Erythrocyte Sodium-Lithium Countertransport in Non-Modulating Offspring and Essential Hypertensive Individuals
Response to Enalapril
Abstract Non-modulators are a subset of essential hypertensive individuals in whom renal hemodynamic and adrenal aldosterone responses to angiotensin II fail to modulate appropriately during high dietary salt intake. The main aim of this study was to investigate the familial aggregation of non-modulation and several erythrocyte Na+ transport systems in normotensive and hypertensive individuals as well as offspring of hypertensive parents. An additional aim was to evaluate the effect of treatment with enalapril on erythrocyte Na+ transport. We studied 15 normotensive subjects (6 males, 27±6 years), 14 untreated modulating essential hypertensive subjects (7 males, 38±7 years), 12 untreated non-modulating essential hypertensive subjects (7 males, 38±6 years), 14 modulating offspring of hypertensive parents (8 males, 25±6 years), and 14 non-modulating offspring of hypertensive parents (8 males, 26±4 years). Blood pressure was recorded with an oscillometric device and renal plasma flow and glomerular filtration rate by clearances of para-aminohippurate and inulin, respectively. Non-modulating subjects were identified as individuals who failed to increase effective renal plasma flow by 30% and decrease filtration fraction by at least 30% 10 days after changing from a low (20 mmol/d) to a high (250 mmol/d) sodium intake. Erythrocyte Na+ transport was characterized by measurements of the Na+-K+ pump, Na+-Li+ countertransport, Na+-K+-Cl− cotransport, passive Na+ permeability, and Na+ content. After the initial studies, hypertensive individuals were treated with enalapril (20 mg/d PO) for 6 months, after which erythrocyte Na+ transport measurements were again made. The main findings were that Na+-Li+ countertransport is increased in non-modulating hypertensive subjects and non-modulating offspring of hypertensive parents, that the increase in blood pressure in response to high salt intake is greater in non-modulating than modulating hypertensive subjects, and that enalapril decreases Na+-Li+ countertransport activity to normal in non-modulating hypertensive subjects. These findings provide support for a possible genetic role in the development of salt sensitivity and suggest that Na+-Li+ countertransport and non-modulation are related phenotypes.
Increased dietary sodium intake is thought to be one of the major environmental factors promoting hypertension in acculturated societies, and in many individuals, BP responds to manipulations of dietary sodium intake.1 2 However, in the population samples characterized in the INTERSALT study,3 mean urinary Na+ excretion was not consistently related to the prevalence of essential hypertension, and in intervention studies,4 5 6 only a minority of essential hypertensive individuals are Na+ sensitive. Why some populations or individuals are salt sensitive and others apparently salt resistant is unknown, but Dahl’s development of an inbred rat model suggested that increased BP during high Na+ intake could be heritable.7 8 A restriction fragment length polymorphism in the renin gene cosegregates with hypertension in the Dahl rat strain,9 and a chromosome (locus 10) has been linked to salt-loaded BP level in another strain—the stroke-prone spontaneously hypertensive rat10 11 —providing further evidence for a genetic substrate for responsiveness to dietary salt. In humans, studies of BP responses to dietary salt manipulation in twins12 and of race-related differences in the prevalence of BP salt sensitivity13 have implicated genetic factors. However, no specific genes causing salt sensitivity in humans have been identified.
Although several causes of Na+-sensitive hypertension are likely, one of the best characterized forms, known as non-modulating essential hypertension, is defined by a failure to appropriately modulate renal vascular and adrenal glomerulosa responsiveness to angiotensin II during high Na+ intake.14 15 People with this hypertensive subtype, which may be present in as many as 40% to 45% of essential hypertensive individuals, must have one of the following characteristics distinguishing them from normal subjects free of a family history of hypertension and the normal responding hypertensive patient: (1) a reduced renal vascular response to angiotensin II on a high salt diet, (2) an adrenal response to angiotensin II that is not changed by high sodium intake, and (3) a failure to increase renal blood flow with chronic Na+ loading.14 Heritability of this hypertension subtype is suggested by the following observations: (1) several characteristics associated with non-modulation are observed in young normotensive offspring of hypertensive individuals,16 17 (2) most non-modulators have a positive family history of hypertension in first-degree relatives, (3) non-modulation is highly concordant in twins, (4) there is a bimodal distribution of renal blood flow responses,18 and (5) there is a significant association of non-modulation and the Na+ sensitivity of hypertension19 with a heritable marker of essential hypertension: erythrocyte SLC.19 20
We undertook the present study to further characterize the relationship of BP and erythrocyte Na+ transport abnormalities with salt-induced modulation of renal blood flow in hypertensive individuals and in the offspring of hypertensive parents. Our first goal was to investigate whether the association of non-modulation with SLC observed by Redgrave and coworkers19 is also found in a geographically (South America) and ethnically (Italians and Spaniards) distinct population and to extend that work by characterizing other RBC transport systems in these patients. Our second aim was to determine whether elevated SLC or other RBC Na+ transport abnormalities were related to non-modulation before the onset of hypertension. To this end, we characterized RBC Na+ transport and renal plasma flow responses to a high Na+ diet in offspring of hypertensive parents, a group genetically predisposed to hypertension.
