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(Hypertension. 1998;31:1088-1096.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Influence of Race and Dietary Salt on the Antihypertensive Efficacy of an Angiotensin-Converting Enzyme Inhibitor or a Calcium Channel Antagonist in Salt-Sensitive Hypertensives

Matthew R. Weir; Steven G. Chrysant; David A. McCarron; Maria Canossa-Terris; Jerome D. Cohen; Patricia A. Gunter; Andrew J. Lewin; Robert F. Mennella; Lance W. Kirkegaard; Jennifer H. Hamilton; Myron H. Weinberger; ; Alan B. Weder

From the Division of Nephrology and Clinical Research Unit, Department of Medicine, University of Maryland School of Medicine, Baltimore (M.R.W.); Oklahoma Cardiovascular and Hypertension Center, Oklahoma City (S.G.C.); Division of Nephrology, Hypertension, and Clinical Pharmacology at Oregon Health Sciences University, Portland (D.A.M.); Miami Heart Research Institute (Fla) (M.C.-T.); St Louis University Health Sciences Center (Mo) (J.D.C); Sandoz Pharmaceuticals Corporation, East Hanover, NJ (P.A.G., R.F.M.); National Research Institute, Los Angeles, Calif (A.J.L.); Hill Top Research, Tacoma, Wash (L.W.K.); Division of Endocrinology, Department of Medicine, Baltimore Veterans Affairs Medical Center (Md) (J.H.H.); Division of Hypertension, Department of Medicine, University of Indiana School of Medicine, Indianapolis (M.H.W.); and Division of Hypertension, Department of Medicine, University of Michigan School of Medicine, Ann Arbor (A.B.W.).

	Abstract

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Abstract—Dietary salt restriction is a recommended adjunct with antihypertensive therapy. There may be racial differences in blood pressure response to salt restriction while on antihypertensive therapy. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (black, n=96; Hispanic, n=63; white, n=232). Participants were initially preselected for stage I to III hypertension and then further selected for salt sensitivity (5 mm Hg increase in diastolic blood pressure after 3 weeks of low salt [88 mmol/d Na⁺] and high salt [>190 mmol/d Na⁺] diet). We compared the antihypertensive effect of an angiotensin-converting enzyme inhibitor (enalapril 5 or 20 mg BID) or a calcium channel antagonist (isradipine 5 or 10 mg BID) during alternating periods of high and low salt intake. The main outcome measure was blood pressure change and absolute blood pressure level achieved with therapy. During the high salt diet (314.7±107.5 mmol/d urinary Na⁺) there was greater downward change in blood pressure with both enalapril and isradipine compared with the low salt diet (90.1±50.8 mmol/d Na⁺); however, the absolute blood pressure achieved in all races was consistently lower on a low salt diet for both agents. Black, white, and Hispanic isradipine-treated salt-sensitive hypertensives demonstrated a smaller difference between high and low salt diets (black, -3.6/-1.6 mm Hg; white, -6.2/-3.9 mm Hg; Hispanic, -8.1/-5.3 mm Hg) than did enalapril-treated patients (black, -9.0/-5.3 mm Hg; white, -11.8/-7.0 mm Hg; Hispanic, -11.1/-5.6 mm Hg). On the low salt diet, blacks, whites, and Hispanics had similar blood pressure control with enalapril and isradipine. On the high salt diet, blacks had better blood pressure control with isradipine than with enalapril, whereas there was no difference in the blood pressure control in whites and Hispanics treated with either drug. Dietary salt reduction helps reduce blood pressure in salt-sensitive hypertensive blacks, whites, and Hispanics treated with enalapril or isradipine. These data demonstrate that controlling for salt sensitivity diminishes race-related differences in antihypertensive activity.

