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Molecular-Based Mechanisms of Mendelian Forms of Salt-Dependent Hypertension

2015; Lippincott Williams & Wilkins; Volume: 65; Issue: 5 Linguagem: Inglês

10.1161/hypertensionaha.114.05092

1524-4563

Theodore W. Kurtz, Anna F. Dominiczak, Stephen E. DiCarlo, Michal Pravenec, R. Curtis Morris,

Sodium Intake and Health

HomeHypertensionVol. 65, No. 5Molecular-Based Mechanisms of Mendelian Forms of Salt-Dependent Hypertension Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBMolecular-Based Mechanisms of Mendelian Forms of Salt-Dependent HypertensionQuestioning the Prevailing Theory Theodore W. Kurtz, Anna F. Dominiczak, Stephen E. DiCarlo, Michal Pravenec and R. Curtis MorrisJr Theodore W. KurtzTheodore W. Kurtz From the Department of Laboratory Medicine, University of California, San Francisco (T.W.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.F.D.); Department of Physiology, Wayne State University, Detroit, MI (S.E.D.); Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P.); and Department of Medicine, University of California, San Francisco (R.C.M.). , Anna F. DominiczakAnna F. Dominiczak From the Department of Laboratory Medicine, University of California, San Francisco (T.W.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.F.D.); Department of Physiology, Wayne State University, Detroit, MI (S.E.D.); Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P.); and Department of Medicine, University of California, San Francisco (R.C.M.). , Stephen E. DiCarloStephen E. DiCarlo From the Department of Laboratory Medicine, University of California, San Francisco (T.W.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.F.D.); Department of Physiology, Wayne State University, Detroit, MI (S.E.D.); Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P.); and Department of Medicine, University of California, San Francisco (R.C.M.). , Michal PravenecMichal Pravenec From the Department of Laboratory Medicine, University of California, San Francisco (T.W.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.F.D.); Department of Physiology, Wayne State University, Detroit, MI (S.E.D.); Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P.); and Department of Medicine, University of California, San Francisco (R.C.M.). and R. Curtis MorrisJrR. Curtis MorrisJr From the Department of Laboratory Medicine, University of California, San Francisco (T.W.K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.F.D.); Department of Physiology, Wayne State University, Detroit, MI (S.E.D.); Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (M.P.); and Department of Medicine, University of California, San Francisco (R.C.M.). Originally published9 Mar 2015https://doi.org/10.1161/HYPERTENSIONAHA.114.05092Hypertension. 2015;65:932–941Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2015: Previous Version 1 IntroductionAlthough the molecular genetic basis of >3000 Mendelian disorders has been determined, much less progress has been made in understanding the mechanisms through which the underlying genetic variants initiate Mendelian disease phenotypes. However, in Mendelian forms of salt-dependent hypertension in humans, it is widely believed that genetic research has successfully led to identification of the primary pathophysiologic mechanism by which genetic variants enable salt (NaCl) to initiate the increased blood pressure (BP) that characterizes these disorders. The primary mechanistic abnormality that enables initiation of the salt-induced hypertension in these Mendelian disorders is of considerable interest irrespective of whatever mechanisms may serve to sustain or exacerbate the hypertension.Causal mutations imparting large effects on BP have been reliably identified in more than a half dozen Mendelian disorders associated with salt (NaCl)-dependent hypertension (Table).1–4 Prevailing theory holds that identification of these molecular genetic defects has clarified the abnormal physiological mechanism that mediates initiation of such Mendelian forms of salt-dependent hypertension.2,3 Specifically, on the basis of coupling of results of the molecular genetic studies with the results of classic physiological studies by Guyton et al,5,6 it is said that "a final common pathway" exists that mediates the initiation of all Mendelian forms of salt-dependent hypertension.2,3Table. Mendelian Forms of Salt-Dependent HypertensionClinical DisorderIncreased Serum MineralocorticoidsCongenital adrenal hyperplasiaYesGlucocorticoid remediable aldosteronismYesFamilial hyperaldosteronism not remediable by glucocorticoidsYesLiddle syndromeNoHypertension exacerbated by pregnancyNoSyndrome of apparent mineralocorticoid excessNoFamilial hyperkalemic hypertensionNoCausal mutations have been identified in all of these disorders.1–4In this critical review, we examine the scientific evidence that is counter to the prevailing