Finally, we investigated whether prolonged converting enzyme inhibition, which has been shown to correct the failure of renal vascular modulation to high Na+ in non-modulators,21 22 23 also affects RBC Na+ transport.
We studied 15 normotensive subjects (6 males, 27±6 years), 14 untreated modulating essential hypertensive subjects (MHT: 7 males, 38±7 years), 12 untreated non-modulating essential hypertensive subjects (NMHT: 7 males, 38±6 years), 14 modulating normotensive offspring of hypertensive parents (MHO: 8 males, 25±5 years), and 14 non-modulating normotensive offspring of hypertensive parents (NMHO: 8 males, 26±5 years).
Hypertensive individuals were recruited from the outpatient hypertension clinic in our hospital. Normotensive subjects and offspring of hypertensive parents were recruited from a larger population in the Buenos Aires area. In these subjects, a very careful examination to exclude hypertension was performed before the beginning of the study.
Secondary forms of hypertension were excluded by history and physical examination, screening biochemical testing, renal echography, and isotopic radiorenographic studies. Renal function was normal in all patients (serum creatinine: 0.8 to 1.0 mg%).
Antihypertensive therapy, consisting of atenolol (50 to 100 mg/d) or sustained-release nifedipine (20 to 40 mg/d), was discontinued in essential hypertensive subjects 5 weeks before the beginning of the study. No subject received oral contraceptives or estrogen before or during the study. Low-renin hypertension was characterized by measurement of plasma renin activity before and after administration of furosemide. Those individuals with baseline plasma renin activity levels less than 0.4 ng/mL per hour who failed to increase their plasma renin activity after furosemide (40 mg PO) were excluded from the study.
Low and High Sodium Diets
Renal hemodynamic studies were performed in all subjects after 10 days of low Na+ intake (20 mmol/24 h) and after 10 days of high Na+ intake (250 mmol/24 h), delivered in a fixed order. The low sodium intake included 2020 calories and 2 g NaCl; subjects received a list of permitted foods and a suggested composition of breakfast, lunch, and dinner. For the high Na+ load, subjects received a standardized hypersodic diet plus an oral supplement of NaCl (6 g/d) to be distributed between lunch and dinner. Since all the subjects who received the low and high sodium diets were outpatients, 24-hour urine samples were collected at the end of each period to measure urinary Na+ excretion for confirmation of Na+ balance and dietary compliance.
Renal Hemodynamic Studies
GFR and ERPF were determined by the simultaneous clearances of inulin and PAH by the method of Schnurr et al.24 FF (GFR/ERPF) was calculated. Briefly, separate intravenous cannulas were placed in a superficial vein of both right and left forearms for infusion and blood sampling purposes, respectively. After a baseline blood sample was taken, a priming dose of inulin (2.6 g) and PAH (0.66 g) was injected. Immediately thereafter, a solution of inulin (13.2 mg/mL) and PAH (48 mg/mL) was infused at a rate of 0.0382 mL/min (Secura B Braun pump) over 70 minutes to maintain a constant plasma level. After 45 minutes, at which time plasma inulin and PAH concentrations had reached a steady-state equilibrium between the infusion rate and renal excretion, three consecutive blood samples were taken. Clearances of inulin and PAH were determined as the steady-state infusion rate divided by the plasma concentration of the respective substances24 measured by standard chemical methods as described elsewhere.25 26
Urinary output–pressure curves were constructed by relating the 24-hour urinary Na+ excretion during low and high sodium diets to their respective mean BP values. The slope of each curve was calculated as the difference in Na+ excretion between low and high Na+ intake conditions divided by the difference in BP between high and low Na+ intake conditions (Slope=ΔUrinary Na+ Excretion/ΔMean BP).