Key Words: sodium, dietary • race • angiotensin-converting enzyme inhibitors • calcium channels

	Introduction

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Agrowing body of clinical findings indicates that there are racial differences in response to antihypertensive drugs. These differences are strongest when black and white populations are compared.^{1 2 3 4 5 6 7} Dietary salt sensitivity and low plasma renin activity have been suggested by some to be critical physiological factors explaining this difference.^{8 9 10 11 12} However, there is no general agreement that race affects the relationship between dietary salt intake and blood pressure.¹³ Some investigators have suggested that diuretics and calcium channel antagonists may have an advantage over other commonly used drugs in controlling blood pressure in patients with low renin such as blacks,^{5 6 7} particularly in salt-sensitive patients.¹⁴ This is based on data from studies that have included only small numbers of patients, and most of these studies suffer from the lack of full titration of dosage of the various antihypertensive drugs studied. No published studies have assessed antihypertensive drug efficacy in Hispanics compared with other racial groups.

This article examines possible racial differences in the response to the full dosing range of isradipine and enalapril in hypertensive black, white, and Hispanic patients on low and high salt diets who had been previously profiled as being salt sensitive (an increase of diastolic blood pressure of 5 mm Hg when dietary salt was increased from approximately 80 to 200 mmol of sodium per day). Another report described the antihypertensive response to isradipine with that to enalapril in salt-sensitive hypertensive patients on alternating low salt and high salt diets without evaluating racial differences.¹⁵

	Methods

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Study Population
Hypertensives aged 21 years of age or older with a diagnosis of stage I through stage III essential hypertension (diastolic blood pressure 95 to 114 mm Hg) were eligible to enter the study after giving written informed consent as approved by the institutional review board for each study site. Patients were also required to be free of clinically significant major organ system diseases, including congestive heart failure, second or third degree heart block without a pacemaker, angina pectoris requiring medication, secondary hypertension, renal dysfunction, and insulin-dependent diabetes mellitus. Patients were also excluded if they needed concomitant medications that could affect blood pressure, such as antidepressants, antiarrhythmic drugs, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory drugs, digitalis, major tranquilizers, or estrogen-containing drugs.

Study Design
This was a randomized, double-blind, placebo-controlled, clinical study performed at 36 sites that assessed the efficacy of low-dose and high-dose monotherapy with enalapril (Vasotec, Merck and Co; low dose, 5 mg BID; high dose, 20 mg BID) and isradipine (Dynacirc, Sandoz Pharmaceuticals; low dose, 5 mg BID; high dose, 10 mg BID) in salt-sensitive hypertensive patients on alternating low and high salt diets. Patients were self-classified as being black, white, Hispanic, or other in origin. The study lasted a total of 20 weeks and consisted of six treatment periods (Fig 1). The first period was a single-blind qualification phase in which antihypertensive medication was discontinued and placebo given. Patients with average sitting diastolic blood pressure 95 mm Hg and 115 mm Hg 3 weeks after antihypertensive drug withdrawal on an ad libitum salt diet qualified for further study.

View larger version (12K): [in this window] [in a new window]   Figure 1. Flow chart/study design.

Periods 2 and 3 involved salt sensitivity testing. All patients regularly met with nutritionists for counseling to achieve compliance with low salt and high salt diets. Patients meeting the initial blood pressure criteria initially underwent a 3-week period ingesting a low salt diet consisting of <80 mmol/d of sodium (period 2). Dietary compliance was assessed by measurement of 24-hour urinary sodium excretion, which was required to be 88 mmol/d (goal of 80 mmol/d ±10%). Subsequently, patients underwent a 3-week period of a high salt diet (period 3). A urinary sodium measurement of 190 mmol/d (goal of 200 mmol/d ±5%) was required. To ensure that the 24-hour urine collections were complete, urinary creatinine measurements were obtained. Patients had to have their 24-hour urinary creatinine values fall within the 95% confidence interval for age, gender, and weight to be considered complete. Blood pressures were determined at the end of the 3-week period of low and high salt intake, and only those patients in whom diastolic blood pressure was 5 mm Hg higher at the end of the salt diet compared with the low salt diet qualified for randomization.

