Salt and Blood Pressure Responses to Calcium Antagonism in Hypertensive Patients
Abstract Since salt intake may affect blood pressure response to antihypertensive drugs, an individual’s salt-sensitivity status may be an important consideration in the selection of a medication. The purpose of this single-blind study was to assess the impact of salt sensitivity on the antihypertensive effects of isradipine. A total of 21 evaluable hypertensive patients (10 white, 11 black) 35 to 73 years of age (mean 55.9 years) were randomized to a low-salt diet (mean 24-hour urine sodium 100±14 mmol) or a high-salt diet (mean 24-hour urine sodium 210±22 mmol) for 7 weeks, followed by crossover to the other diet after a 2-week washout period. On each diet regimen, patients received placebo for 2 weeks, followed by optimal titration of isradipine (2.5 to 10 mg BID) for blood pressure control during the last 5 weeks. On the high-salt diet, salt-sensitive hypertensives (mean arterial blood pressure increase ≥5 mm Hg, n=5) exhibited a systolic/diastolic blood pressure change of −18.7/−19.6 mm Hg from 157.2/102.9 mm Hg after 5 weeks of isradipine treatment, whereas on a low-salt diet, blood pressure change was −6.9/−12.0 mm Hg from 148.7/97.3 mm Hg. Non–salt-sensitive patients (n=16) exhibited a systolic/diastolic blood pressure change of −12.6/−7.6 mm Hg from 155.3/98.6 mm Hg on the high-salt diet and −19.2/−10.9 mm Hg from 161.0/102.6 mm Hg on the low-salt diet after treatment with isradipine. The absolute blood pressure attained in both salt-sensitive and non–salt-sensitive patients was almost identical with isradipine therapy despite variation in dietary salt, although slightly higher doses of isradipine were required in the salt-sensitive group. Consequently, isradipine, and perhaps calcium antagonists in general, manifests a more robust blood pressure–lowering effect in the setting of high sodium intake. This effect does, however, appear to be largely confined to individuals who are salt sensitive.
Hypertension is a well-known risk factor of cardiovascular complications. In the United States alone, there are an estimated 50 million hypertensive patients.1 One of the most important advances in the last decade has been the recognition that the pathophysiological mechanisms of essential hypertension vary between individuals, influenced by factors such as genetics, age, race, sex, salt sensitivity, and obesity.2
Early research suggested a strong association between dietary salt and high blood pressure, and it was generally assumed that reducing the intake of salt would benefit all hypertensive persons.3 4 5 More recently, it has been demonstrated that a blood pressure–lowering response to reduced dietary salt intake occurs in only about half of the adult population.6 A large meta-analysis examining the results of studies on the impact of dietary salt on blood pressure demonstrated that there was a benefit of salt reduction in older hypertensives, who were presumably more salt sensitive, yet less of a benefit in younger patients with and without hypertension.7 Presumably, the latter patients were less salt sensitive. Nevertheless, the generalizability of this analysis is limited by the short average duration of the individual studies, ie, 14 days (normotensives) and 29 days (hypertensives). Efforts to find a genetic or physiological marker to identify salt-sensitive patients and target them for low dietary salt therapy have largely been unsuccessful, although there is clinical evidence that older, obese, and African-American hypertensives tend to be more salt sensitive than the general population.8
While low dietary salt therapy may improve blood pressure in some individuals, there is some concern that extreme salt restriction (<20 mmol sodium per day) may have long-term medical risks (ie, adverse effects on renal function and lipid metabolism) that could outweigh any benefits of blood pressure reduction; however, modest (≈100 mmol sodium per day) sodium restriction has not been associated with potentially adverse metabolic effects or health outcomes.9 Furthermore, while a low-salt diet lowers blood pressure in some hypertensive and normotensive individuals, blood pressure actually may rise in others.10 However, an explanation for this phenomenon may be that if salt has no overall effect in the cohort, by chance some individuals will manifest random blood pressure fluctuations in the upward direction.