Characterization of Modulating and Non-Modulating Hypertension
The criteria used to define modulation status was for a subject to reach a minimum increase of 30% in ERPF and a decrease of at least 30% in FF after moving from a low to high sodium intake. Subjects who failed to achieve these renal hemodynamic changes were considered non-modulators. In this way, we previously found in 20 normotensive subjects (15 males; age range, 18 to 50 years) that after 10 days of low Na+ intake ERPF was 562.27±142.73 mL/min per 1.73 m2, and after 10 days of high Na+ intake it was 736.87±170.54 (mean 31% increase). FF after low Na+ intake was 0.30±0.09 and after high Na+ intake was 0.20±0.09 (mean 33% reduction). The 24-hour urinary Na+ excretion after low Na+ intake was 50.71±7.45 mmol and after high Na+ intake was 184.44±24.77.
In 30 essential hypertensive individuals previously studied with the same methodology, we found two subgroups. One, the modulating hypertensive (MHT) subgroup, had a normal increment, similar to that of the normotensive individuals, in ERPF from 636.03±135.30 to 840.29±193.24 mL/min per 1.73 m2 (mean 32% increase) with a similar reduction in FF from 0.20±0.04 to 0.13±0.06 (mean 35% decrease), whereas the other group, the non-modulators (NMHT), did not have changes in ERPF (low, 665.92±215.88; high, 664.90±263.85 mL/min per 1.73 m2) or FF (low, 0.21±0.06; high, 0.23±0.08). We performed a second study in 10 modulators and 8 non-modulators after 6 months of the initial study to evaluate the reproducibility of this finding. The results showed the following: ERPF for modulators: low Na+, 620.8±106; high Na+, 814±110 mL/min per 1.73 m2; FF for modulators: low Na+, 0.20±0.04; high Na+, 0.14±0.04; ERPF for non-modulators: low Na+, 705±180; high Na+, 750±210 mL/min per 1.73 m2; FF for non-modulators: low Na+, 0.20±0.06; high Na+, 0.20±0.04.
In modulating subjects, 24-hour Na+ excretion was 22.00±7.91 mmol under low Na+ intake and 248.00±45.38 under high Na+ intake. Non-modulators showed a similar 24-hour urinary Na+ excretion (low, 27.87±20.16; high, 238.38±28.60 mmol). A brief report has been presented elsewhere.16
Erythrocyte Cation Transport Determinations
In 12 normotensive, 12 MHT, 10 NMHT, 10 MHO, and 10 NMHO subjects of the studied population, erythrocyte cation transport determinations were made. All RBC Na+ transport tests were performed in fasted normotensive and hypertensive offspring and hypertensive subjects after 10 days of low and high Na+ intakes.
SLC measurements were made in the above-mentioned subjects according to the original method described by Canessa et al.27 28 For loading, 2 mL washed RBCs (hematocrit 20%) were incubated for 3 hours at 37°C in a loading solution consisting of (mmol/L) LiCl 150, Tris-MOPS 10 (pH 7.4 at 37°C), and glucose 10. Lithium was removed by washing six times with a washing solution of (mmol/L) MgCl2 75, sucrose 85, and Tris-MOPS 10 (pH 7.4 at 4°C). A 50% cell suspension in washing solution was used for measurement of hematocrit, hemoglobin, intracellular Na+ content, and Na+ fluxes.
The SLC was measured as the difference between Li+ effluxes from Li+-loaded RBCs into Mg+ and Na+ media. The Na+ medium contained (mmol/L) Na+ 150, glucose 10, Tris-MOPS 10 (pH 7.4 at 37°C), and ouabain 0.1; the Mg2+ medium contained (mmol/L) MgCl2 75, Tris-MOPS 10 (pH 7.4 at 37°C), glucose 10, sucrose 85, and ouabain 0.1. The 50% suspension of Li+-loaded RBCs was diluted to a 4% to 5% hematocrit with cooled (4°C) Mg2+ and Na+ medium, and the resultant cell suspension was divided into three aliquots and incubated for 60 minutes at 37°C. Fluxes were stopped by transferring aliquots of Mg2+ and Na+ suspended RBCs to an ice bath at 20, 40, and 60 minutes. After cooling, aliquots were centrifuged at 7000g for 5 minutes, and the supernatants were removed. Lithium concentration was determined in the Mg2+ and Na+ medium by atomic absorption spectrophotometry using appropriately bracketed standards.
