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Istituto di Semeiotica Medica-Fondazione Don C. Gnocchi-ONLUS and Laboratorio di Informatica e Statistica, Istituto di Pedagogia (M.R.), University of Parma, I 43100 Parma, Italy; and Istituto Scientifico Ospedale S. Luca, IRCCS—Istituto Auxologico Italiano (G.P.), and LaRC-Centro di Bioingegneria, Fondazione Don C. Gnocchi, Politecnico di Milano (M.D.R.), 20148 Milan, Italy
Address all correspondence and requests for reprints to: Paolo Coruzzi, M.D., Unità Cardiovascolare, University of Parma, Fondazione Don Carlo Gnocchi, Piazzale dei Servi 3, I 43100 Parma, Italy. E-mail: paolo.coruzzi{at}unipr.it
Abstract
To evaluate the actual role of potassium depletion on blood pressure, 11 hypertensive patients were placed on a 10-day isocaloric diet providing a daily potassium intake of either 18 or 80 mmol, with each subject serving as his or her own control; the intake of sodium (220 mmol/day) and other minerals was kept constant. On day 11 each patient was also subjected to central volume expansion by water immersion associated with either normal or low potassium intake. After a 10-day period of low potassium intake, systolic blood pressure increased (P < 0.02) by 5 mm Hg, whereas serum potassium decreased (P < 0.001) by 0.9 mmol/L; no significant changes in urinary sodium and a marked increase in urinary calcium excretion (P < 0.001) were found during the 10-day low potassium intake. PRA (P < 0.02) and plasma aldosterone (P < 0.04) concentrations also decreased during low potassium intake in hypertensive patients. Even though an identical natriuretic response was found during the water immersion experiments with either high or low potassium in the whole hypertensive group, the evaluation of hypertensive subjects in relation to salt sensitivity enabled us to disclose pronounced differences in the natriuretic and calciuretic response.
In fact, although an impaired natriuretic ability and moderate calcium loss were particularly found during water immersion in those hypertensive subjects exhibiting a lower salt sensitivity index, a predominant calcium depletion appeared to be the most important consequence of potassium depletion in the hypertensive subjects with a higher salt sensitivity index. By confirming that potassium depletion may exacerbate essential hypertension, our data also suggest that not only sodium restriction, but also potassium and calcium supplementation, could be particularly advisable in salt-sensitive hypertensive patients.
AMONG DIETARY factors playing an important role in the pathogenesis and management of essential hypertension (1), potassium is known to modulate the pressor effect of dietary sodium chloride. In fact, both normal and hypertensive subjects, ingesting a low potassium diet may exhibit lower sodium excretion than that observed during normal potassium intake (2, 3); consequently, it has been concluded that sodium retention may contribute to blood pressure elevation during potassium depletion. On the other hand, both these acute and chronic experimental procedures did not take into account a major determinant of renal sodium excretion, such as the salt sensitivity condition (4); furthermore, it should be emphasized that potassium deficiency is a contraindication for iv sodium administration and that diagnostic testing with saline infusion should be undertaken only when the serum potassium levels are above 3.5 mmol/L (5, 6).
Water immersion to the neck (WI) induces an isotonic-isooncotic central volume expansion without resorting to exogenous fluid infusion; hemodynamic (7, 8) and humoral (9, 10) effects are similar to those obtained during iv short-term saline administration (2 L/2 h).
The aim of this study was to investigate WI-induced changes in blood pressure, sodium, potassium, and calcium urinary excretion and plasma levels of vasoactive hormones during either normal or low potassium intake in hypertensive subjects evaluated for salt sensitivity.
