models, such as

How Do VSM Cells in Blood Vessels Respond to High Salt Intake?

As described above, endogenous CTSs are thought to contribute to the pathogenesis of salt-sensitive hypertension in patients and animals (Goto et al. 1992, Hamlyn et al. 1996, Hasegawa et al. 1987). Indeed, chronic administration of ouabain to rats caused hypertension, which was suppressed by SEA0400 (Iwamoto et al. 2004a). We further found that the blood from deoxycorticosterone acetate–salt-hypertensive rats contained humoral vasoconstrictors. Importantly, arterial infusion of SEA0400

Therapeutic Potential of NCX Inhibitors in Salt-Sensitive Hypertension

Vascular NCX1 may play a key role in salt-sensitive hypertension, which makes the NCX1 protein a fascinating drug target. To date, specific NCX inhibitors, such as KB-R7943 (Iwamoto et al. 1996) and SN-6 (Iwamoto et al. 2004c), as well as SEA0400 (Matsuda et al. 2001), have been developed. These NCX inhibitors, possessing a common benzyloxyphenyl structure, seem to interact with a specific receptor site in the NCX1 molecule (Iwamoto et al. 2001, Iwamoto et al. 2004b, Iwamoto et al. 2004c).

Acknowledgments

This review was supported by grants-in-aid for scientific research (16590213) from the Ministry of Education, Science and Culture of Japan and grants from the Uehara Memorial Foundation and the Salt Science Research Foundation (no. 0526).

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This review focuses on the sodium–calcium exchangers (NCX) in the left anterior descending coronary artery smooth muscle. Bathing tissues in Na⁺-substituted solutions caused them to contract. In cultured smooth muscle cells, it increased the cytosolic Ca²⁺ concentration and extracellular entry of ⁴⁵Ca²⁺. All three activities were attributed to NCX since they were inhibited by NCX inhibitors. The tissues also expressed the sarco/endoplasmic reticulum (SER) Ca²⁺ pump SERCA2b whose activity was much greater than that of NCX. Inhibiting SERCA2b with thapsigargin decreased the NCX-mediated ⁴⁵Ca²⁺ accumulation by the cells. The decrease was not observed in cells loaded with the Ca²⁺-chelator BAPTA. The results are consistent with a limited diffusional space model with a proximity between NCX and SERCA2b. NCX molecules appear to be colocalized with the subsarcolemmal SERCA2b based on studies on membrane flotation experiments and microscopic fluorescence imaging of antibody-labeled cells. Thapsigargin inhibition of SERCA2b moved NCX even closer to SER. This provides a model for the NCX-mediated Ca²⁺ refilling of SER in the arterial smooth muscle. The model for the NCX-mediated refilling of the depleted SER proposed for smooth muscle did not apply to endothelium in which NCX levels were greater and SERCA levels were lower than in smooth muscle. The effect of thapsigargin on the NCX-mediated Ca²⁺ accumulation which was observed in smooth muscle was absent in the endothelium. We propose that the coupling between NCX and smooth muscle may be tissue dependent.
Na+/Ca2+ exchanger 1/2 double-heterozygote knockout mice display increased nitric oxide component and altered colonic motility
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The Na⁺/Ca²⁺ exchanger (NCX) is a plasma membrane transporter involved in regulating intracellular Ca²⁺ concentrations. NCX is critical for Ca²⁺ regulation in cardiac muscle, vascular smooth muscle, and nerve fibers. To determine the role of NCX1 and NCX2 in gastrointestinal tissues, we examined electric field stimulation (EFS)-induced responses in the longitudinal smooth muscle of the distal colon in NCX1 and NCX2 double-heterozygote knockout mice (Double HET). We found that the amplitudes of EFS-induced relaxation that persisted during EFS were greater in Double HET than in wild-type mice (WT). Under the non-adrenergic, non-cholinergic (NANC) condition, EFS-induced relaxation in Double HET was similar in amplitude to that of WT. In the experiments in which l-NNA was added under NANC conditions following the EFS, the magnitudes of EFS-induced relaxation were smaller in Double HET than those in WT. In addition, an NCX inhibitor, SN-6, enhanced EFS-induced relaxation but did not affect EFS-induced relaxation under NANC condition, as in Double HET. Moreover, the magnitudes of relaxation induced by NOR-1, which generates NO, were greater in Double HET compared with WT. Similarly, SN-6 potentiated the magnitudes of NOR-1–induced relaxation. In this study, we demonstrate that NCX regulate colonic motility by altering the sensitivity of the inhibitory component.
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A mathematical model of calcium dynamics in vascular smooth muscle cell (SMC) was developed based on data mostly from rat mesenteric arterioles. The model focuses on (a) the plasma membrane electrophysiology; (b) Ca²⁺ uptake and release from the sarcoplasmic reticulum (SR); (c) cytosolic balance of Ca²⁺, Na⁺, K⁺, and Cl⁻ ions; and (d) IP₃ and cGMP formation in response to norepinephrine (NE) and nitric oxide (NO) stimulation. Stimulation with NE induced membrane depolarization and an intracellular Ca²⁺ ([Ca²⁺]_i) transient followed by a plateau. The plateau concentrations were mostly determined by the activation of voltage-operated Ca²⁺ channels. NE causes a greater increase in [Ca²⁺]_i than stimulation with KCl to equivalent depolarization. Model simulations suggest that the effect of [Na⁺]_i accumulation on the Na⁺/Ca²⁺ exchanger (NCX) can potentially account for this difference. Elevation of [Ca²⁺]_i within a concentration window (150–300 nM) by NE or KCl initiated [Ca²⁺]_i oscillations with a concentration-dependent period. The oscillations were generated by the nonlinear dynamics of Ca²⁺ release and refilling in the SR. NO repolarized the NE-stimulated SMC and restored low [Ca²⁺]_i mainly through its effect on Ca²⁺-activated K⁺ channels. Under certain conditions, Na⁺–K⁺-ATPase inhibition can result in the elevation of [Na⁺]_i and the reversal of NCX, increasing resting cytosolic and SR Ca²⁺ content, as well as reactivity to NE. Blockade of the NCX's reverse mode could eliminate these effects. We conclude that the integration of the selected cellular components yields a mathematical model that reproduces, satisfactorily, some of the established features of SMC physiology. Simulations suggest a potential role of intracellular Na⁺ in modulating Ca²⁺ dynamics and provide insights into the mechanisms of SMC constriction, relaxation, and the phenomenon of vasomotion. The model will provide the basis for the development of multi-cellular mathematical models that will investigate microcirculatory function in health and disease.
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Reversal of the plasma membrane Na⁺/Ca²⁺ exchanger (NCX) has been shown to mediate Ca²⁺ influx in response to activation of G-protein linked receptors. Functional coupling of reverse-mode NCX with canonical transient receptor potential channels (TRPC), specifically TRPC6, has recently been demonstrated by our laboratory to mediate Ca²⁺ influx in rat aortic smooth muscle cells (RASMCs) following ATP stimulation. In this communication, we provide further detail of this functional coupling by indirectly measuring NCX reversal. We found that NCX reversal, induced by the removal of extracellular Na⁺, was increased following stimulation with ATP and the diacylglycerol analog 1-Oleoyl-2-acetyl-sn-glycerol. This increased NCX reversal was attenuated by SKF-96365, an inhibitor of non-selective cation channels, and by activation of protein kinase C with phorbol ester 12-tetradecanoylphorbol-13 acetate. These data are consistent with the known properties of TRPC6 and further support that functional coupling of TRPC6 and NCX occurs via a receptor-operated, rather than store-operated, cascade in RASMCs.
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We developed a method to quantitatively evaluate the potency of Na⁺/Ca²⁺ exchanger (NCX) inhibitors with fluorescence microscopy in NCX1-transfected HEK 293 cells. The reverse mode and forward mode NCX activities were measured as the ascending slope of the early phase increase in cytoplasmic Ca²⁺ concentration after change to low Na⁺ extracellular solution and the descending rate (inverse of the exponential time constant) on return to normal solution, respectively. Both modes of NCX were inhibited by SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline) and KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate), and the concentration-inhibition relationships for both inhibitors were in good agreement with those previously reported in voltage clamped cardiomyocytes.
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View full text