Na+-K+ Pump and Na+-K+-Cl− Cotransport Maximal Na+ Efflux Rate
Measurements were carried out with RBCs loaded with Na+ by the nystatin method as described by Canessa et al.27 For Na+ loading, 2 mL washed RBCs was added to 10 mL of an Na+ loading solution consisting of (mmol/L) NaCl 70, KCl 70, Tris-MOPS 10 (pH 7.4 at 4°C), and sucrose 55, with 150 mL of a nystatin solution (10 mg in 2.5 mL dimethyl sulfoxide). RBCs were incubated for 20 minutes at 4°C; nystatin was then removed by centrifuging the solution at room temperature and washing four times at 35°C with a solution of (mmol/L) NaCl 70, KCl 70, Tris-MOPS 10 (pH 7.4 at 4°C), sucrose 55, K2HPO4 buffer 1 (pH 7.4), and glucose 10 as well as 0.1% albumin. In the first wash, the Na+-loaded RBCs were equilibrated for 10 minutes in the 35°C water bath and for 4 minutes during the last three washes. The cells were subsequently washed with a cold (4°C) choline solution composed of (mmol/L) choline chloride 148, MgCl2 1, and Tris-MOPS 10 (pH 7.4 at 4°C). A suspension at approximately 50% hematocrit was made for measurements of hemoglobin, hematocrit, intracellular Na+ content, and Na+ fluxes.
For measurement of Na+-K+ pump function, 0.2 mL of the 50% cell suspension was added to 7 mL of a medium consisting of (mmol/L) choline chloride 140, KCl 10, MgCl2 1, Tris-MOPS 10 (pH 7.4 at 37°C), and glucose 10, without or with ouabain (0.1 mmol/L).
For measurement of Na+-K+-Cl− cotransport, 0.8 mL of the 50% cell suspension was added to 7 mL of a medium consisting of (mmol/L) choline chloride 148, MgCl2 1, Tris-MOPS 10 (pH 7.4 at 37°C), glucose 10, and ouabain 0.1, without or with 1 mmol/L furosemide (33 mg in 100 mL of 1 mol/L Tris base [1 mol/L furosemide] and then made up to 1 mmol/L with medium). After the addition of the cell suspension to each medium, 1.5 mL of the flux medium containing the suspended RBCs was put into each of five tubes. Duplicate tubes were incubated at 37°C for 5 minutes, and triplicate tubes were incubated for 25 minutes for pump medium and 65 minutes for cotransport medium.
Cellular Na+ content was measured by means of suitable standards. The osmolarity of all solutions used for flux measurements was adjusted to 298±5 mOsm/L.
We repeated Na+-K+ pump and cotransport measurements five times in blood samples obtained from two normal control subjects and demonstrated a coefficient of variation of less than 10%. Hemoglobin concentration was measured throughout the experiment, with flux measurements discarded when variations were greater than 3% compared with the original cells.29
Sodium passive permeability was estimated in nystatinized cells as the fractional rate of sodium efflux into an Na+-free medium containing ouabain and furosemide.
Flux measurements were repeated in the hypertensive subjects after 6 months of treatment with enalapril. Subjects who had not reached satisfactory BP control (BP <150/100 mm Hg) were withdrawn from the study.
The protocol was approved by the Research Committee of the Hospital Instituto de Cardiología, Academia Nacional de Medicina. Written informed consent was required of all subjects before they entered into the study.
Parameters were not significantly biased from gaussian distributions, but because sample sizes were small, we mainly used distribution-free methods for sample comparisons. We used the Wilcoxon signed rank test for differences between parameters of the same sample with different sodium diets or with enalapril and the Mann-Whitney test for the comparison of two groups in independent samples. Data are reported as mean±SD. For the analysis of the rate of Na+ excretion variation to mean BP variation with Na+ diet in all groups (normotensive, NMHO, MHO, NMHT, and MHT), we applied an ANOVA one-way fixed effects model, followed by the least significant difference test for post hoc comparisons. A value of P<.05 was considered to be statistically significant.
Characteristics of the five groups studied are shown in Table 1⇓. At baseline, systolic and diastolic BPs were higher in hypertensive than in normotensive subjects as expected, but the difference between MHT and NMHT was not significant. Systolic and diastolic BPs in hypertensive offspring were not significantly different from those of normotensive subjects at baseline or after either high or low Na+ diets. Changing from a low to a high salt diet increased BP significantly only in NMHT (P<.05).