Calcium antagonists have been shown to reduce blood pressure effectively in hypertensive patients who tend to be salt sensitive (eg, the middle-aged and older, blacks, the overweight, and individuals with low-renin hypertension).9 Few studies have been conducted to assess the blood pressure response of antihypertensive drugs in a population specifically identified as being salt sensitive or salt resistant. The purpose of this pilot investigation was to study the effect of the calcium antagonist isradipine on blood pressure in salt-sensitive and non–salt-sensitive hypertensive patients on low- and high-salt diets. A unique aspect of this trial was that the salt-sensitivity status of study participants was determined before assessment of blood pressure response to a pharmacological agent during periods of high and low dietary sodium intake. Only one other small study11 evaluated differences in blood pressure responses to calcium antagonist therapy in patients previously profiled for salt sensitivity during varying dietary salt consumption.
Black and white patients of either sex between the ages of 21 and 70 years with mild to moderate essential hypertension (diastolic blood pressure of 95 to 114 mm Hg) were eligible for inclusion into the study. Women of childbearing potential were excluded from the study, as were patients with clinically significant concurrent medical conditions, including cardiac, renal, hepatic, gastrointestinal, or endocrinologic disease. Also excluded were patients with known hypersensitivity or serious adverse reaction to isradipine or related drugs, recent history of smoking or drug or alcohol abuse, or clinically relevant mental disorder. Potential study participants were also excluded if they used concomitant medications that might interfere with the efficacy and safety evaluation of the study drug or if they had used an investigational drug within the previous 4 weeks. Additionally, patients were excluded if they needed concomitant medications, including antihypertensives (except the study drug), monoamine oxidase inhibitors, antiarrhythmic drugs, digitalis, hypnotics or minor tranquilizers (except those used for the treatment of sleep disturbances), psychotropic drugs, or estrogen-containing drugs. All patients signed an informed-consent form as approved by the institutional review board of the University of Maryland School of Medicine.
This was a single-blind crossover study, performed at a single center, designed to evaluate the effect of isradipine therapy in salt-sensitive and non–salt-sensitive patients 21 to 70 years of age with mild to moderate essential hypertension. Statistical analysis was performed at a separate center in a blinded fashion. Salt sensitivity was defined as a directionally appropriate mean arterial blood pressure change (increase of ≥5 mm Hg during high salt or reduction of ≥5 mm Hg on low salt during the 2 weeks immediately before the first isradipine treatment period). The entire study lasted 18 weeks (see the Figure⇓). During the 4-week lead-in period, patients were maintained on a normal diet and discontinued any prior therapy with antihypertensives. Patients with qualifying hypertension (sitting diastolic blood pressure between 95 and 114 mm Hg on two consecutive visits, ie, the last two visits of the 4-week lead-in placebo period) continued into the next part of the study and were randomized to either a low-salt (40 mmol sodium per day) or high-salt (195 mmol per day) diet plus placebo for 2 weeks. All patients were instructed to follow a low-salt diet prescribed by a registered dietitian. Patients on the high-salt diet were given an additional 155 mmol sodium per day as sodium chloride tablets in addition to their low-salt (40 mmol sodium per day) diet. Compliance was assessed by short visits with the dietitian every week, weekly pill counts, and 24-hour urinary sodium analysis. Dietary instruction was given for less (40 mmol sodium per day) and more (195 mmol sodium per day) dietary salt than what we expected could be accomplished in an outpatient setting to achieve an approximate twofold change in diet. Moreover, this is a level of dietary salt consumption that is in the physiological range and can be obtained in clinical practice. After a diet stabilization period of 2 weeks of taking either high- or low-salt diet plus placebo, patients received isradipine at an initial dose of 2.5 mg BID, with possible escalation every 10 days to 10 mg BID, for 5 weeks while maintaining their assigned salt diet. All patients were on their final dose of isradipine for a minimum of 2 weeks. Isradipine was titrated to achieve an average sitting diastolic blood pressure of <95 mm Hg and at least 10 mm Hg less than the baseline value. On completion of one salt diet, patients were crossed over to the other salt diet after a 2-week placebo washout period. The 5-week isradipine titration period was subsequently repeated during consumption of the alternate sodium diet. Isradipine and placebo were provided in identical capsules to maintain blinding. Patients were instructed to take two isradipine capsules each day, 12 hours apart, throughout the study.
