Nocturnal Decline in Blood Pressure Is Attenuated by NaCl Loading in Salt-Sensitive Patients With Essential Hypertension
Noninvasive 24-Hour Ambulatory Blood Pressure Monitoring
Abstract We investigated the effect of NaCl on the circadian blood pressure rhythm in patients with essential hypertension classified according to the presence or absence of salt sensitivity. We obtained 24-hour noninvasive ambulatory blood pressure measurements in 64 Japanese patients with mild to moderate essential hypertension who ate a low NaCl diet (50 mmol/d) for 1 week, followed by a high NaCl diet (340 mmol/d) for 1 week. Twenty-six patients whose mean blood pressure was increased more than 10% by NaCl loading were classified as salt sensitive. The remaining 38 patients were classified as salt resistant. The nocturnal decline in mean blood pressure was significantly smaller in salt-sensitive patients (8.3±1.0%) than in salt-resistant patients (11.5±0.9%) (P<.05) during a high NaCl diet but was similar in both groups during a low NaCl diet. There was no significant difference in the prevalence of the non-dipper pattern between groups on a low NaCl diet, but the prevalence of the non-dipper pattern was significantly higher in salt-sensitive patients than in salt-resistant patients on a high NaCl diet (0.57 versus 0.26, χ2=6.4; P=.02; odds ratio, 3.82). These findings suggest that the NaCl loading blunted the nocturnal decline in blood pressure in salt-sensitive patients but not in salt-resistant patients.
NaCl has been widely recognized as an important factor in the development of hypertension.1 2 However, excessive amounts of dietary NaCl do not always elevate blood pressure because the pressure response to NaCl loading varies among individuals.3 4 5 Although the role of salt sensitivity in hypertension has not been fully clarified, proposed mechanisms include expansion of fluid volume,6 inappropriate suppression of the renin-angiotensin system,3 4 abnormal response of sympathetic nervous activity,5 6 and the intracellular accumulation of sodium and calcium.3
Studies have shown that 24-hour ABPM is useful for assessing white coat hypertension,7 episodic hypertension,8 and the effects of antihypertensive agents.9 Individuals with a non-dipper circadian pattern of blood pressure in which the nocturnal decline in blood pressure is diminished or absent have an increased risk of cerebrovascular and cardiovascular complications compared with individuals with a dipper circadian rhythm.10 11 12 13 14 Data on the effects of NaCl intake on diurnal changes in blood pressure, especially nocturnal blood pressure, are limited.
We investigated the effect of NaCl intake and salt sensitivity on the circadian rhythm of blood pressure using 24-hour noninvasive ambulatory blood pressure measurements in 64 Japanese patients with mild to moderate essential hypertension who ate a low NaCl diet (50 mmol/d) for 1 week, and then a high NaCl diet (340 mmol/d) for 1 week.
We studied 64 Japanese inpatients with mild to moderate essential hypertension (37 men and 27 women; mean age, 50.6±1.5 years). Office blood pressure measurements were obtained in the outpatient clinic of Hiroshima University School of Medicine. Hypertension was defined in the untreated state as a systolic blood pressure >160 mm Hg and/or a diastolic blood pressure >95 mm Hg in the sitting position on at least three different occasions. Patients had no evidence of advanced target organ damage such as left ventricular hypertrophy, severe retinopathy, or proteinuria. Patients with secondary forms of hypertension were excluded by appropriate clinical and biochemical tests. None of the patients had a history of cardiovascular or cerebrovascular disease, hypercholesterolemia, diabetes mellitus, liver disease, or renal disease. Informed consent for participation was obtained from all subjects.
Dietary Manipulation of NaCl
Patients did not take any antihypertensive agents for at least 4 weeks before the study. One week before the study subjects were given a regular diet that contained 170 mmol of NaCl daily to allow the systemic sodium balance and blood pressure to stabilize. Subjects then ate a low NaCl diet (50 mmol/d) for 1 week, followed by a high NaCl diet (340 mmol/d) for 1 week. The NaCl content of the high NaCl diet was increased by the addition of Slow-Sodium tablets (10 mmol NaCl per tablet; Mission Pharmaceutical Co) to the diet. The dietary content of potassium (100 mmol/d) and calcium (40 mmol/d) was kept constant throughout the study. The caloric intake was 40 cal/kg daily. Meals were prepared in the Hiroshima University Hospital kitchen. Rigid compliance to the diet was confirmed by measuring the 24-hour urinary excretion of sodium, chloride, and potassium throughout the study.