ERPF, GFR, and FF did not differ significantly among the five subject groups during the low salt dietary phase. Switching to the high salt diet induced the expected normal rise in ERPF (average, 34.78%) in normotensive subjects, with no significant change in GFR. FF therefore decreased by an average of 31.58%. On the basis of the criteria mentioned above, 14 of 26 hypertensive subjects and 14 of 28 hypertensive offspring were modulators. When divided by modulating status, both MHT and MHO had significant rises in ERPF (MHT, 58%; MHO, 36%) and falls in FF (MHT, −32%; MHO, −30%) (Table 2⇓). As expected, changes in non-modulators were not significant (NMHT: ERPF, 8%; FF, −16%; NMHO: ERPF, 15%; FF, −10%) (Table 2⇓).
Pressure–urinary Na+ output curves at different Na+ intakes for the five groups are shown in Fig 1⇓. Normotensive subjects and hypertensive offspring had similar BP responses to a high Na+ intake. However, when hypertensive offspring were classified by modulating status, the slope of the pressure–urinary Na+ output curve for non-modulators compared with modulators was significantly reduced (P<.05; Table 3⇓, Fig 1⇓). Likewise, in NMHT, a decreased slope (P<.05; Table 3⇓) was observed compared with MHT. Additionally, both curves shifted to the right compared with normotensive or hypertensive offspring curves (Fig 1⇓).
RBC Na+ Transports
As shown in Table 4⇓ and Fig 2⇓, compared with SLC in normotensive subjects, SLC during the low Na+ dietary phase was significantly higher in both NMHT and NMHO compared with MHT and MHO. During the high Na+ dietary phase, SLC remained higher in NMHT and NMHO, and mean values were not significantly different during low and high Na+ diets in normotensive subjects, NMHT, or hypertensive offspring.
During the low Na+ diet, only NMHO had significantly lower Na+-K+-Cl− cotransport values than normotensive subjects (Table 4⇑). After the change to the high Na+ diet, Na+-K+-Cl− cotransport fell significantly in both MHT and NMHT. Conversely, in normotensive subjects and hypertensive offspring, the high Na+ diet failed to alter Na+-K+-Cl− cotransport. However, in normotensive subjects after 10 days on the high Na+ diet, Na+-K+-Cl− cotransport was significantly higher than in all of the other four groups.
Na+-K+ Pump Activity
During the low Na+ diet, mean Na+-K+ pump activity was higher in normotensive subjects than in any other group, although the difference between normotensive subjects and NMHT was not significant (Table 4⇑). After the switch to the high Na+ diet, pump activity fell significantly in NMHT and MHT. In MHO the pump activity was significantly decreased. In normotensive subjects the pump activity remained unchanged. The high salt diet resulted in pump activities that were significantly lower in all groups compared with normotensive subjects.
As expected, changes in RBC Na+ content were generally directionally opposite to those in pump activity. During the low Na+ dietary phase, Na+ content was higher in all groups than in normotensive subjects, although the difference was not significant in MHO. The high Na+ diet resulted in significant rises in Na+ content in all groups except the normotensive subjects (Table 4⇑).
Na+ permeability did not change significantly in the four groups compared with normotensive subjects after the switch from the low to high Na+ diet (Table 4⇑).
Effects of Enalapril
Hypertensive subjects were treated with enalapril for 6 months. On day 170, the subjects were returned to an Na+ intake of 250 mmol/d, which was continued until RBC fluxes were again measured on day 180. Enalapril treatment resulted in declines in BP from 158.3±8/102.5±3 mm Hg to 145.5±8/94.2±6 in MHT (P<.001) and from 166.5±11/109.5±5 mm Hg to 143±8/91±6 in NMHT (P<.0001). The BP decrease induced by enalapril was similar in both modulators and non-modulators. As shown in Fig 2⇑, SLC was normalized in enalapril-treated MHT and NMHT. A slight and significant increase was induced in MHT, whereas in NMHT, enalapril decreased the previously elevated values. These changes resulted in a mean SLC in enalapril-treated hypertensive subjects that was not significantly different from that in normotensive subjects. Enalapril produced small and inconsistent changes in Na+-K+ pump activity, Na+ permeability, and Na+ content. Na+-K+-Cl− cotransport increased after enalapril treatment in NMHT (from 262±3 to 299±19 mmol/L, P<.005).
