Prevailing theory holds that abnormally large increases in renal salt retention and cardiac output are early pathophysiologic events mediating initiation of most instances of salt-induced hypertension. This theory has come under increasing scrutiny because it is based on studies that lack measurements of sodium balance and cardiac output obtained during initiation of salt-loading in proper normal controls, i.e., salt-resistant subjects with normal blood pressure. Here we make the case for a “vasodysfunction” theory for initiation of salt-induced hypertension: In response to an increase in salt intake, a subnormal decrease in total peripheral resistance that involves a subnormal decrease in renal vascular resistance, in the absence of abnormally large increases in sodium retention and cardiac output, is the hemodynamic abnormality that usually mediates initiation of salt-induced increases in blood pressure (BP). It is the failure to normally decrease vascular resistance in response to salt loading that enables a normal increase of cardiac output to initiate the salt-induced increase in blood pressure. This theory is based on the results of properly controlled studies which consistently demonstrate that in salt-sensitive subjects, salt-loading initiates increased BP through a hemodynamic mechanism that: 1) does not usually involve early increases in sodium retention and cardiac output greater than those which occur with salt-loading in normal controls, and 2) usually involves an early failure to decrease vascular resistance to the same extent as that observed during salt-loading in normal controls. Multiple mechanisms including disturbances in nitric oxide and sympathetic nervous system activity likely underlie this subnormal vasodilatory response to salt that usually precedes and initiates salt-induced hypertension.

Abstract-We tested the traditional hypothesis that an abnormally enhanced renal reclamation of dietary NaCl alone initiates its pressor effect ("salt sensitivity"). Under metabolically controlled conditions, we grouped 23 normotensive blacks as either salt-sensitive (SS) or salt-resistant (SR), depending on whether or not dietary NaCl loading did or did not increase mean arterial blood pressure (MAP) by Ն5 mm Hg. We determined whether dietary NaCl loading induces greater increases in external Na ϩ balance, plasma volume, and cardiac output in SS, compared with any in SR subjects, and differential changes in systemic vascular resistance (SVR) that could account for the pressor differences between SS and SR subjects. Using impedance cardiography, we measured cardiac output and SVR daily at 4-hour intervals throughout the last 3 days of a 7-day period of low NaCl intake (30 mmol per day) and throughout a subsequent 7-day period of NaCl loading (250 mmol per day). In the 11 SS subjects, compared with the 12 SR subjects, NaCl loading induced no greater increases in Na ϩ balance, body weight, plasma volume, and cardiac output. Yet, from days 2 to 7 of NaCl loading, changes of MAP in SS diverged progressively from those in SR. From days 2 to 4, progressive increases of MAP in SS subjects reflected importantly impaired decreases of SVR, as judged from "normal" decreases of SVR in SR subjects. In SS and SR subjects combined, changes in both MAP and SVR on day 2 strongly predicted changes in MAP on day 7. In many normotensive blacks, vascular dysfunction is critical to the initiation of a pressor response to dietary NaCl. Key Words: blood pressure Ⅲ sodium chloride Ⅲ electrolyte balance Ⅲ vascular resistance Ⅲ cardiac output S alt sensitivity, blood pressure (BP) that varies directly with dietary NaCl, characterizes much of human "essential" hypertension and increases the likelihood of the occurrence of hypertension, cardiovascular disease, and death. 1-3 It is widely formulated that dietary NaCl induces a persisting pressor effect only by an abnormal enhancement of its renal reclamation that entrains over days this physiological sequence: positive Na ϩ balance, plasma volume expansion, a transient increase in cardiac output (CO), and a sustained increase in systemic vascular resistance (SVR). As formulated, the increase in CO peaks during the initial 3-to 4-day period of NaCl loading, when it alone elicits the initial pressor effect of NaCl and SVR remains "normal." The pressor effect is sustained by the increase in SVR, which occurs in normal autoregulatory response to the increase in CO. 4 -6 Although the restrictively renal dysfunction formulated accords with many observations, 7,8 recent observations in animal models of genetically determined salt-sensitive hypertension accord with the formulation that dietary NaCl loading can induce a pressor effect that depends on a dysfunctional vascular response to dietary NaCl. 9,10 Neither formulation has been tested rigorously in humans. That would require examining the effec...

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.)

NMR feasibility was established for a coaxial hydrophobic‐membrane bioreactor containing isolated rat hepatocytes with features designed to mimic the human liver. A novel triple‐tuned NMR probe and a perfusion system controlling temperature, gas concentrations, flow‐rate, and pH were used. We determined the optimum coaxial interfiber distance (i.e. diffusion distance) for maintaining hepatocyte viability in two bioreactor prototypes. Prototype no. 1 and no. 2 had diffusion distances of 500 μm and 200 μm, respectively. Cell viability was established by 31P NMR and trypan blue exclusion. Only prototype no. 2 maintained cell viability for more than 6 h, indicating the importance of diffusion distance. 31P spectra obtained over this 6 h time period were similar to in vivo spectra of rat liver. The 31P spectra were found to be more sensitive to subacute cell viability than trypan blue exclusion. In the 1H and 31P spectra, 1H2O and inorganic phosphate signals were split in two at all flow‐rates, probably due to bulk magnetic susceptibility effects originating from the three bioreactor compartments. MRI was useful for quality control and determining flow dynamics, fiber integrity, and cell inoculate distribution. MRI revealed that the inner fibers were not centered in either prototype. Although an increased flow‐rate did not influence spectral resolution or chemical shifts, significant degradation of MRI quality occurred above 50 mL/min. NMR spectroscopy and imaging provide valuable, real‐time information on cell biochemistry and flow dynamics which can be used in development and monitoring of bioreactors designed as artificial livers. © 1998 John Wiley & Sons, Ltd.