On completion of the single-blind phase, each qualified patient was sequentially assigned a five-digit randomized patient number and a corresponding treatment package at each study site. The randomization schedule was computer generated by Sandoz Pharmaceuticals, Inc, the study sponsor. The unit of randomization was the individual patient. All patients received matching study drug in identical capsule form. Drug therapy was unblinded after all data had been entered, all queries resolved, and the database locked.

All patients were subsequently randomized in period 4 to five different therapeutic groups: placebo, low-dose isradipine, high-dose isradipine, low-dose enalapril, or high-dose enalapril. During period 4, patients remained on the high salt diet begun in period 3 for an additional 4-week period while receiving one of the five therapies. At the conclusion of period 4, all patients were switched to a low salt diet with placebo for a period of 3 weeks (period 5). In period 6, the patients continued a low salt diet and received one of the five therapies to which they had been previously randomized in period 4 for an additional 4 weeks.

Drug Treatment
All drug treatments were administered twice daily according to a forced titration schedule whereby initial doses were doubled after 1 week and treatment was continued for 3 more weeks. Low-dose isradipine began with 2.5 mg BID and increased to 5 mg BID, high-dose isradipine 5 mg BID to 10 mg BID, low-dose enalapril 2.5 mg BID to 5 mg BID, and high-dose enalapril began with 10 mg BID and increased to 20 mg BID.

Blood pressure was measured 12±1 hours after the last dose of study medication. Blood pressure measurements were made after the patients had been seated for 15 minutes by trained certified personnel. Two readings were made at 3-minute intervals and were averaged for analysis. Systolic blood pressure was recorded at Korotkoff phase I and diastolic blood pressure at Korotkoff phase V.

Study procedures included medical history, physical examination (beginning and end of the study), resting 12-lead ECG (beginning and end of the study), chest roentgenography (beginning of the study if not done in previous 12 months), clinical laboratory evaluation (beginning and end of the study), and blood pressure and weight measurements (weekly to biweekly). All patients were required to collect 24-hour urine specimens accurately as assessed by creatinine excretion and to demonstrate good compliance with prescribed drug regimens as verified by pill counts at each visit (within 20%). Patients were withdrawn from the study if diastolic blood pressure remained elevated (>115 mm Hg) or if, in the opinion of the physician investigator, it was in the patient's best interest to be discontinued from study therapy.

All blood pressure and urine data are reported for the last visit of each study period 2 through 6.

Statistical Analysis
Clinical trial data were recorded on case report forms and entered into a central database by the study monitor (ClinTrial Inc, Nashville, Tenn). Statistical analyses were performed by an independent entity (Medical Research Services, Highland Heights, Ky) using Statistical Analysis System (SAS) version 6.11. Distribution of factors such as gender, race, and body frame within treatment groups was compared by means of the Cochran-Mantel-Haenszel ² test with adjustment for center and age group. The primary efficacy variables in the study were trough sitting diastolic and systolic blood pressure in the completed patient population. The primary efficacy analysis involved comparison of the low salt and high salt treatment phases. Mean changes compared with zero for each treatment group were compared with the paired t test. Mean changes between treatment groups were compared by means of an ANOVA model with effects for treatment center and their interaction. Analogous analyses were performed for each race and dietary compliance. The secondary efficacy analyses assessed impact of pharmacotherapy versus placebo on either high salt or low salt diet. Mean changes were compared with zero for each treatment group with the paired t test. Dunnett's test was used to compare mean changes between each treatment group and the placebo group. Statistical comparisons for blood pressure changes were based on mean arterial pressure. Each test was two-tailed, and significance was accepted at the .05 level. All variables are expressed as mean±SD.