Study procedures included medical history, physical examination (weekly), 12-lead electrocardiogram (beginning and end of the study), chest roentgenogram (beginning of the study if not done in previous 6 months), clinical laboratory evaluation (beginning and end of the study), and blood pressure and pulse rate measurements (weekly). Twenty-four-hour urine collections for salt and creatinine, and ambulatory blood pressure monitoring were done before and at the conclusion of each pharmacotherapy intervention.
Blood pressure was measured by mercury sphygmomanometer on the same arm in the sitting and standing positions. Three consecutive blood pressure measurements were taken at no less than 30-second intervals. The recorded blood pressure was the average of the three measurements. One-minute pulse rate was recorded after the blood pressure measurements. All blood pressure and pulse measures throughout the study were made at trough, approximately the same time of day, always between 8 am and 10 am, 12±2 hours after the last dose.
All inferential analyses were performed using the Statistical Analysis System (SAS) program (Version 6.07, SAS Institute Inc, Cary, NC). A two-sided significance level of .05 was used for all statistical tests. The analysis of variance model for a 2×2 crossover design to test for a carryover effect (sequence effect) of diet contained effects for sequence (high-salt/low-salt or low-salt/high-salt), patient nested with sequence, diet, and period.
Patients were categorized into salt-sensitive and non–salt-sensitive groups according to the formula LSP=DIA+0.33 (SYS-DIA) or HSP=DIA+0.33 (SYS-DIA), where LSP is the mean arterial blood pressure during the low-salt-diet placebo period and HSP is the mean arterial blood pressure during the high-salt-diet placebo period, DIA is the diastolic blood pressure, and SYS-DIA is the pulse pressure. If HSP minus LSP was equal to or greater than five, then the patient was classified as salt sensitive.
Demographic and vital signs data were summarized as the mean±SD and range for continuous variables and frequencies and percentages for categorical variables. Stratified analyses according to salt-sensitivity status are presented.
Primary study end points were the difference in blood pressure and the differences in drug dose at the end of the high- and low-sodium treatment phases within each of the two groups of salt-sensitive and non–salt-sensitive individuals. There was no evidence of a significant carryover effect (sequence effect).
A total of 24 patients were enrolled in this study. Of these, 22 met the inclusion/exclusion criteria and were randomized to single-blind therapy. Of the 22 patients randomized, 21 completed both the low-salt and high-salt diets (evaluable population). Demographic parameters of the evaluable patient population are summarized in Table 1⇓. Mean age was 55.9 years (range 35 to 73 years); 57% were men and 43% were women; 48% were white and 52% were black. Mean duration of hypertension was 10 years (range 1 to 20 years). There were no statistical differences between the two groups with regard to any of the demographic variables.
Dietary Salt Intake
Twenty-four-hour urine collections were corrected for completeness as determined by the mean creatinine production (milligrams per 24 hours) for the five collections. The mean urinary salt excretion was 101±14 mEq/24 h on low salt intake and 210±22 mEq/24 h on the high-salt diet, for the entire study cohort. These results were in concert with our expectations to achieve a twofold variation in daily salt ingestion using outpatient teaching without intensive training or special diets.
The primary objective of this study was to compare the effect of isradipine on blood pressure in salt-sensitive and non–salt-sensitive white and black hypertensives on low- and high-salt diets. A total of 21 hypertensive patients with normal renal function were evaluated. Vital signs analyses showed no significant carryover effect; therefore, an analysis of low-salt- and high-salt-diet groups is presented, using pooled data from group 1 and group 2. Baseline vital signs were not significantly different between patients randomized to the low-salt/high-salt diet sequence (group 1) and those randomized to the high-salt/low-salt diet sequence (group 2). Optimal titration of antihypertensive treatment with isradipine occurred during the last 5 weeks of each diet. No statistically significant differences were found in isradipine dosages between high-salt diet (titrated to 8.3 mg BID) and low-salt diet (titrated to 7.6 mg BID) periods for all evaluable patients or for salt-sensitive and non–salt-sensitive patients analyzed separately (see Table 2⇓). However, the salt-sensitive patients required approximately 60% more isradipine dosage to overcome the effect of the higher-salt diet on blood pressure. This difference was not statistically significant (P=.15) due to the small sample size (n=5). Mean changes in vital sign parameters after 5 weeks of isradipine therapy are derived from measurements taken after 2 weeks of placebo treatment on each diet.