Subjects and Methods
Eleven uncomplicated, hypertensive, but otherwise healthy subjects (eight men and three women), ranging in age from 23–46 yr, were entered into the study after informed consent had been obtained. Each hypertensive subject had an out-patient diastolic blood pressure measurement by conventional sphygmomanometry in excess of 95 mm Hg (seated posture), with the arm in the horizontal position after 5 min of quiet sitting, on at least three occasions documented for at least 3 months before the study and had never received any antihypertensive treatment. The patients had no major symptoms or signs of target organ damage, nor did they have other major diseases besides hypertension; renal disease was excluded by documenting normal urinalysis and creatinine clearance. Cardiac hypertrophy was excluded by a complete M-mode echocardiogram monitored by two-dimensional echocardiography. Individuals receiving estrogens, nonsteroidal antiinflammatory agents, or drugs known to influence salt, potassium, calcium, water, or hemodynamic function were excluded. The study was performed under out-patient conditions.
Experimental protocol
The patients were instructed by the our institution dietician to follow a diet of approximately 75 g protein, 200 mmol sodium, and 60 mmol potassium daily; this closely paralleled their usual sodium and potassium intakes. After complying with these diets for 3 days, the subjects were allowed entry into the study. Each subject was studied on two separate occasions while receiving either a high (80 mmol/day) or a low (18 mmol/day) potassium diet; each study period lasted for 10 days. Body weight, blood pressure, and 24-h urinary sodium, potassium, calcium, and creatinine excretion were all monitored for the last 3 days of each study period. The diets were formulated from low protein bread, cream cheese, skimmed milk, rice, oil, margarine, pasta and tomato, ship-biscuit, and tea.
Except for potassium intake, the diet was identical during the two study periods and provided 25–40 Cal/kg BW energy, 0.8–1.0 g/kg BW protein, 900 mg calcium/day, and 30 mmol sodium/day. Appropriate amounts of sodium chloride were added to the diet to maintain a daily sodium intake of 220 mmol. Caloric content was adjusted for individual requirements.
WI studies
On day 11, after the completion of the two diet periods at either high or low potassium intake, each hypertensive subject was subjected to acute extracellular volume expansion by WI, thereby acting as his or her own control. WI was carried out as follows. At 0800 h after an overnight fast and fluid deprivation (10 h), an antecubital vein was catheterized for blood sampling; the subjects voided, received 200 mL water to drink, then sat quietly outside the immersion tank for 2 h at a room temperature between 26 ± 0.4 and 27 ± 0.4 C (preimmersion study). The water load was repeated hourly throughout the study. Then they stepped into the immersion tank and sat on an adjustable chair with water to the neck at constant temperature (34 ± 0.5 C) with their arms outside the tank in the horizontal position; the subjects remained in the tank for 2 h (immersion study) and stepped out of it at hourly intervals to void urine.
At the end of each hour of the test, before the subjects stood to void, blood was drawn for serum sodium, potassium, hematocrit, creatinine, PRA, and plasma aldosterone (PA) measurements. The hourly urine volumes were measured, and the concentrations of creatinine, sodium, potassium, and calcium were determined.
Both resting and WI arterial blood pressure were measured in the seated posture with a noninvasive fully automatic monitor (model 90207, Spacelabs, Redmond, WA) with the arm in the same position before and during WI.
Blood for PRA and PA measurements was drawn with plastic syringes and then placed immediately into chilled plastic tubes containing ethylenediamine tetraacetate (potassium salt). The plasma was separated in a refrigerated centrifuge at 4 C. Samples were frozen and stored at -20 C until assayed.
Assessment of salt sensitivity
According to a method previously described (11) the 11 hypertensive patients were given a low salt diet containing 30 mmol sodium/day for 14 days, provided by the dietary department of the hospital. During the first 7 days, 190 mmol sodium chloride were added to the daily intake. Total caloric intake was estimated to keep body weight constant. Throughout the study, compliance was assessed by measuring daily urinary sodium excretion. At 0700 h on days 7 and 14, the patients rested in quiet room in the supine position; they had fasted overnight and were hydrated by ingesting 300 mL water/h. Systolic and diastolic blood pressures were measured in the seated subjects, after a 30-min resting period, for 2 h, from 0800–1000 h, at 5-min intervals using the previously described noninvasive oscillometric technique. Average values for systolic and diastolic blood pressures during the 2-h period from 0800–1000 h correlates very closely with the full 24-h averages (12). As suggested by previous experiences (13), a significant 10% or greater drop in mean arterial pressure (the sum of diastolic and one third the pulse pressure), calculated as the difference between the average of 25 readings during the high or low salt periods, may be identified as a salt-sensitive response, whereas a reduction in mean arterial pressure less than 10% is destined as a salt-resistant response. Although this salt sensitivity classification is reproducible, its definition is variable, and it separates patients into 2 distinct groups (13, 14, 15, 16).