theory of a final common pathway proposed to account for initiation of all known Mendelian forms of salt (NaCl)-dependent hypertension in humans.2,3 One of the key questions we raise and that has not been considered in previous reviews of Mendelian forms of salt-dependent hypertension is how did this theory on the initiation of all Mendelian forms of salt-dependent hypertension come to prevail even though the hemodynamic mechanism described in the final common pathway of the theory has not been shown to mediate initiation of Mendelian forms of salt-dependent hypertension in humans or in animals? In addition to questioning whether the final common pathway of prevailing theory accounts for the initiation of all Mendelian forms of salt-dependent hypertension, we present a different pathway through which the genetic alterations may often mediate initiation of hypertension in these disorders.Prevailing Theory on How Mendelian Gene Defects Enable Salt to Initiate HypertensionThe prevailing theory holds that in all known Mendelian forms of salt-dependent hypertension in humans (Table), a genetically determined increase in activity of the epithelial sodium channel (ENaC) in the aldosterone sensitive distal nephron or the sodium-chloride cotransporter (NCC) in the distal convoluted tubule is the primary mechanistic abnormality that enables salt to initiate the hypertension.2,3,7,8 If so, how do genetically induced increases in renal tubular activity of ENaC or NCC enable increases in salt intake to initiate hypertension? According to prevailing theory, mutations that increase renal tubular activity of ENaC or NCC cause abnormally large increases in renal reabsorption of salt that increase salt balance.2,3,7,8 It is said that mutations that increase salt balance raise BP through mechanisms that can be readily explained via an initial increase in plasma volume and cardiac output.7 Specifically, an abnormal increase in renal tubular activity of ENaC or NCC is held to induce an abnormally large increase in the renal reabsorption of salt and water which in turn causes abnormally large increases in intravascular volume and cardiac output and therefore BP.2,3,7 The level of systemic vascular resistance is said to be normal during the initiation of hypertension induced by increased renal reabsorption of salt.2 This sequence of events is depicted in Figure 1, and according to Lifton et al,2 it constitutes a final common pathway for the pathogenesis of hypertension including all Mendelian forms of salt-dependent hypertension.Download figureDownload PowerPointFigure 1. The prevailing theory for the pathogenesis of Mendelian forms of salt-dependent hypertension. This sequence of events has been proposed to represent a final common pathway for the pathogenesis of hypertension.2 In this formulation,2 systemic vascular resistance is explicitly held to be normal during the onset of hypertension, and thus, salt-induced abnormalities in systemic vascular resistance are not involved in initiation of the salt-induced hypertension. The level of systemic vascular resistance is said to become abnormal only after blood pressure has increased and only after the increased cardiac output has initiated the phenomenon of autoregulation.2 Note that this pathway does not display, or take into consideration, the changes in cardiac output and systemic vascular resistance that occur in normal salt-resistant controls when salt retention is induced by increasing dietary intake of salt. The term systemic vascular resistance is synonymous with the term total peripheral resistance. Reprinted from Lifton et al2 with permission from the publisher. Copyright © 2001, Elsevier.Lifton et al2 have noted that according to Ohm's law, arterial pressure is proportional to 2 factors: cardiac output and vascular resistance. As shown in Figure 1, the prevailing theory holds that an increase in renal salt reabsorption that expands plasma volume and transiently increases cardiac output is sufficient to account for the initiation of salt-dependent hypertension (Figure 1). Because systemic vascular resistance is said to remain normal during the initiation of salt-induced increases in BP, the theory holds that abnormalities in systemic vascular resistance are not involved in the initiation of salt-induced hypertension. The theory holds that vascular resistance becomes abnormal only later through a phenomenon termed autoregulation that reverses cardiac output toward normal and gives rise to the increased systemic vascular resistance that enables the hypertension to persist.2,9–12Questioning the Prevailing TheoryThe prevailing theory of the pathogenesis of Mendelian forms of salt-dependent hypertension is said to fit nicely into our understanding of the physiology of BP regulation, with the increased intravascular volume resulting in increased cardiac output because of increased stroke volume and a rise in BP according to