Five patients were classified as salt sensitive according to the formula described in the “Methods” section. Blood pressure measurements during placebo for salt-sensitive and non–salt-sensitive patients on each diet are summarized in Table 3⇓. As seen in this table, greater blood pressure reductions were observed in the high-salt diet group than in the low-salt diet group. On the high-salt diet, salt-sensitive patients had sitting systolic/diastolic blood pressure change of −18.7/−19.6 mm Hg after 5 weeks of isradipine therapy. On the low-salt diet, the change was −6.9/−12.0 mm Hg. Standing systolic and diastolic blood pressure measurements showed similar results (data not shown). There were no consistent changes in heart rate or weight (data not shown) for these patients.
Among the 16 non–salt-sensitive patients, sitting diastolic blood pressure measurements showed decreases at all time points in both the high-salt and low-salt diet groups. After 5 weeks of isradipine therapy, sitting systolic/diastolic blood pressure change was −12.6/−7.6 mm Hg on the high-salt diet and −19.2/−10.9 mm Hg on the low-salt diet (Table 3⇑). Standing systolic and diastolic blood pressure measurements showed similar reductions (data not shown). Heart rate was unaffected, and weight decreased slightly (data not shown) on both diets. However, the absolute level of blood pressure attained with isradipine therapy in each group was almost identical irrespective of dietary salt consumption (salt-sensitive [n=5], 138.5/83.3 mm Hg on high-salt versus 141.8/85.3 mm Hg on low-salt diet, a difference of +3.3/+1.7 mm Hg; non–salt-sensitive [n=16], 142.7/91.0 mm Hg on high-salt versus 141.8/91.7 mm Hg, a difference of −0.9/−0.7 mm Hg). Because of the small size of the evaluable patient population (n=21) and the limited number of salt-sensitive patients (n=5), the results must be interpreted with caution. There is not sufficient statistical power to detect an influence of dietary salt. However, with a value of P=.15 with n=5, it may be suggestive that there is an influence. Reduction of blood pressure was statistically significant for all periods of isradipine therapy except for the salt-sensitive group, for systolic blood pressure on the low-salt diet.
Twenty-four-hour ambulatory blood pressure monitoring results support the results obtained from blood pressure measurements taken with a standard mercury sphygmomanometer. As seen in Table 4⇓, salt-sensitive patients on a high-salt diet exhibited the greatest reduction in blood pressure with optimally titrated isradipine. On the high-salt diet, salt-sensitive patients had a systolic/diastolic blood pressure change of −22.0/−10.1 mm Hg after isradipine therapy, whereas on the low-salt diet the change in blood pressure was −0.5/−3.2 mm Hg (P<.01 for mean arterial pressure difference). In non–salt-sensitive patients, systolic and diastolic blood pressure was similarly reduced on both the high- and low-salt diets (−13.5/−13.5 mm Hg and −14.9/−9.2 mm Hg, respectively; P=NS). Absolute levels of systolic and diastolic blood pressure attained with isradipine therapy were not statistically different between salt diets in both the salt-sensitive and non–salt-sensitive groups.
In this pilot study, the impact of salt sensitivity on the antihypertensive effects of the calcium antagonist isradipine was evaluated. For all 21 evaluable hypertensive patients taken together, mean sitting and standing systolic and diastolic blood pressures were significantly reduced after optimal titration of antihypertensive treatment with isradipine on both the high- and low-salt diets. Our findings demonstrate that similar levels of blood pressure can be achieved in salt-sensitive and non–salt-sensitive individuals taking isradipine, a calcium antagonist. This effect is achieved because of the more robust antihypertensive properties of the calcium antagonist during a high-salt diet. These results are similar to the observations from a similar study by Resnick et al.11 However, the salt-sensitive individuals received a slightly higher medication dose (P=.15) to achieve the same level of blood pressure control during periods of high sodium intake as that seen in the non–salt-sensitive patients. Our data highlight the important point that an individual’s salt-sensitivity status influences blood pressure response, particularly during periods of high sodium intake; nevertheless, the attenuating effect on blood pressure lowering of a high-sodium diet can be overcome by uptitration of drug doses.