	Results

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Qualification Data
A total of 1916 patients were screened. After documentation of adequate compliance with low and high dietary salt intake and after blood pressure criteria for salt sensitivity were obtained, 464 were randomized to the double-blind drug treatment phase. A total of 397 patients completed the trial, of whom 232 were white, 96 black, and 63 Hispanic. The patients of six other races were not included in analysis. Fig 2 illustrates the outcome of all patients randomized into the clinical trial. Ad libitum, prequalification urinary sodium excretion averaged 166±75.2 mmol/d in all participants, with averages of 173.2±77.7 mmol/d in the white population, 156.9±64.4 mmol/d in the black population, and 156.5±81.2 mmol/d in the Hispanic population (P=.11 between the three races).

View larger version (37K): [in this window] [in a new window]   Figure 2. Profile of the randomized controlled trial showing progress through the various stages of the trial, including flow of participants, withdrawals, and timing of primary and secondary outcome measures.

Demographics
Table 1 illustrates the demographic characteristics of the various study groups for the patients ultimately completing the trial. During the qualification phase, there were no significant differences in age, duration of hypertension, height, weight, or body mass index. Black hypertensives had increases in blood pressure with increasing dietary salt (all data reported as systolic/diastolic [mean arterial pressure] mm Hg) (enalapril group, +11.6/8.4 [9.4] mm Hg; isradipine group, +12.4/7.8 [9.3] mm Hg) that were similar to those of the white hypertensives (enalapril group, +14.1/8.9 [10.6] mm Hg; isradipine group, +13.4/9.1 [10.5] mm Hg) and Hispanic hypertensives (enalapril group, 9.3/7.7 [8.2] mm Hg; isradipine group, 11.9/8.2 (9.4) mm Hg). Additionally, urinary sodium values on the low salt and high salt diets at qualification were not significantly different between any of the races (P>.77). There was a preponderance of women in the blacks randomized to receive isradipine, which reflected the only nearly significant gender difference of the study populations (P=.07).

View this table: [in this window] [in a new window]   Table 1. Demographic Characteristics of Patient Populations (n=391) Who Completed the Study

Dietary Salt and Antihypertensive Efficacy
Table 2 and Fig 3 outline the effect of dietary salt on the antihypertensive responses to the two drug therapies based on race. In general, with the exception of systolic blood pressure reduction with enalapril in Hispanics, both drugs (low and high dose combined) demonstrated greater reduction of systolic and diastolic blood pressure from baseline in all races while the patients were on the high salt diet compared with the low salt diet (blacks on high salt/enalapril, -10.3/-8.6 [-9.1] mm Hg versus low salt/enalapril, -7.7/-5.5 [-6.3] mm Hg; P=.11) (whites on high salt/enalapril, -15.0/-10.9 [-12.2] mm Hg versus low salt/enalapril, -12.7/-9.0 [-10.2] mm Hg; P=.11) (Hispanics on high salt/enalapril, -11.4/-9.6 [-10.5] mm Hg versus low salt/enalapril, -13.3/-7.5 [-9.4] mm Hg; P=.75) (blacks on high salt/isradipine, -15.9/-12.1 [-13.3] mm Hg versus low salt/isradipine, -7.1/-5.9 [-6.3] mm Hg; P<.0001) (whites on high salt/isradipine, -14.8/-9.4 [-11.2] mm Hg versus low salt/isradipine, -7.6/-4.2 [-5.4] mm Hg; P<.0001) (Hispanics on high salt/isradipine, -13.7/-8.9 [-10.5] mm Hg versus low salt/isradipine, -10.0/-6.0 [-7.3] mm Hg; P=.23.) This difference is due to the higher baseline blood pressure during the high salt diet (ie, salt sensitivity).

View this table: [in this window] [in a new window]   Table 2. Effect of Dietary Salt on Antihypertensive Responses to Enalapril and Isradipine in Salt-Sensitive Black, White, and Hispanic Hypertensives1

View larger version (36K): [in this window] [in a new window]   Figure 3. Blood pressure reductions (placebo in the first column, drug therapy in the second column, in millimeters of mercury) with enalapril and isradipine (low and high dose combined) in salt-sensitive black (), white (), and Hispanic () hypertensives on high salt and low salt diets. Raw data are in the text and in Table 2. Statistical significance and mean arterial pressures are in the text.