Ohm's law.13 This theory, which could also be termed the volume-loading/cardiac output theory, rests on the untested assumption that genetic variants that increase renal tubular activity of ENaC or NCC hemodynamically account for the initiation of all Mendelian forms of salt-dependent hypertension entirely by transiently causing abnormally high levels of cardiac output, ie, without also usually causing, or needing to be accompanied by, an abnormality in systemic vascular resistance (Figure 1). Accordingly, the present analysis focuses on several related questions: (1) is, or is not, the hemodynamic initiation of all known Mendelian forms of salt-dependent hypertension in humans (Table) usually mediated through a transient abnormally high level of cardiac output and a normal level of systemic vascular resistance? (2) In individuals with mutations underlying Mendelian forms of salt-dependent hypertension (Table), and who consume typical modern diets with abundant amounts of salt, are mutation-dependent increases in renal tubular activity of ENaC or NCC usually sufficient to account for induction of the hypertension? Or must the mutations also do something else? (3) In individuals with these mutations who consume abundant amounts of salt, are mutation-dependent increases in renal tubular activity of ENaC or NCC even necessary to account for increased risk of salt-dependent hypertension? Or could the mutations increase risk of salt-dependent hypertension even if they did not cause increases in renal tubular activity of ENaC or NCC?Prevailing Theory on How Mendelian Gene Defects Enable Salt to Initiate Hypertension: What Is the Hemodynamic Evidence?What is the evidence for the prevailing theory that an abnormally high level of cardiac output, but not of systemic vascular resistance, mediates the hemodynamic initiation of Mendelian forms of salt-dependent hypertension (Figure 1)?2 Surprisingly, there are no published studies of the serial changes in cardiac output and systemic vascular resistance that occur in humans or in animals during initiation of salt-induced hypertension in these disorders. This raises the question, on what hemodynamic evidence is the theory based?Some Mendelian forms of salt-dependent hypertension are characterized by increased circulating levels of mineralocorticoid hormones, such as aldosterone or deoxycorticosterone (DOC; Table). Therefore, in support of the prevailing theory, some investigators3 have cited studies by Montani et al6 of the hemodynamic changes, ie, changes in cardiac output and systemic vascular resistance, that occur during initiation of salt retention and hypertension induced by administering aldosterone into animals ingesting a high-salt diet. However, as discussed further, the cited studies of Montani et al6 do not include adequate controls. When the results of studies using appropriate normal controls are taken into consideration, it becomes apparent that the prevailing theory does not adequately explain how the combination of excess aldosterone and a high-salt diet initiates hypertension.Is an Aldosterone-Dependent Abnormality in Systemic Vascular Resistance Involved in the Initiation of Hypertension Induced by Aldosterone and a High-Salt Diet?As shown in Figure 2A to 2C, hemodynamic studies by Montani et al6 demonstrate that systemic vascular resistance seems to begin increasing above baseline during the initiation of salt retention and increased BP induced by intravenous administration of large amounts of aldosterone into dogs ingesting a high-salt diet (≈6 mmol/kg body weight per day). This raises the question, when salt retention is induced by aldosterone and a high-salt diet, is an aldosterone-dependent abnormality in systemic vascular resistance involved in initiation of the hypertension? To address this question, one must first define what constitutes a normal level of vascular resistance in response to initiation of salt retention with a high-salt diet alone, ie, without supplemental aldosterone. Unfortunately, Montani et al6 did not report the changes in systemic vascular resistance that normally occur in control dogs when salt-retention is induced by increasing salt intake alone, ie, without supplemental aldosterone (Figure 2A–2C). However, other investigators have reported the changes in systemic vascular resistance that occur in normal control dogs when salt retention is induced by administering a high-salt diet without supplemental aldosterone.14Download figureDownload PowerPointFigure 2. A–C, Sequential hemodynamic changes that occur with initiation of salt retention in dogs. Changes in cardiac output, systemic vascular resistance, and mean arterial pressure, respectively, that occur when salt retention is induced by switching dogs from a high-salt intake without concomitant administration of aldosterone, to a high-salt intake with concomitant administration of aldosterone (data derived from Montani