ABPM was performed from day 6 to day 7 of each dietary period using a TM2420 device (AND Co), a noninvasive ambulatory blood pressure monitor, that was attached to the upper left arm. Blood pressure was measured by the Korotkoff microphone methods during stepwise deflations (3.0±1.0 mm Hg/step) of the cuff. The within-run precision of blood pressure and heart rate measurements was ±4.0 mm Hg and ±5.0%, respectively. The reliability of this device has been previously confirmed.15 16 Blood pressure and heart rate measurements were obtained at 30-minute intervals. A non-dipper pattern was defined as a difference in the mean blood pressure of less than 10% between the daytime (6 am to 9 pm) and nighttime (9 pm to 6 am) hours. Patients were confined to their ward during the study and maintained on a regular schedule. They woke at approximately 6 am and the room light was turned off at 9 pm. Salt sensitivity was also defined by the percent change in the mean 24-hour blood pressure that resulted between the low NaCl diet (50 mmol/d) and the high NaCl diet (340 mmol/d). Subjects in whom NaCl loading induced a ≥10% change in mean blood pressure were classified as SS, and subjects in whom NaCl loading induced a <10% change were classified as SR.
Measurement of Clinical Parameters
After a 30-minute rest period, fasting serum concentrations of total cholesterol, creatinine, glucose, and electrolytes; the PRA; and the plasma concentration of norepinephrine were collected in a supine position in a quiet, dark, and air-conditioned room maintained at a constant temperature (22°C to 25°C) at 8:30 am on day 7 of each dietary period. Blood samples were placed in prechilled tubes containing EDTA and in polystyrene tubes. After separation, plasma and serum were stored at −80°C until analysis. Serum concentrations of total cholesterol, creatinine, glucose and electrolytes, and urinary electrolytes were determined by routine chemical methods. The PRA was measured by a radioimmunoassay. The plasma concentration of norepinephrine was measured by high-performance liquid chromatography.
Results are presented as mean±SEM. Baseline characteristics of the two groups were compared by ANOVA. The difference in change in parameters between SS and SR patients was determined by ANCOVA using baseline data as the covariates. After adjusting for confounders that significantly differed between SS and SR groups, differences in the distribution of dipper and non-dipper patterns determined by ABPM between SS and SR patients were analyzed by the χ2 test. A value of P<.05 was considered statistically significant.
Salt-Sensitive and Salt-Resistant Patients
ABPM identified 26 patients as SS (14 men and 12 women; mean age, 54.5±2.3 years) and 38 patients as SR (23 men and 15 women; mean age, 49.4±2.0 years).
Baseline parameters were similar in the SS and SR patients during the regular diet (Table 1⇓).
Effects of Dietary NaCl on Clinical Characteristics
During a low NaCl diet, there were no significant differences in parameters between the SS and the SR patients except for the PRA, which was higher in SR patients than in SS patients (P<.05) (Table 2⇓). During a high NaCl diet, body weight (P<.01) and urinary sodium excretion (P<.001) increased significantly and the PRA (P<.01) decreased significantly in all patients. Mean blood pressures during a high NaCl diet were significantly higher in SS patients than in SR patients. The percent change in mean blood pressure at night was smaller in the SS group than in the SR group during a high NaCl diet (8.3±1.0% versus 11.5±0.9%, P<.05) but was similar in both groups during a low NaCl diet.
Prevalence of Dipper and Non-Dipper Types
A non-dipper pattern was observed in 13 (50%) of 26 SS patients and in 10 (26%) of 38 SR patients during the regular diet. There was no significant difference in the frequency of the non-dipper pattern between groups during a low NaCl diet (SS patients: 12/26 [46%] versus SR patients: 12/38 [32%]). The frequency of the non-dipper pattern was significantly higher in SS patients than in SR patients during a high NaCl diet (15/26 [57%] versus 10/38 [26%]; χ2=6.4; P=.02; odds ratio, 3.82).
The NaCl-induced increase in blood pressure was correlated with the nocturnal decline in blood pressure during a high NaCl diet (Figure⇓) but not during a low NaCl diet.
The nocturnal decline in blood pressure was attenuated by NaCl loading in SS patients compared with SR patients in the present study. The prevalence of non-dippers was significantly higher in the SS group than in the SR group during a high NaCl diet, whereas there was no significant difference in the frequency of the non-dipper pattern between groups during a low NaCl diet. Our results suggest that the blunted nocturnal decline in blood pressure induced by NaCl loading may be a specific characteristic of SS patients. A recent study showed that a high NaCl diet caused abnormal diurnal changes in blood pressure in spontaneously hypertensive rats but not in Wistar-Kyoto rats.6 These observations suggest that the dietary content of NaCl should be kept fairly constant for assessment of the diurnal blood pressure variation.