Race and Antihypertensive Efficacy
As shown in Table 2 and Fig 3, enalapril therapy resulted in somewhat greater blood pressure reduction in whites and Hispanics than in blacks, particularly during low salt consumption (enalapril/high salt, -15.0/-10.9 [-12.2] mm Hg in whites versus -10.3/-8.6 [-9.1] mm Hg in blacks; P=.05) (enalapril/high salt, -11.4/-9.6 [-10.2] mm Hg in Hispanics versus -10.3/-8.6 [-9.1] mm Hg in blacks; P=.61) (enalapril/low salt, -12.7/-9.0 [-10.2] mm Hg in whites versus -7.7/-5.5 [-6.3] mm Hg in blacks; P=.09) (enalapril/low salt, -13.3/-7.5 [-9.4] mm Hg in Hispanics versus -7.7/-5.5 [-6.3] mm Hg in blacks; P=.18). There were no significant differences between the whites and Hispanics for enalapril on either diet. On the other hand, isradipine therapy resulted in a similar level of blood pressure change in all racial groups irrespective of dietary salt consumption (isradipine/high salt, -14.8/-9.4 [-11.2] mm Hg in whites versus -15.9/-12.1 [-13.3] mm Hg in blacks; P=.16) (isradipine/high salt, -13.7/-8.9 [-10.5] mm Hg in Hispanics versus -15.9/-12.1 [-13.3] mm Hg in blacks; P=.19) (isradipine/low salt, -7.6/-4.2 [-5.4] mm Hg in whites versus -7.1/-5.9 [-6.3] mm Hg in blacks; P=.55) (isradipine/low salt, -10.0/-6.0 [-7.3] mm Hg in Hispanics versus -7.1/-5.9 [-6.3] mm Hg in blacks; P=.63).

Drug Therapy and Antihypertensive Efficacy
As shown in Table 2 and Fig 3, isradipine provided better blood pressure reduction in blacks (-15.9/-12.1 [-13.3] mm Hg) compared with enalapril (-10.3/-8.6 [-9.1] mm Hg) on the high salt diet (P=.01), although no significant differences in antihypertensive effect were evident between the two drugs on the low salt diet (isradipine, -7.1/-5.9 [-6.3] mm Hg versus enalapril, -7.7/-5.5 [-6.3] mm Hg; P=.99). Isradipine and enalapril therapy resulted in similar blood pressure reduction in whites on the high salt diet (isradipine, -14.8/-9.4 [-11.2] mm Hg versus enalapril, -15.0/-10.9 [-12.2] mm Hg; P=.38). However, on the low salt diet, enalapril was more effective (isradipine, -7.6/-4.2 [-5.4] mm Hg versus -12.7/-9.0 [-10.2] mm Hg; P=.0002). In Hispanics, isradipine and enalapril provided similar blood pressure reduction on high salt (enalapril, -11.4/-9.6 [-10.2] mm Hg versus isradipine, -13.7/-8.9 [-10.5] mm Hg; P=.92) and low salt (enalapril, -13.3/-7.5 [-9.4] mm Hg versus isradipine, -10.0/-6.0 [-7.3] mm Hg; P=.45) diets.