The salt sensitivity index, however, is a continuous variable that allows quantification of a different degree of salt sensitivity for each individual (17); accordingly, we used here the salt sensitivity index, calculated as the change in mean arterial pressure divided by the change in urinary sodium excretion rate (18), which shows the effect that changes in sodium intake have on blood pressure.
WI and salt sensitivity tests were randomly assigned.
Laboratory procedures
PRA (Renin-Kit, Liso-phase, Sclavo, Milan, Italy) and PA (Coat-A-Count Aldosterone, Diagnostic Products, Los Angeles, CA), were determined by RIA. Sodium and potassium levels were measured in serum and urine by internal standard flame photometry. Urine was collected in bottles carefully washed with distilled water; a 10 N hydrochloric acid solution was added, and urinary calcium was measured by atomic absorption spectrophotometry. Serum and urinary creatinine levels were determined (Technicon analyzer, Rome, Italy).
Statistics
Values are the mean ± SE. Statistical evaluation was performed by Student’s t test for paired and unpaired values or, where appropriate, by repeated measures ANOVA. Regression analysis was performed by Pearson’s correlation coefficient test. Differences were considered significant at P < 0.05.
Results
Balance studies
Compared with the normal potassium (80 mmol/day) diet, the low (18
mmol/day) potassium intake did not produce significant changes in serum
sodium and diastolic pressure, whereas a significant suppression of PRA
from 0.47 ± 0.08 to 0.25 ± 0.05 ng/L·s (P
< 0.02) and PA from 1082 ± 161 to 710 ± 101 pmol/L
(P < 0.04) was found during potassium depletion.
Altering potassium intake produced a striking decrease in the plasma
potassium concentration (from 4.1 ± 0.05 to 3.2 ± 0.1
mmol/L; P < 0.001) accompanied by a significant
increase in systolic blood pressure (from 141 ± 2 to 146 ±
2 mm Hg; P < 0.02; Table 1
).
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shows the individual urinary
excretion of sodium, potassium, and calcium of the 11 hypertensive
subjects after ingesting 80 and 18 mmol potassium daily, respectively,
for 10 days. Changes in potassium intake did not significantly modify
urinary sodium excretion (from 199 ± 12 to 210 ± 14
mmol/day; P = NS); conversely, there was a striking
reduction in urinary potassium excretion from 67 ± 2 to 20
± 1.5 mmol/day; P < 0.0001, accompanied by a
pronounced alteration in urinary calcium excretion from 4.7 ± 0.9
to 7.2 ± 1 mmol/day; P < 0.001).
|
As shown in Table 3, central
hypervolemia by WI induced a quite identical, significant increase in
urinary volume (from 3.5 ± 0.6 to 9.9 ± 0.6 mL/min and from
2.4 ± 0.5 to 9.2 ± 0.5 mL/min, respectively;
P < 0.0001) and sodium excretion [from 186 ± 28
to 396 ± 34 µmol/min (P < 0.001) and from
182 ± 24 to 431 ± 39 µmol/min (P <
0.0001) respectively, during high or low potassium intake].
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A significant suppression of PRA [from 0.46 ± 0.09 to 0.25 ± 0.04 (P < 0.003) and from 0.26 ± 0.06 to 0.16 ± 0.04 ng/L·s (P < 0.006), respectively] and PA [from 1082 ± 161 to 504 ± 73 (P < 0.002) and 710 ± 101 to 467 ± 58 pmol/L (P < 0.007), respectively] was obtained during the two WI experiments, either on normal or low potassium intake, whereas no significant changes were found in hematocrit, creatinine clearance, or mean arterial pressure.