Although the mechanism of the blunted nocturnal decline in blood pressure in SS patients during a high NaCl diet remains unclear, there are a number of potential explanations. Studies have shown that factors that regulate blood pressure, such as sympathetic nervous activity,2 5 body fluid volume,5 PRA,3 4 intracellular sodium and free calcium metabolism,3 17 renal hemodynamics,4 and nitric oxide production,4 are altered by changes in the dietary intake of NaCl. Because these factors also contribute to a circadian rhythm of blood pressure, the NaCl-induced changes in these factors may account for the difference in the change in nocturnal decline in blood pressure.
Previous studies have shown that abnormalities in autonomic nervous system function, especially in sympathetic nervous activity, inhibit the nocturnal decline in blood pressure.18 19 20 Studies have suggested that sympathetic nervous activity dysfunction is increased by a high NaCl diet in SS patients2 5 and by NaCl-induced hypertension in animal models,6 resulting in an increase in blood pressure. However, the plasma concentrations of norepinephrine as one of the indexes of sympathetic nervous system were similar in SS and SR patients during low and high NaCl diets. Therefore, the difference in blood pressure between SS and SR patients could not be explained by the different sympathetic nerve activity. Because we did not measure the plasma concentration of norepinephrine during the nighttime or throughout 24 hours, in the present study we could not determine whether an abnormal response of sympathetic nervous activity in SS patients may have been responsible for the absence of the nocturnal decline in blood pressure during a high NaCl diet. Further study is needed to clarify the diurnal blood pressure in response to NaCl intake and the autonomic nervous system.
The nocturnal decline in blood pressure is diminished in the presence of diseases that cause expansion of fluid volume, such as primary aldosteronism,21 toxemia of pregnancy,22 and renal failure.23 SS patients and rats are not able to prevent excessive fluid volume expansion in response to a high NaCl intake, suggesting that the natriuretic and diuretic responses may be impaired in the salt sensitivity, resulting in an increase in blood pressure. These findings suggest that an increase in body fluid volume may be a mechanism of the diminished nocturnal decline in blood pressure during a high NaCl diet. In the present study, however, changes in body weight, as indexes of changes in extracellular fluid volume, by NaCl loading were similar in SS and SR patients, in agreement with our previous report.24 Thus, changes in extracellular fluid volume by NaCl loading may not contribute to this mechanism in patients with essential hypertension.
The renin-angiotensin-aldosterone system may also play a role in the regulation of diurnal blood pressure. Brandenberger et al25 demonstrated that a nighttime decrease in renin secretion contributed to the nocturnal reduction in blood pressure. The suppression of the renin-angiotensin-aldosterone system by NaCl loading may lead to the reduction in the diurnal variation of blood pressure. The suppression of PRA induced by a high NaCl diet was significantly smaller in SS patients than in SR patients. This inappropriate suppression of the renin-angiotensin system in SS patients may have contributed to the decreased nocturnal decline in blood pressure.
The non-dipper pattern has been defined in various ways: as a mean nocturnal blood pressure ≤10% of the average daytime blood pressure, a mean nocturnal blood pressure that is ≤10 mm Hg of the average daytime blood pressure, and a nocturnal increase in mean blood pressure compared with the average daytime blood pressure. The prevalence of non-dipper pattern tended to be higher in the present study with all three diets (regular NaCl: 40.6%; low NaCl: 37.5%; high NaCl: 39.1%) than in previous reports (17.1% to 40%).15 16 26 27 28 A study using more rigid criteria (a decrease in systolic/diastolic pressure <10/5 mm Hg from daytime to nighttime) found a 17% prevalence of the non-dipper pattern,15 but studies based on criteria similar to those used in the present study found rates of prevalence of 25% to 35%.16 26 27 The higher prevalence of the non-dipper pattern in the present study may have been related to the inpatient setting. In many studies, ABPM is performed on an outpatient basis, and thus differences in daytime activity may contribute to variations in blood pressure. Patients in the present study followed the same daily routine, which may have reduced the influence of daytime activity in blood pressure.
In conclusion, the decline in nocturnal blood pressure was attenuated by NaCl loading in SS patients, resulting in an increased prevalence of the non-dipper pattern in these subjects. This abnormal diurnal blood pressure variation in response to a NaCl diet may be a common characteristic of SS patients.
Selected Abbreviations and Acronyms
|ABPM||=||ambulatory blood pressure monitoring|
|PRA||=||plasma renin activity|
This study was supported in part by grants-in-aid for Scientific Research (7407065 and 8457639) from the Ministry of Education, Science and Culture of Japan and a grant from Foundation for Total Health Promotion. The authors thank Sumiko Nakamura for preparing the diets and Yuko Omura for her secretarial assistance.
- Received August 18, 1996.
- Revision received October 21, 1996.
- Accepted January 28, 1997.
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