Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives

Abstract

AY, Lakatta EG. Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives. Am J Physiol Regul Integr Comp Physiol 294: R1248-R1254, 2008. First published February 20, 2008 doi:10.1152/ajpregu.00782.2007.-Factors that mediate increases in salt sensitivity of blood pressure with age remain to be clarified. The present study investigated 1) the effects of high-NaCl intake on two Na pump inhibitors, endogenous ouabain (EO) and marinobufagenin (MBG), in middle-aged and older normotensive Caucasian women; and 2) whether individual differences in EO and MBG are linked to variations in sodium excretion or salt sensitivity. A change from 6 days of a lower (0.7 mmol ⅐ kg Ϫ1 ⅐ day Ϫ1 )-to 6 days of a higher (4 mmol ⅐ kg Ϫ1 ⅐ day Ϫ1 )-NaCl diet elicited a sustained increase in MBG excretion that directly correlated with an increase in the fractional Na excretion and was inversely related to age and to an age-dependent increase in salt sensitivity. In contrast, EO excretion increased only transiently in response to NaCl loading and did not vary with age or correlate with fractional Na excretion or salt sensitivity. A positive correlation of both plasma and urine levels of EO and MBG during salt loading may indicate a casual link between two Na pump inhibitors in response to NaCl loading, as observed in animal models. A linear mixed-effects model demonstrated that age, dietary NaCl, renal MBG excretion, and body mass index were each independently associated with systolic blood pressure. Thus, a sustained increase in MBG in response to acutely elevated dietary NaCl is inversely linked to salt sensitivity in normotensive middle-aged and older women, and a relative failure of MBG elaboration by these older persons may be involved in the increased salt sensitivity with advancing age. marinobufagenin; ouabain; hypertension NUMEROUS STUDIES HAVE REPORTED that the magnitude of the systolic blood pressure (SBP) response to acute changes in dietary NaCl intake, i.e., salt sensitivity of blood pressure, increases with advancing age (16,20,27,(32)(33)(34)(35). Specific determinants of the greater blood pressure response of older persons to dietary NaCl, however, remain to be identified.NaCl ingestion results in an increase in plasma volume and natriuresis. It has been postulated for some time that endogenous substances [sodium pump inhibitors (SPI)] are stimulated by increased Na intake and increase natriuresis by inhibiting renal tubular Na pumps to prevent renal reabsorption of filtered Na (6,18,30). However, such substances were not purified adequately in early studies, and their assays were nonspecific (17).More recently, SPI assays have improved and become more specific (3,14), and studies in various animal models and in humans have documented an increased elaboration of SPI in response to NaCl loading. This research has focused largely on two SPI: an endogenous ouabain (EO) and a bufadienoide, marinobufagenin (MBG). Differences in the kinetics and tissue actions of thes...

Dietary Sodium Restriction and Association with Urinary Marinobufagenin, Blood Pressure, and Aortic Stiffness

“…Urine MBG excretion (corresponding to each of the 14 24-hour collections) and plasma MBG levels (last week of each sodium condition) were assessed using a competitive fluoroimmunoassay as reported previously in detail (10,(16)(17)(18). Briefly, urine and plasma samples were extracted using C18 SepPak cartridges (Waters Inc., Cambridge, MA), and MBG was measured using a fluoroimmunoassay (Dissociation-Enhanced Lanthanide Fluorescent Immunoassay) based on a murine anti-MBG 4G4 monoclonal antibody recently described in detail (19).…”

“…Creatinine clearance, MBG clearance, and sodium-filtered and fractional excretion of sodium were calculated as described previously (16). Other blood assays were performed using standard methodology.…”

Endogenous digitalis: pathophysiologic roles and therapeutic applications

“…50 This pattern of ouabain response after salt loading has also been observed in Dahl salt-sensitive rats 82,83 and in humans with normal blood pressure. 84 Several lines of evidence support the idea that endogenous ouabain has a prohypertensive role; these include the 'adducin paradigm', 85 the induction of hypertension in ouabain-treated rodents, the elevation of endogenous ouabain levels in hypertensive rats, and the central prohypertensive action of this hormone. In rats, chronic peripheral administration of low doses of ouabain (10-50 μg/kg per day) increased arterial pressure and induced cardiac hypertrophy.…”

Research Progress of Marinobufagenin and Salt-Sensitive Hypertension

“…Body reconstructs stress urinary natriuretic function to extrect the sodium retention in the body and increase nocturnal sodium excretion passively, then compensatory elevated blood pressure at night and showed Non-dipper change. (Anderson et al, 2008). It was thought that EO has a more important role in blood pressure regulation, but subsequent research has found the lower concentration of MBG can cause vasoconstriction relative to uabain in blood vessels of individuals.…”

“…Many researches indicated that MBG was closely related to blood pressure (Anderson et al, 2008). It was thought that EO has a more important role in blood pressure regulation, but subsequent research has found the lower concentration of MBG can cause vasoconstriction relative to uabain in blood vessels of individuals.…”