Abstract-In healthy, mostly normotensive blacks, 19 salt-sensitive (SS) and 18 salt-resistant (SR), we tested the hypothesis that, in SS subjects, dietary NaCl loading induces its initial pressor effect by inducing a normal increase of cardiac output, while failing to induce a normal pressor-offsetting vasodilatation, consequent to its inhibition by asymmetrical dimethylarginine that is abnormally increased by NaCl. In SS and SR subjects, dietary NaCl loading, 250 from 30 mmol/d, over a 7-day period, induced similar, immediate increases in external Na ϩ balance (by day 2, Ϸ360 mmol), plasma volume (ϩ11%), and cardiac output (ϩ8%). In SR subjects, from day 1, transient decreases occurred in both systemic vascular resistance (nadir: Ϫ13%, day 2) and mean arterial pressure (nadir: Ϫ5%, day 2). In SS subjects, systemic vascular resistance did not change over days 1 to 3, whereas mean arterial pressure increased progressively after day 1, ultimately by 10 mm Hg. Failure of systemic vascular resistance to normally decrease, while cardiac output normally increased, accounted for salt's initial pressor effect in the SS subjects. In SS subjects, baseline plasma levels of asymmetrical dimethylarginine (0.76 mol/L) and symmetrical dimethylarginine (0.60 mol/L), which does not affect vasodilatation, approximated those in SR subjects. In SS but not SR subjects, NaCl loading induced increases in asymmetrical dimethylarginine on both days 2 (ϩ38%, median) and 7 (ϩ14%, median). Symmetrical dimethylarginine changed in neither group. For all of the subjects combined, changes in asymmetrical dimethylarginine on day 2 predicted changes in systemic vascular resistance (Rϭ0.751; PϽ0.001) and mean arterial pressure (Rϭ0.527; Pϭ0.006) on day 2 and similarly on day 7. These observations support the hypothesis tested. (Hypertension. 2011;58:380-385.) • Online Data Supplement Key Words: blood pressure Ⅲ blacks Ⅲ sodium chloride, dietary Ⅲ asymmetrical dimethylarginine Ⅲ symmetrical dimethylarginine B lood pressure (BP) that is, or is not, increased by dietary NaCl loading is deemed salt-sensitive (SS) or salt-resistant (SR), as are those so affected. Hypertension and fatal cardiovascular disease occur more frequently in the SS than in the SR. [1][2][3] In the traditionally formulated pathophysiological initiation of salt sensitivity, an abnormally enhanced renal reclamation of NaCl and commensurate water induces intravascular "volume loading" which leads to an excessive increase of cardiac output (CO) that alone initiates salt's pressor effect. 4,5 However, recent observations in SS blacks 6 suggest that the pressor effect of dietary NaCl loading might be initiated by NaCl's induction of a normal increase of CO, whose direct pressor effect fails to be offset by normal vasodilatation but instead is amplified by inhibition of this vasodilatation. Asymmetrical dimethylarginine (ADMA) is a major endogenous inhibitor of vasodilatation by inhibiting the endothelial synthesis of NO, which relaxes vascular smooth muscle. 7,8 In isolated rat arte...

Abstract-Normotensive salt sensitivity, a putative precursor of hypertension, might be quite frequent in African Americans (blacks) and less frequent in Caucasian Americans (whites), but only when dietary potassium is deficient and not when maintained well within the normal range. We tested this hypothesis in 41 metabolically controlled studies of 38 healthy normotensive men (24 blacks, 14 whites) who ate a basal diet low in sodium (15 mmol/d) and marginally deficient in potassium (30 mmol/d) for 6 weeks. Throughout the last 4 weeks, NaCl was loaded (250 mmol/d); throughout the last 3, potassium was supplemented (as potassium bicarbonate) to either mid-or high-normal levels, 70 and 120 mmol/d. Salt sensitivity, defined as an increase in mean arterial blood pressure Ն3 mm Hg with salt loading, was deemed "moderate" if increasing Յ10 mm Hg and "severe" if increasing more. When dietary potassium was 30 mmol/d, salt loading induced a mean increase in blood pressure only in blacks (PϽ0.001), and salt sensitivity occurred in most blacks but not whites (79% vs 36% (PϽ0.02). Supplementing potassium only to 70 mmol/d attenuated moderate salt sensitivity similarly in blacks and whites; 120 mmol/d abolished it, attenuated severe salt sensitivity, which occurred in a quarter of affected blacks, and suppressed the frequency and severity of salt sensitivity in blacks to levels similar to those observed in whites. These observations demonstrate that in most normotensive black men but not white men, salt sensitivity occurs when dietary potassium is even marginally deficient but is dose-dependently suppressed when dietary potassium is increased within its normal range. Such suppression might prevent or delay the occurrence of hypertension, particularly in the many blacks, in whom dietary potassium is deficient. (Hypertension. 1999;33:18-23.)