The results of the present study confirm previous findings of the existence of modulators and non-modulators in established hypertension, demonstrate the presence of both subtypes in the normotensive offspring of hypertensive parents, and confirm the relationship of RBC SLC activity and the non-modulating subtype of hypertension. In addition, we show (1) that mean SLC activity is significantly elevated in NMHT and NMHO in this group of subjects studied in Latin America; (2) NMHT and to a lesser degree NMHO are more salt sensitive than MHT and MHO, respectively, since all NMHT predominantly increased BP more than 30% after high Na+ intake; and (3) enalapril normalizes SLC in NMHT after 6 months of treatment.
Previous observations have supported the possibility of a heritable basis for the NMHT phenotype,16 17 18 19 20 21 and our findings of both increased SLC and a significant decrease in the slope of the pressure–urinary Na+ output curve in NMHO suggest that impaired renal vasodilatation and consequent salt sensitivity precede the development of hypertension in affected individuals. This observation is of interest because it is thought that an impairment of the pressor natriuresis mechanism is one way that the kidney could cause hypertension.30 31 32 Although the mechanism underlying this pressure-dependent natriuresis has remained unresolved, interest in its elucidation has been stimulated by the premise that it constitutes a major link between sodium excretion and BP regulation. In this regard some investigators have suggested that an alteration in renal medullary hemodynamics and/or changes in renal interstitial hydrostatic pressure may be responsible for this phenomenon.33 34 Our findings suggest that NMHO may be at risk of developing salt-sensitive hypertension, a speculation supported by the recent documentation of Gordon et al35 of a well-characterized non-modulating normotensive subject who subsequently developed hypertension. Since non-modulation is present in normotensive offspring of hypertensive parents, it should be possible to study the heritability of the non-modulating phenotype in multigenerational families even before hypertension develops. Studies aimed at elucidating the genetic basis of non-modulation are presently underway (N.K. Hollenberg, personal communication, 1996).
Although the mechanism leading to hypertension in sodium-sensitive subjects and non-modulators is unknown, the inappropriate suppression of the renin-angiotensin aldosterone system, a greater volume expansion, and the intracellular accumulation of sodium and calcium could be factors involved in this mechanism.6 36
Our findings confirm the observations of Redgrave et al19 on the association of increased SLC activity in non-modulators, suggesting that this predisposition may be mediated by the same genetic factors responsible for increased SLC, which has been shown to be associated with impaired glucose tolerance and with salt sensitivity of BP in essential hypertensive individuals.20
In the present study we also investigated the effect of enalapril on RBC sodium transport in individuals with hypertension and demonstrated that enalapril treatment normalizes RBC Na+-Li+ countertransport in non-modulating subjects. The changes we note are consistent with previous observations that ACE inhibitors can affect SLC37 and are of further interest in light of observations that ACE inhibitor treatment can also correct the renal vascular abnormalities of non-modulation.20 21 The mechanism by which ACE inhibition resets SLC is unknown but seems unlikely to be mediated through the effects of ACE inhibitors on the renin-angiotensin system. Although one early study suggested a relationship of SLC to plasma renin activity,32 this was not confirmed in a larger population-based study.38 One intriguing possibility is that the effect of enalapril is related to the improvement in insulin resistance reported with ACE inhibitor treatment, as an action of insulin on the countertransporter has been described.39 However, this effect of insulin—a decrease in the affinity of the external Na+-loading site of the Na+-Li+ countertransporter—would not be detected in our assay.
The other effects of enalapril on membrane transport are less consistent but do support our previous findings that ACE inhibitor treatment tends to normalize Na+-K+-Cl− transport in hypertensive individuals.40 Since dietary salt loading may affect Na+-K+-Cl− transport, this effect of ACE inhibition may be related to normalization of sodium balance in NMHT as the result of correction of the renal hemodynamic lesion. It is possible that the effect of dietary salt and enalapril on cotransport could be mediated through a recently described endogenous factor with the biological profile of a loop diuretic.41
In conclusion, the observations that non-modulating offspring of hypertensive parents show a renal hemodynamic deficiency and SLC alterations suggest that this non-modulation may be an inherited abnormality. In addition, long-term treatment with enalapril is able to correct renal hemodynamic deficiency and RBC SLC abnormalities in non-modulating essential hypertensive subjects, which may be of further interest.
Selected Abbreviations and Acronyms
|ERPF||=||effective renal plasma flow|
|GFR||=||glomerular filtration rate|
|RBC||=||red blood cell|
A.J. Ramírez is a Member of the Research Career of the Consejo Nacional de Investigaciones Cientificas y Técnicas (CONICET).
- Received November 19, 1996.
- Revision received December 10, 1996.
- Accepted December 10, 1996.
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