As previously shown in Table 3
, the magnitude of the natriuretic
response exhibited by the whole hypertensive group during the two WI
experiments was identical (P = NS); on the other hand,
when sodium excretion was expressed as a function of salt sensitivity
(quantified by the salt sensitivity index), a greater percent increase
in sodium excretion (r = 0.69; P < 0.02) was
found in those individuals with a higher salt sensitivity index,
undergoing central volume expansion by WI with concomitant potassium
depletion than in those undergoing WI at normal potassium intake
(Fig. 1). During WI, there was also
evidence of a weak, but not significant, correlation (r = 0.57;
P < 0.06) between urinary sodium and calcium excretion
during WI with concomitant normal potassium intake. Nevertheless, the
same isotonic-isooncotic maneuver, performed during mild potassium
depletion, disclosed a highly positive correlation (r = 0.89;
P < 0.001) between urinary sodium and calcium
excretion in the 11 hypertensive subjects (Fig. 2).
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In our study we found that dietary potassium restriction increases systolic blood pressure in subjects with mild essential hypertension. This short-term study allowed us to induce substantial potassium depletion over a 10-day period; therefore, even though no long-term implications can be drawn from the data, it may be suggested, in keeping with previous epidemiological studies (19, 20, 21), that potassium depletion plays a critical role in the pathogenesis of essential hypertension.
Among several factors possibly involved in mediating the hypertensive effects of potassium depletion, sodium retention is believed to assume a pivotal role in both normotensive and hypertensive subjects (3, 22).
In fact, when maintained on a low potassium intake for 10 days, our hypertensive subjects exhibited a natriuretic ability identical to that obtained during normal potassium intake; this preserved natriuretic response during potassium depletion was found not only at the end of the 10-day study period, but also during short-term central volume expansion by WI. Whereas the present data would suggest that potassium depletion has no role in modulating the natriuretic response in the whole hypertensive group during WI, the evaluation of the hypertensive group in relation to salt sensitivity disclosed a WI-induced greater percent increase in sodium excretion in the hypertensive subjects with a higher salt sensitivity index.
It is well known that a salt sensitivity condition, a major determinant of renal sodium excretion (4), may be induced by dietary potassium deficiency and that, conversely, the pressor response to sodium is markedly reduced by potassium supplementation (23). In fact, it has been demonstrated that even a modestly deficient dietary intake of potassium can strongly enhance the renal retention of dietary salt (2) and thereby its pressor potential in salt-sensitive normotensive men. On the other hand, the salt sensitivity of essential hypertension is characterized by a modest degree of volume expansion due to a long-standing tendency to sodium retention; in this situation, a superimposed sudden volume expansion, such as that induced by WI, may elevate circulating fluid volume to the point that an overflow accounting for increased natriuresis occurs in salt-sensitive subjects (24). As natriuretic responses are directly related to the degree of underlying volume expansion (25), the natriuretic ability exhibited by subjects with a higher salt sensitivity index does not represent a contradictory or surprising result.
Our data also suggest that potassium depletion increases urinary
excretion of calcium; similar increments in urinary calcium excretion
were observed when extracellular fluid volume expansion and hypokalemia
were produced experimentally by the administration of mineralocorticoid
(26), and these findings are consistent with previous
reports that potassium supplementation lowers urinary calcium excretion
(3, 27). In our study significant calcium losses during
potassium depletion were detected during both balance studies and acute
WI experiments. More specifically, as shown in Fig. 2, the weak
correlation between calcium and sodium excretion obtained during WI at
normal potassium intake was highly significant during potassium
depletion, thereby demonstrating that at normal to high sodium intake,
potassium depletion exacerbates urinary calcium losses. Furthermore, WI
experiments during potassium depletion revealed that hypertensive
subjects with a higher salt sensitivity index may exhibit a greater
percent increase in urinary calcium excretion. Thus, the maintained
natriuretic ability found in those subjects with higher salt
sensitivity index could be mediated not only by the degree of
underlying volume expansion but also by a well known natriuretic effect
of calcium (Ca2+) through an increase in the
renal tubular Ca2+ concentration
(28).
