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A key question in hypertension is: How is long-term blood pressure controlled? A clue is that chronic salt retention elevates an endogenous ouabain-like compound (EOLC) and induces salt-dependent hypertension mediated by Na+/Ca2+ exchange (NCX). The precise mechanism, however, is unresolved. Here we study blood pressure and isolated small arteries of mice with reduced expression of Na+ pump α1 (α1+/−) or α2 (α2+/−) catalytic subunits. Both low-dose ouabain (1–100 nm; inhibits only α2) and high-dose ouabain (≥1 μm; inhibits α1) elevate myocyte Ca2+ and constrict arteries from α1+/−, as well as α2+/− and wild-type mice. Nevertheless, only mice with reduced α2 Na+ pump activity (α2+/−), and not α1 (α1+/−), have elevated blood pressure. Also, isolated, pressurized arteries from α2+/−, but not α1+/−, have increased myogenic tone. Ouabain antagonists (PST 2238 and canrenone) and NCX blockers (SEA0400 and KB-R7943) normalize myogenic tone in ouabain-treated arteries. Only the NCX blockers normalize the elevated myogenic tone in α2+/− arteries because this tone is ouabain independent. All four agents are known to lower blood pressure in salt-dependent and ouabain-induced hypertension. Thus, chronically reduced α2 activity (α2+/− or chronic ouabain) apparently regulates myogenic tone and long-term blood pressure whereas reduced α1 activity (α1+/−) plays no persistent role: the in vivo changes in blood pressure reflect the in vitro changes in myogenic tone. Accordingly, in salt-dependent hypertension, EOLC probably increases vascular resistance and blood pressure by reducing α2 Na+ pump activity and promoting Ca2+ entry via NCX in myocytes.
Elevated blood pressure (BP), hypertension, is prevalent in developed societies, and is a major risk factor for disability and death (Kaplan, 2002; Chobanian et al. 2003). Salt (NaCl) retention by the kidneys typically leads to hypertension (Guyton, 1990; Kaplan, 2002; Johnson et al. 2005). Indeed, monogenic diseases of renal salt retention raise BP; in contrast, salt wasting syndromes lower BP (Lifton et al. 2001). Mutation, knockout or duplication of genes that affect BP induce either salt-dependent hypertension or unusual forms of salt-independent hypertension (Takahashi & Smithies, 1999). In essential hypertension, the primary defect may be an acquired renal injury rather than a genetic defect (Johnson et al. 2005). Nevertheless, none of those studies have addressed the question of precisely how salt retention leads to chronic hypertension (Kaplan, 2002; Johnson et al. 2005). In this paper we elucidate downstream molecular mechanisms and clarify the link between salt and hypertension.
Mean arterial BP depends primarily on cardiac output (CO) and total peripheral systemic vascular resistance (TPR) (Berne & Levy, 2001): at constant CO, mean BP ≈ CO × TPR. Acute plasma volume expansion elevates BP by increasing CO (Borst & Borst-de Geus, 1963; Guyton, 1990). With sustained volume expansion, however, TPR rises to maintain the elevated BP while CO declines (Borst & Borst-de Geus, 1963; Guyton, 1990). This condition of high TPR and near-normal CO is commonly observed in humans with essential hypertension (Cowley, 1992; Kaplan, 2002). Nevertheless, long-term control of BP is still poorly understood.
The shift from high CO to high TPR, called ‘whole-body autoregulation’, has been attributed to regulation of blood flow to meet metabolic demand (Guyton, 1990; Kaplan, 2002). This view is controversial (Julius, 1988), however, and the mechanisms are unresolved (Kaplan, 2002; Johnson et al. 2005). According to one hypothesis (Fig. 1) (Blaustein, 1977), salt retention promotes secretion of an endogenous cardiotonic (and vasotonic) steroid that inhibits Na+ pumps, including those in vascular smooth muscle. By raising the cytosolic Na+ concentration ([Na+]cyt), this agent would be expected to promote Na+/Ca2+ exchanger (NCX)-mediated Ca2+ entry into the myocytes. This should elevate the cytosolic Ca2+ concentration ([Ca2+]cyt), and thus increase TPR by enhancing myogenic tone, the intraluminal pressure-induced intrinsic arterial constriction that is prominent in small resistance arteries (Hill et al. 2001). Indeed, recent evidence reveals that NCX type-1 (NCX1) in arterial myocytes plays a central role in ouabain-induced hypertension and salt-dependent hypertension (Iwamoto et al. 2004b).
Figure 1. Proposed mechanism for the pathogenesis of salt-dependent hypertension Interventions such as chronic administration of exogenous ouabain, use of heterozygous null mutant mice and treatment with agents that interfere with ouabain's action or the Na+/Ca2+ exchange (NCX) are indicated on the left.
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Here we show that exogenous ouabain, at low concentrations approaching circulating EOLC levels, elevates [Ca2+]cyt and augments vasoconstriction of pressurized small arteries. Moreover, mice heterozygous for α2 Na+ pumps (James et al. 1999) (α2+/−, which mimic the effects of nanomolar ouabain), but not mice heterozygous for α1 (α1+/−), have altered artery function and elevated BP. These data demonstrate, for the first time, that modulation of α2 Na+ pump activity, and not α1, regulates small artery contractility and exerts long-term control over BP (Fig. 1).