Review articleSalt-Sensitive Hypertension, Na+/Ca2+ Exchanger, and Vascular Smooth Muscle

Section snippets

A Link Between Dietary Salt Intake and Blood Pressure

Early Studies on the Role of Cardiotonic Steroids in Salt-Sensitive Hypertension

Early Studies on the Role of NCX in VSM

Critical Role of Vascular NCX1 in Salt-Sensitive Hypertension

How Do VSM Cells in Blood Vessels Respond to High Salt Intake?

Therapeutic Potential of NCX Inhibitors in Salt-Sensitive Hypertension

Acknowledgments

Am J Med

J Biol Chem

J Biol Chem

Trends Pharmacol Sci

Ouabain augments Ca2+ transients in arterial smooth muscle without raising cytosolic Na+

Am J Physiol

Pathogenesis of essential hypertension. A link between dietary salt and high blood pressure

Hypertension

Sodium/calcium exchange: its physiological implications

Physiol Rev

Effects of SEA0400 on mutant NCX1.1 Na+–Ca2+ exchangers with altered ionic regulation

Mol Pharmacol

Remission of essential hypertension after renal transplantation

N Engl J Med

Genetic influence of renal homografts on the blood pressure of rats from different strains

Proc Soc Exp Biol Med

The α2-isoform of Na–K–ATPase mediates ouabain-induced hypertension in mice and increased vascular contractility in vitro

Am J Physiol

Intersalt revisited: further analyses of 24 hour sodium excretion and blood pressure within and across populations. Intersalt Cooperative Research Group

Bone Miner J

Antihypertensive compounds that modulate the Na–K pump

Ann N Y Acad Sci

Interaction of the Na+–K+ pump and Na+–Ca2+ exchange via [Na+]i in a restricted space of guinea-pig ventricular cells

J Physiol

Physiology and pharmacology of endogenous digitalis-like factors

Pharmacol Rev

Blood pressure control: special role of the kidneys and body fluids

Science

Role of dietary salt in hypertension

J Am Coll Nutr

Endogenous ouabain, sodium balance and blood pressure: a review and a hypothesis

J Hypertens

Increase in plasma ouabainlike inhibitor of Na+, K+–ATPase with high sodium intake in patients with essential hypertension

J Clin Hypertens

Review article
Salt-Sensitive Hypertension, Na⁺/Ca²⁺ Exchanger, and Vascular Smooth Muscle

Ouabain augments Ca²⁺ transients in arterial smooth muscle without raising cytosolic Na⁺

Effects of SEA0400 on mutant NCX1.1 Na⁺–Ca²⁺ exchangers with altered ionic regulation

The α₂-isoform of Na–K–ATPase mediates ouabain-induced hypertension in mice and increased vascular contractility in vitro

Interaction of the Na⁺–K⁺ pump and Na⁺–Ca²⁺ exchange via [Na⁺]_i in a restricted space of guinea-pig ventricular cells

Increase in plasma ouabainlike inhibitor of Na⁺, K⁺–ATPase with high sodium intake in patients with essential hypertension