et al6). D–F, Changes in cardiac output, systemic vascular resistance, and mean arterial pressure, respectively, that occur when salt retention is induced by switching normal dogs from a low-salt intake to a high-salt intake without giving supplemental aldosterone (data derived from Krieger et al14). Note that in normal control dogs (D–F) in which salt retention is initiated by a high-salt intake alone (without supplemental aldosterone), cardiac output increases and systemic vascular resistance decreases such that blood pressure does not change. In contrast, in the experimental dogs in which salt retention is induced by the combination of a high-salt intake with supplemental aldosterone (A–C), cardiac output increases, but systemic vascular resistance fails to decrease. The different blood pressure responses between aldosterone treated dogs (C) and normal dogs (F) are largely because of different vascular resistance responses to salt retention (B versus E), not different cardiac output responses to salt retention (A versus D).In normal salt-resistant control dogs maintained on a low-salt diet and not given aldosterone, studies by Krieger et al14 demonstrate that the normal cardiovascular response during the onset of sodium retention induced by greatly increasing salt intake alone (from 0.5 mmol/kg per day to 7 mmol/kg per day) is a near 10% increase in cardiac output (Figure 2D) together with vasodilation and a near 10% decrease in systemic vascular resistance (Figure 2E). Thus, in normal control dogs not given aldosterone, the distinct increase in cardiac output observed during the onset of sodium retention induced by greatly increasing salt intake alone is not sufficient to increase BP because the normal animals, ie, animals not given aldosterone, vasodilate and decrease systemic vascular resistance (Figure 2D–2F). Studies by DeClue et al15 have shown that normal control dogs not treated with aldosterone can tolerate massive salt loading (≤20–34 mmol/kg per day) and massive sodium retention (as judged by increases in 22Na space) without developing hypertension. In contrast, the presumed sodium retention and the increases in cardiac output that occur on administration of aldosterone into dogs ingesting a high-salt diet (≈ 6 mmol/kg body weight per day) are associated with the onset of hypertension because the increases in cardiac output are not accompanied by normally expected pressor offsetting decreases in systemic vascular resistance (Figure 2A–2C).6In light of the observations of Krieger et al14 (Figure 2D–2F) and DeClue et al15 made during induction of salt retention in normal control dogs not given aldosterone, the studies of Montani et al6 (Figure 2A–2C) indicate that during induction of salt retention by administration of aldosterone with a high-salt diet, an aldosterone-dependent failure to normally reduce systemic vascular resistance is involved in initiation of hypertension. This aldosterone-dependent failure to normally vasodilate and rapidly reduce systemic vascular resistance during the onset of salt retention is not apparent from the studies of Montani et al6 because their experiments did not include the requisite normal control group, ie, did not include a separate control group of normal salt-resistant dogs studied before and during salt retention induced by administering a high-salt diet alone, ie, without supplemental aldosterone.6 Montani et al6 also did not include experiments measuring the effects on cardiac output and vascular resistance of initiating aldosterone treatment in animals ingesting control diets containing low amounts of salt. The foregoing observations are at odds with the prevailing theory that an abnormality in systemic vascular resistance is not involved in the initiation of hypertension in patients with Mendelian disorders characterized by abnormally high levels of aldosterone. These observations are consistent with the possibility that an aldosterone-dependent abnormality in systemic vascular resistance, ie, an aldosterone-dependent failure to normally vasodilate and reduce systemic vascular resistance during salt retention, is involved in the initiation of salt-dependent hypertension in Mendelian disorders characterized by abnormally high levels of aldosterone (Table).How Does the Combination of DOC and a High-Salt Intake Initiate Hypertension? Implications for the Pathogenesis of Mendelian Forms of Hypertension With Increased Circulating Levels of DOCDisorders of congenital adrenal hyperplasia that are caused by mutations that decrease the activity of 11β-hydroxylase or 17α-hydroxylase are often associated with hypertension.1 These disorders were the first Mendelian forms of hypertension in which the responsible genes were cloned and causative mutations were identified, originally through the work on 11β-hydroxylase deficiency by White et al1,16 and on 17α-hydroxylase deficiency by the Waterman laboratory.17,18 