Abstract-We tested the hypothesis that the Na ϩ component of dietary NaCl can have a pressor effect apart from its capacity to complement the extracellular osmotic activity of Cl Ϫ and, thus, expand plasma volume. We studied 35 mostly normotensive blacks who ingested a low-NaCl diet, 30 mmol/d, for 3 weeks, in the first and third of which Na ϩ was loaded orally with either NaHCO 3 or NaCl, in random order (250 mmol/d). In subjects adjudged to be salt sensitive (nϭ18; ⌬ mean arterial pressure: Ն5 mm Hg with NaCl load), but not in salt-resistant subjects (nϭ17), loading with NaHCO 3 was also pressor. The pressor effect of NaHCO 3 was half that of NaCl: mean arterial pressure (millimeters of mercury) increased significantly from 90 on low NaCl to 95 with NaHCO 3 and to 101 with NaCl. The pressor effect of NaCl strongly predicted that of NaHCO 3. As judged by hematocrit decrease, plasma volume expansion with NaCl was the same in salt-resistant and salt-sensitive subjects and twice that with NaHCO 3 , irrespective of the pressor effect. In salt-sensitive subjects, mean arterial pressure varied directly with plasma Na ϩ concentration attained with all Na ϩ loading. In salt-sensitive but not salt-resistant subjects, NaHCO 3 and NaCl induced decreases in renal blood flow and increases in renal vascular resistance; changes in renal blood flow were not different with the 2 salts. Responses of renal blood flow and renal vascular resistance to NaHCO 3 were strongly predicted by those to NaCl. In establishing the fact of "sodium-selective" salt sensitivity, the current observations demonstrate that the Na ϩ component of NaCl can have pressor and renal vasoconstrictive properties apart from its capacity to complement Cl Ϫ in plasma volume expansion.

Abstract-In 16 African Americans (blacks, 14 men, 2 women) with average admission mean arterial pressure (MAP, mm Hg) 99.9Ϯ3.5 (meanϮSEM), we investigated whether NaCl-induced renal vasoconstriction attends salt sensitivity and, if so, whether supplemental KHCO 3 ameliorates both conditions. Throughout a 3-week period under controlled metabolic conditions, all subjects ate diets containing 15 mmol NaCl and 30 mmol potassium (K ϩ ) (per 70 kg body wt [BW] per day). Throughout weeks 2 and 3, NaCl was loaded to 250 mmol/d; throughout week 3, dietary K ϩ was supplemented to 170 mmol/d (KHCO 3 ). On the last day of each study week, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) using renal clearances of PAH and inulin. Ten subjects were salt sensitive (SS) (⌬MAP Ͼϩ5%) and 6 salt resistant (SR). In NaCl-loaded SS but not SR subjects, RBF (mL/min/1.73 m 2 ) decreased from 920Ϯ75 to 828Ϯ46 (PϽ0.05); filtration fraction (FF, %) increased from 19.4Ϯ to 21.4 (PϽ0.001); and renal vascular resistance (RVR) (10 3 ϫmm Hg/[mL/min]) increased from 101Ϯ8 to 131Ϯ10 (PϽ0.001). In all subjects combined, ⌬MAP varied inversely with ⌬RBF (r ϭϪ0.57, Pϭ0.02) and directly with ⌬RVR (r ϭ 0.65, Pϭ0.006) and ⌬FF (r ϭ 0.59, Pϭ0.03), but not with MAP before NaCl loading. When supplemental KHCO 3 abolished the pressor effect of NaCl in SS subjects, RBF was unaffected but GFR and FF decreased. The results show that in marginally K ϩ -deficient blacks (1) NaCl-induced renal vasoconstrictive dysfunction attends salt sensitivity; (2) the dysfunction varies in extent directly with the NaCl-induced increase in blood pressure (BP); and (3) is complexly affected by supplemented KHCO 3 , GFR and FF decreasing but RBF not changing. In blacks, NaCl-induced renal vasoconstriction may be a pathogenetic event in salt sensitivity. (Hypertension. 1999;33:633-639.)

Acute vasopressor responses to stress are adrenergically mediated and hence potentially subject to differential modulation by dietary potassium and sodium. The greater vasopressor responsiveness in blacks compared with whites might then be consequent not only to a high dietary salt intake but also to a marginally reduced dietary potassium intake. Under controlled metabolic conditions, we compared acute vasopressor responses to cold and mental stress in black and white normotensive men during three successive dietary periods: (1) while dietary potassium was reduced (30 mmol K+/70 kg per day) and salt was restricted (10 to 14 days); (2) while salt was loaded (15 to 250 mmol Na+/70 kg per day) (7 days); and (3) while salt loading was continued and potassium was either supplemented (70 mmol K+/70 kg per day) (7 to 21 days) in 9 blacks and 6 whites or continued reduced (30 mmol K+/70 kg per day) (28 days) in 4 blacks (time controls). At the lower potassium intake, cold-induced increase in forearm vascular resistance in blacks was twice that in whites during both salt restriction and salt loading. Normalization of dietary potassium attenuated cold-induced increases in both forearm vascular resistance and systolic and diastolic blood pressures in blacks but only in systolic pressure in whites. In blacks but not in whites, normalization of dietary potassium attenuated mental stress-induced increases in systolic and diastolic pressures. In normotensive blacks but not whites, a marginally reduced dietary intake of potassium reversibly enhances adrenergically mediated vasopressor responsiveness to stress. That responsiveness so enhanced over time might contribute to the pathogenesis of hypertension in blacks.