Some investigators suggest that calcium antagonists reduce blood pressure irrespective of dietary salt consumption.9 Several theories have been proposed to explain these observations, but none are proven with certainty. Calcium antagonists block the transport of calcium across cell membranes, thereby inhibiting cardiac and vascular smooth muscle contraction and decreasing peripheral resistance and blood pressure.12 Research suggests an association between salt sensitivity and calcium metabolism. McCarron et al13 demonstrated that calcium excretion in the urine is increased when dietary salt is increased in normal individuals. Resnick et al14 showed that salt-sensitive, low-renin hypertensive individuals have significantly lower serum ionized calcium levels than non–salt-sensitive, normal-renin individuals. Serum levels of 1,25-dihydroxy vitamin D3 [1,25(OH)D3] and parathyroid hormone (PTH) are increased in these individuals, probably in response to these low calcium levels.15 Thus, elevations in these hormones may be responsible for the blood pressure increases characterized by salt sensitivity, as 1,25(OH)D3 and PTH are known to stimulate intracellular calcium influx and may elevate calcium content in vascular smooth muscle cells.9 Increasing calcium concentration in the vascular smooth muscle can trigger vasocontraction. If the hypothesis is correct, calcium antagonists may be particularly useful for treating high blood pressure in salt-sensitive patients, through a reduction of calcium content in vascular smooth muscle. Calcium antagonists also may facilitate blood pressure reduction in the face of higher dietary salt through their ability to facilitate natriuresis.16 Calcium antagonists have proven natriuretic effects, likely through an ability to directly inhibit renal tubular sodium reabsorption. However, a direct relationship between sodium excretion and the antihypertensive activity of calcium antagonists has not been previously demonstrated.
During isradipine therapy, no evidence of weight gain occurred during higher or lower dietary salt in the salt-sensitive patients, whereas among the salt-resistant patients there was a slight (−1.0 kg) but not significant weight reduction on the low-salt diet during isradipine treatment. These observations support the idea that the natriuretic activity of calcium antagonists may be important in salt-sensitive patients. Sitting and standing heart rates were not significantly changed at any of the weekly visits during the 5 weeks of isradipine treatment.
We purposefully evaluated final or net blood pressure achieved in all the treatment groups, because change in blood pressure is influenced by multiple factors, including dietary salt consumption, dose of drug, and pretreatment blood pressure. Each of these factors can influence the other; for example, as examined in this report, the influence of dietary salt consumption on blood pressure. However, the absolute blood pressure level attained (and how this is achieved) is critically important, since the final blood pressure level, not the change in blood pressure, determines long-term cardiovascular disease risk.
Emphasizing the final achieved blood pressure rather than the drug-induced change in blood pressure may be more reflective of cardiovascular risk but was not the intent of our study, which was to assess the impact of salt-sensitivity status and dietary salt on the antihypertensive properties of the calcium antagonist isradipine. Our results clearly demonstrate the more robust antihypertensive properties of the calcium antagonist in patients who are salt sensitive and consuming greater dietary salt. One might infer from these observations that salt intake may be liberalized in non–salt-sensitive patients or that it is not necessary to restrict dietary salt in patients whose blood pressure is controlled on a calcium antagonist. However, larger clinical trials need to more carefully explore these possibilities.
The small number of patients with hypertension in our convenience sample that seemed paradoxically to show that a greater percentage of whites were salt sensitive compared with blacks should not detract from our observations, since approximately 50% or more of hypertensives are likely salt sensitive irrespective of race.6 The important point was the trend toward greater medication requirement for the salt-sensitive patients on a high-salt diet. This observation has not been previously reported.
The results of this study provide supporting evidence that the calcium antagonist isradipine is a safe and effective antihypertensive agent in salt-sensitive and non–salt-sensitive patients with mild to moderate essential hypertension irrespective of dietary salt consumption, which is in the physiological range of what is observed in general clinical practice.
This study was supported by an educational grant from Sandoz Research Institute. We would like to thank Jacqueline Brandenburg and Valerie Heisler for their expert secretarial assistance.
- Received September 16, 1996.
- Revision received October 29, 1996.
- Accepted January 21, 1997.
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