Decreases in activity of either of these enzymes can give rise to increased circulating levels of mineralocorticoid hormones, including DOC. There are no published studies of the serial changes in cardiac output and systemic vascular resistance that occur during initiation of salt-dependent increases in BP in humans or animals with mutations in 11β-hydroxylase or 17α-hydroxylase. However, there are published studies of the systemic hemodynamic changes that occur during initiation of salt-dependent increases in BP in animals given DOC or metyrapone, a pharmacological inhibitor of 11β-hydroxylase.Obst et al19 reported that in mice, increases in systemic vascular resistance, not increases in cardiac output, mediate the initiation of hypertension induced by administration of DOC and salt (DOC–NaCl). The finding that DOC–NaCl treatment can induce hypertension even when increases in cardiac output are prevented by β-adrenergic blockade also indicates that increases in cardiac output are not always necessary for DOC–NaCl to initiate hypertension.20 Similarly, Miller et al21 reported that in some pigs, administration of deoxycortisterone together with ≈5 mmol NaCl/kg body weight per day initiated hypertension by inducing increases in systemic vascular resistance without inducing increases in cardiac output. In other pigs, the hypertension was initiated by increases in cardiac output that were not offset by decreases in systemic vascular resistance that might normally be expected to occur with salt retention.21 In studies by Ferrario et al22 in dogs given DOC together with ≈ 5 mmol NaCl/kg body weight per day, BP increased with salt retention because systemic vascular resistance failed to sufficiently decrease and offset the pressor effect of a 20% increase in cardiac output. Thus, Ferrario et al22 concluded that alterations in vascular reactivity may play a role in the elevated pressure associated with DOC excess. Unfortunately, none of these studies of DOC–NaCl hypertension included a control group of normal salt-resistant animals studied before and during salt retention induced by administering a high-salt diet alone, ie, without DOC. Nevertheless, the results of all of these hemodynamic studies performed during induction of salt retention by administering DOC and NaCl are consistent with the possibility that a mineralocorticoid-dependent abnormality in systemic vascular resistance, ie, a failure to normally decrease systemic vascular resistance during salt retention, is often required for the combination of DOC and NaCl to initiate hypertension.The Mendelian form of salt-dependent hypertension caused by mutations that impair 11β-hydroxylase activity1,2 can be pharmacologically mimicked by giving salt and metyrapone, an inhibitor of 11β-hydroxylase. To investigate the mechanisms whereby inhibition of 11β-hydroxylase enables salt to induce hypertension in dogs, Bravo et al23 studied the hemodynamic effects induced by administering metyrapone with a low-salt diet or with a high-salt diet. They found that in dogs given a low-salt diet, metyrapone caused a 31% increase in cardiac output and a simultaneous decrease in total peripheral resistance such that BP did not change.23 However, initiation of a high-salt diet in these metyrapone-treated dogs induced a prompt increase in BP by causing an increase in total peripheral resistance without causing a further increase in cardiac output.23 Therefore, Bravo et al23 concluded that increases in cardiac output do not provide a sufficient explanation on how inhibition of 11β-hydroxylase activity enables salt to initiate hypertension. These observations are at odds with the prevailing theory for initiation of Mendelian forms of salt-dependent hypertension that are characterized by increased circulating levels of mineralocorticoids, such as DOC and DOC metabolites.2How Does Salt Initiate the Increased BP in Mendelian Forms of Salt-Dependent Hypertension That Do Not Involve Increased Circulating Levels of Mineralocorticoids?At least 4 Mendelian forms of salt-dependent hypertension have been described in which the increased BP does not seem to involve increased circulating levels of mineralocorticoids (Table). There are no published studies of the changes in cardiac output and systemic vascular resistance that occur during initiation of salt-induced increases in BP in humans or animals with any of the gene defects underlying these Mendelian forms of salt-dependent hypertension. This raises the question, what is the hemodynamic evidence for the prevailing theory (Figure 1) for initiation of salt-induced hypertension in these Mendelian disorders? In support of the theory, some investigators7,13 have cited the work of Guyton et al.5,10,12Guyton et al5,10,12 studied the serial hemodynamic changes that occur during initiation of a nongenetic form of salt-dependent hypertension induced by administering large amounts of salt into dogs