Dose of Drug Therapy and Antihypertensive Efficacy
As illustrated in Table 3, higher doses of enalapril resulted in improved blood pressure reduction in whites and blacks on both high and low salt diets. The following values were found in whites: (high salt, -16.8/-12.1 [-13.6, high dose] mm Hg versus -13.4/-9.8 [-11.0, low dose] mm Hg; P=.13) (low salt, -16.3/-10.9 [-12.7, high dose] mm Hg versus -9.5/-7.3 [-8.0, low dose] mm Hg; P=.009). The following values were found in blacks: (high salt, -12.3/-10.1 [-10.8, high dose] mm Hg versus -8.5/-7.3 [-7.7, low dose] mm Hg; P=.19) (low salt, -10.8/-6.2 [-7.7, high dose] mm Hg versus -5.0/-5.0 [-5.0, low dose] mm Hg; P=.35). On the other hand, higher doses of isradipine did not further reduce blood pressure in either blacks or whites on the high salt diet. The following values were found in blacks: (high salt, -16.2/-11.3 [-12.9, high dose] mm Hg versus -15.6/-13.1 [-13.9, low dose] mm Hg; P=.69) (low salt, -7.9/-6.6 [-7.0, high dose] mm Hg versus -6.1/-4.9 [-5.3, low dose] mm Hg; P=.56). The following values were found in whites: (high salt, -12.9/-9.2 [-10.4, high dose] mm Hg versus -16.8/-9.6 [-12.0, low dose] mm Hg; P=.36) (low salt, -8.9/-4.5 [-6.0, high dose] mm Hg versus -6.2/-4.0 [-4.7, low dose] mm Hg; P=.49). On the low salt diet, higher doses of isradipine had a small effect in further reducing both diastolic and systolic blood pressure (blacks, -7.9/-6.6 [-7.0, high dose] mm Hg versus -6.1/-4.9 [-5.3, low dose] mm Hg; P=.56) (whites, -8.9/-4.5 [-6.0, high dose] mm Hg versus -6.2/-4.0 [-4.7, low dose] mm Hg; P=.49). Data for Hispanics are not provided because of the small numbers of patients when subdivided into low (enalapril, n=18; isradipine, n=9) and high (enalapril, n=10; isradipine, n=13) doses of drug therapy.

View this table: [in this window] [in a new window]   Table 3. Effect of Dose of Enalapril and Isradipine With Changes in Dietary Salt in Black and White Hypertensives

Influence of Dietary Salt on Absolute Blood Pressure Change With Antihypertensive Therapy
Table 4 illustrates absolute blood pressure changes after 4 weeks of enalapril or isradipine therapy in conjunction with changes in dietary salt (a comparison of blood pressure changes after periods 4 and 6). A reduction in dietary salt clearly enhanced the antihypertensive activity of enalapril in blacks (-9.0/-5.3 [-6.6] mm Hg; P=.0004), whites (-11.8/-7.0 [-8.6] mm Hg; P=.0001), and Hispanics (-11.1/-5.6 [-7.4] mm Hg; P=.0002). However, there was less influence of dietary salt on the net antihypertensive response to isradipine in both blacks and whites compared with enalapril (blacks, -3.6/-1.6 [-2.3] mm Hg versus -9.0/-5.3 [-6.6] mm Hg; P=.05) (whites, -6.2/-3.9 [-4.7] mm Hg versus -11.8/-7.0 [-8.6] mm Hg; P=.003). Salt reduction resulted in similar absolute blood pressure changes in Hispanics regardless of therapy (enalapril, -11.1/-5.6 [-7.4] mm Hg versus isradipine, -8.1/-5.3 [-6.2] mm Hg; P=.64).

View this table: [in this window] [in a new window]   Table 4. Influence of Dietary Salt Reduction on Absolute Blood Pressure Change During Enalapril and Isradipine Therapy

	Discussion

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The purpose of this analysis was to characterize the antihypertensive efficacy of an angiotensin-converting enzyme (ACE) inhibitor and a calcium channel antagonist in salt-sensitive black, white, and Hispanic hypertensives with stage I to stage III hypertension during high and low dietary salt intakes. Our results indicate that dietary salt reduction facilitates blood pressure reduction with both enalapril and isradipine therapy in all three races. Moreover, our data indicate that there are few race-related differences in antihypertensive activity in salt-sensitive patients.