By defining the dietary salt sensitivity index of hypertensive subjects, we were able to demonstrate that although both impaired natriuretic ability and moderate calcium losses are primarily found in those subjects with lower salt sensitivity index, calcium depletion is the most important consequence of potassium depletion in those exhibiting a higher salt sensitivity index. We also found no significant difference in circulating vasopressor hormones during the two WI experiments; PRA and plasma aldosterone were similarly and significantly suppressed during WI studies with either normal or low potassium intake.
In this regard our data are identical to recent results showing that a 6-day low potassium diet coupled with a normal to high sodium intake produced increased urinary calcium levels and elevations of ambulatory systolic blood pressure in hypertensive subjects; on the other hand, no significant difference in urinary sodium excretion, renal hemodynamics, muscle sympathetic nerve activity, PRA, PA, or plasma norepinephrine were found in the hypertensive group on the low potassium diet compared with those on a high potassium intake (29).
Other mechanisms by which potassium depletion may induce increased pressor effect in hypertension, could be by changes in systemic and renal vascular resistances, whereas the effects of potassium depletion on the arginine vasopressin system and baroreceptor sensitivity are not completely understood (30). More recently, it has been reported that potassium administration can enhance endothelial function in essential hypertensive patients (31), an effect that could explain any beneficial action of potassium in patients with essential hypertension.
Hypertensive subjects have been shown to present an increase in urinary
calcium excretion despite a lower dietary calcium intake
(32); this apparent paradox has been referred to as a
renal calcium leak, and several studies have clearly suggested that
urinary calcium excretion was significantly higher in salt-sensitive
subjects compared with those who were salt-resistant (33, 34). In addition, the preserved natriuretic ability exhibited by
hypertensives with a higher salt sensitivity index could not
paradoxically represent a favorable phenomenon; as it has been recently
demonstrated that even mild calcium deficiencies are responsible for
the high salt intake in humans (35), our data support the
idea that a dangerous vicious circle may take place in this subgroup
of essential hypertensive subjects, i.e.
natriuresis
K+
depletionhypercalciuriaCa2+
deficiencyhigh sodium intakenatriuresis. Thus, our results seem
to confirm that hypertensive patients with higher salt sensitivity
index are at major risk for calcium leak, which, in turn, might
represent an exacerbating factor of their hypertensive state (36, 37).
Several experimental and clinical studies suggest that calcium depletion elevates blood pressure (34, 38); in a recent prospective study of nutritional factors in hypertension, an important inverse correlation was found between potassium intake and the risk for hypertension, and a complex interplay among potassium, calcium, sodium, and magnesium in the genesis of hypertension has also been suggested (39).
As salt-sensitive hypertension has been demonstrated to be an independent cardiovascular risk factor (18), a high dietary intake of potassium could provide the observed protection against hypertension and cardiovascular disease (40), which have plagued humankind since we began eating a modern high sodium, low potassium diet. A protective effect of high dietary intake of potassium has been confirmed in animals by Tobian et al., who showed that dietary K+ supplements could prevent both renal (41) and cerebral (42) arteriolar lesions in Dahl S and stroke-prone spontaneously hypertensive rats independently of a lowering of arterial pressure. More recently, the same group provided clear evidence that a high K+ diet not only protects the arterial endothelial cells, but also may reduce the rise of blood pressure caused by a high NaCl diet (43).
In conclusion, our study confirms that potassium depletion may exacerbate essential hypertension by modifying natriuretic ability and calcium excretion in hypertensive subjects evaluated for degree of salt sensitivity; our data also suggest that not only sodium restriction, but also potassium and calcium supplementation, could be particularly advisable in salt-sensitive hypertensive patients.
Received November 3, 2000.
Revised February 7, 2001.
Accepted February 16, 2001.
References
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