in which renal mass had been surgically reduced by 70%. In this model in which aldosterone levels do not seem to be increased,24 Guyton et al12,25–27 concluded that salt loading induces hypertension by causing transient abnormally large increases in cardiac output, whereas systemic vascular resistance initially remains normal, ie, unchanged. However, those studies of Guyton et al12,25–27 did not include measurements of the changes in cardiac output and systemic vascular resistance that occur during initiation of salt loading in normal salt-resistant control dogs with intact kidneys. Because the studies of Guyton et al12,25–27 lacked such measurements in normal controls, it is not possible to determine whether the responses they observed in cardiac output or systemic vascular resistance during initiation of salt loading and hypertension were normal or abnormal.In studies on normotensive salt-sensitive humans and animals that have included salt-resistant normal controls, an abnormal systemic vascular resistance response to salt loading, not a transient abnormal cardiac output response to salt loading, is the salt-dependent hemodynamic abnormality that usually mediates initiation of the salt-induced increases in BP.28–33 Specifically, throughout initiation of salt loading in most salt-sensitive normotensive subjects tested, the increases in sodium balance and transient increases in cardiac output are not abnormally high, ie, not greater than those occurring during salt-loading in salt-resistant normal controls.29,30,33 Salt loading usually induces substantial and readily detectable increases in salt retention and transient increases in cardiac output in salt-resistant normotensive controls and in salt-sensitive normotensive subjects.29,30,33 In contrast, throughout initiation of salt loading in most salt-sensitive normotensive subjects, systemic vascular resistance is abnormal because it fails to decrease to a normal extent, ie, to the same extent as that usually observed during salt loading in salt-resistant normal controls.29,30,33 Thus, the final common pathway of prevailing theory for initiation of salt-dependent hypertension is inconsistent with the results of salt-loading studies in salt-sensitive normotensive subjects versus salt-resistant normotensive controls.Importance of Salt-Loading Studies in Normotensive SubjectsWe are focusing on the results of salt-loading studies in normotensive subjects rather than on those of salt-loading studies in hypertensive subjects because we are mainly interested in the mechanisms whereby dietary salt initiates hypertension rather than the mechanisms whereby dietary salt exacerbates hypertension. The mechanisms whereby salt exacerbates hypertension may not reflect the mechanisms whereby salt initiates hypertension and could be influenced by the duration of pre-existing hypertension and other confounding factors that are difficult to ascertain. It should be noted that the results of hemodynamic and metabolic studies of dietary salt loading that compared salt-sensitive hypertensives versus salt-resistant hypertensives34,35 differ from the results of those that compared salt-sensitive normotensives versus salt-resistant normotensives.28–30,35 It is also important to note that the salt-loading study comparing salt-sensitive hypertensives versus salt-resistant hypertensives34 did not include normal controls, ie, normotensive salt-resistant individuals. Because that study did not include normal controls, it did not determine whether the cardiac output and sodium balance responses to salt loading were normal or abnormal in the salt-sensitive hypertensives or in the salt-resistant hypertensives.The normal response to initiation of salt loading, ie, the usual response in salt-resistant normotensive controls, is a rapid and substantial decrease in systemic vascular resistance.29,30,33 Accordingly, in salt-sensitive normotensive subjects, the observation that systemic vascular resistance usually changes little from baseline during initiation of salt-induced increases in BP signals the existence of an abnormality in systemic vascular resistance that often plays a critical role in the initiation of salt-induced hypertension. The prevailing volume-loading/cardiac output theory for the pathogenesis of Mendelian forms of salt-dependent hypertension does not take into account the fact that the normal response to initiation of salt loading is vasodilation and a decrease in systemic vascular resistance.28–33 Thus, the prevailing theory overlooks the possibility that mutations causing Mendelian forms of salt-dependent hypertension enable salt to initiate the hypertension by causing an abnormality in systemic vascular resistance, specifically, a failure to normally vasodilate and decrease systemic vascular resistance in response to salt loading.Vasodysfunction Theory to Explain How Mendelian Gene Defects Enable Salt to Initiate Hyperten