The frequency, severity, and mortality from hypertensive vascular disease are greater in blacks.¹ Furthermore, when compared with whites and other ethnic groups, blacks respond with less blood pressure reduction to ß-blockers and ACE inhibitors, although clinically significant blood pressure reductions with these agents may occur.^{1 2 3 4 5 6 7} While Hispanics do not appear to have an increased prevalence of hypertension, there are similarities in the association between socioeconomic factors and mortality for both blacks and Hispanics. Although there are limited published data concerning the efficacy of antihypertensive drugs in Hispanics, the clinical perception is that compared with whites, there are no overall differences in response to most commonly used drugs. Hypertensive disease in blacks is characterized by hemodynamic and biochemical factors that are somewhat different than those seen in whites.^{11 12} Hypertensives of black descent more frequently exhibit salt sensitivity, a variable tendency toward expanded plasma volume, lower plasma renin levels, and increased renal vascular resistance.^{8 9 10 16 17 18 19 20 21 22 23 24} Some of the biochemical differences that have been described between blacks and whites such as reduced natriuretic and vasodilatory substances (eg, dopamine, prostaglandins, and kinins), different sodium-potassium and sodium-lithium countertransport in red blood cells, and diminished sympathetic nervous system function may explain in part their tendency toward renal salt and water retention and expanded plasma volume.^{17 18 19 20 21 22 23 24 25 26} The pathophysiological factors that characterize hypertensive disease in blacks have led to the assumption that dietary salt restriction and pharmacological therapy that enhances salt and water excretion will likely be more effective in facilitating blood pressure reduction as opposed to therapies that would target an activated renin angiotensin system. However, a contrary view may be that the excessive intrarenal vasoconstriction seen in black hypertensives may in part be related to overactivity of the intrarenal renin angiotensin system. Consequently, reversing angiotensin II–mediated intrarenal vasoconstriction may facilitate blood pressure reduction by enhancing natriuresis.

Previous clinical studies have suggested that blacks do not respond as well to ß-blockers or ACE inhibitors as nonblack hypertensive patients, perhaps because of their lower plasma renin levels and greater salt sensitivity.^{1 2 3 4 5 6 7} On the other hand, these clinical studies have not explored full dose titration of these drugs, nor have studies been conducted to test the influence of these drugs specifically on sodium handling by the kidney.

The perception in clinical practice is that diuretics and calcium channel antagonists are as effective in treating blacks as in treating whites. This observation could be related to the natriuretic properties of these drugs.²⁷ Only small clinical studies have been performed to assess the antihypertensive activity of ACE inhibitors or calcium channel antagonists in patients on low and high salt diets who have previously been categorized as salt sensitive.¹⁴

The results of our clinical trial demonstrate that a reduction in dietary salt facilitates blood pressure reduction in combination with either an ACE inhibitor or a calcium channel antagonist in salt-sensitive black, Hispanic, and white hypertensives. The absolute blood pressure achieved in all races is consistently lower on the low salt diet irrespective of the antihypertensive agent used. However, there are differences between the two drug therapies. Blood pressure was less affected by dietary salt restriction in isradipine-treated patients than in those treated with enalapril, except in Hispanics. This observation may be related to the lower salt diet creating a more angiotensin II–dependent form of hypertension, which could be more susceptible to the effects of an ACE inhibitor compared with a calcium channel antagonist.

Reduced dietary salt consumption in blacks, Hispanics, and whites resulted in similar absolute blood pressure levels with enalapril and isradipine treatment; however, during the high salt diet blacks had lower systolic and diastolic pressures with isradipine (139.3/90.4 mm Hg) than enalapril-treated (146.2/96.8 mm Hg) patients. On the other hand, there were no significant differences in absolute systolic or diastolic blood pressure levels reached during the high salt diet between blacks, Hispanics (data not shown), and whites when enalapril was titrated to a higher dose. This observation may be related to either the ability of higher doses of the ACE inhibitor to suppress serum aldosterone²⁸ or to antagonize intrarenal vasoconstriction and facilitate salt and water excre-tion.^{29 30} Other clinical studies have demonstrated that higher doses of ACE inhibitors eliminate some of the racial differences in response to these medications.³¹

The results of our study cannot be extrapolated to non–salt-sensitive hypertensives. However, in clinical practice, with increasing age and greater obesity, particularly in black hypertensives, there is a greater propensity for salt sensitivity, which was the main focus of our clinical trial. Since all of the patients that we studied—black, Hispanic, and white—were salt sensitive, one cannot assume that salt sensitivity status explains some of the racial differences in response to the antihypertensive therapies used in our clinical trial.

In summary, our results demonstrate that dietary salt reduction can enhance blood pressure reduction with both calcium channel antagonists and ACE inhibitors in salt-sensitive black, Hispanic, and white hypertensives. The calcium channel antagonist therapy appears more resistant to the effects of dietary salt compared with the ACE inhibitor enalapril. The reason for this difference is unknown. Both drugs possess intrinsic natriuretic properties.¹⁶ Perhaps the biology of the vasodilatory properties of the two drugs are sufficiently different to explain these observations. Also interesting, but not explainable, is the ability of the higher doses of enalapril to overcome the effects of greater dietary salt in facilitating blood pressure reduction. The basic point regarding whether the results of prior studies showing racial differences in response to antihypertensive medication are due to different prevalences of salt sensitivity or other unknown factors can now be answered. We controlled for salt sensitivity and showed lesser differences in drug responsiveness between races.

	Acknowledgments

 
This study was supported by a research grant from Sandoz Pharmaceuticals, Inc, East Hanover, NJ. We wish to acknowledge the dedicated and expert secretarial assistance of Valerie Heisler and Shirley Townsend. The Participating Investigators included the following: Maria Canossa-Terris, MD, Miami, Fla; A. Carr, MD, Augusta, Ga; R. Centor, MD, Birmingham, Ala; Steven G. Chrysant, MD, Oklahoma City, Okla; R. Coalson, MD, Dayton, Ohio; Jerome D. Cohen, MD, St Louis, Mo; G. Eisner, MD, Washington, DC; R. Graham, MD, Altamonte Springs, Fla; J. Gray, MD, Golden Valley, Minn; Clarence Grun, MD, and Keith Norris, MD, Los Angeles, Calif; Bruce P. Hamilton, MD, and J. Hamilton, MD, Baltimore, Md; L. Hebert, MD, and W. Bay, MD, Columbus, Ohio; J. Holtzman, MD, Minneapolis, Minn; Lance W. Kirkegaard, MD, Tacoma, Wash; N. Lasser, MD, Newark, NJ; Andrew J. Lewin, MD, Los Angeles, Calif; T. Littlejohn, MD, Winston Salem, NC; A. Mangione, MD, PharmD, Jenkintown, Pa; David A. McCarron, MD, Portland, Ore; D. Nash, MD, Syracuse, NY; J. Ondrejicka, MD, Jacksonville Beach, Fla; S. Oparil, MD, Birmingham, Ala; L. Resnick, MD, Detroit, Mich; S. Rosenblatt, MD, Irvine, Calif; D. Ruff, MD, San Antonio, Tex; A. Salel, MD, Encinitas, Calif; D. Schumacher, MD, Columbus, Ohio; H. Serfer, DO, Hollywood, Fla; J. Sullivan, MD, Memphis, Tenn; A. Taylor, MD, PhD, Houston, Tex; R. Townsend, MD, Philadelphia, Pa; Alan B. Weder, MD, Ann Arbor, Mich; Myron H. Weinberger, MD, Indianapolis, Ind; Matthew R. Weir, MD, Baltimore, Md.

	Footnotes

 
Reprint requests to Matthew R. Weir, MD, Nephrology Division, University of Maryland Hospital, 22 S Greene St, Baltimore, MD 21201.

Received July 24, 1997; first decision August 14, 1997; accepted December 22, 1997.

	References

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