Diet rich in fruits, vegetables, and dairy products, known as the Dietary Approaches to Stop Hypertension (DASH) diet, is known to reduce blood pressure (BP) in hypertensive patients. More recently, the DASH diet was shown to reduce oxidative stress in hypertensive and nonhypertensive humans. However, the main nutritional components responsible for these beneficial effects of the DASH diet remain unknown. Because the DASH diet is rich in potassium (K), magnesium (Mg), and alkali, we performed a randomized, double-blinded, placebo-controlled study to compare effects of potassium magnesium citrate (KMgCit), potassium chloride (KCl), and potassium citrate (KCit) to allow dissociation of the three components of K, Mg, and citrate on 24-hour ambulatory BP and urinary 8-isoprostane in hypertensive and prehypertensive subjects, using a randomized crossover design. We found that KCl supplementation for 4 weeks induced a significant reduction in nighttime SBP compared with placebo (116 ± 12 vs 121 ± 15 mm Hg, respectively, p <0.01 vs placebo), whereas KMgCit and KCit had no significant effect in the same subjects (118 ± 11 and 119 ± 13 mm Hg, respectively, p >0.1 vs placebo). In contrast, urinary 8-isoprostane was significantly reduced with KMgCit powder compared with placebo (13.5 ± 5.7 vs 21.1 ± 10.5 ng/mgCr, respectively, p <0.001), whereas KCl and KCit had no effect (21.4 ± 9.1 and 18.3 ± 8.4, respectively, p >0.1 vs placebo). In conclusion, our study demonstrated differential effects of KCl and KMgCit supplementation on BP and the oxidative stress marker in prehypertensive and hypertensive subjects. Clinical significance of the antioxidative effect of KMgCit remains to be determined in future studies.
We performed a randomized, double-blinded, placebo-controlled crossover study to compare effects of potassium magnesium citrate (KMgCit), potassium chloride (KCl), and potassium citrate (KCit) on 24-hour ambulatory blood pressure (BP) in hypertensive and prehypertensive subjects. To avoid the confounding influence of K or Mg depletion, which may further contribute to BP elevation, we excluded patients treated with diuretics. Because recent studies have demonstrated benefit of the Dietary Approaches to Stop Hypertension (DASH) diet in reducing oxidative stress in patients with heart failure with preserved ejection fraction, gestational diabetes, and polycystic ovarian disease, we also compare effects of KMgCit, KCl, and KCit versus placebo on a urinary marker of oxidative stress.
Methods
Thirty subjects with prehypertension (n = 6) or stage I hypertension (n = 24) participated in the study after providing written informed consent. The study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center. All subjects had systolic blood pressure between 120 and 159 mm Hg and diastolic between 80 and 99 mm Hg on 3 determinations by oscillometric technique in the seated position. The subjects had no history of diabetes mellitus, renal impairment (serum creatinine > 1.4 mg/dl), active cardiac or liver disease, esophageal-gastric ulcer, gastroesophageal reflux disease, chronic diarrhea, chronic nonsteroidal anti-inflammatory drug use, treatment with diuretics, renal tubular acidosis, hypercalcemia, or hypocalcemia. Each subject underwent a 4-phase study, using a randomized crossover design. During each phase, subjects received one of the study drugs each for 4 weeks: (1) placebo phase (microcrystalline cellulose diluted in water twice daily), (2) KCl phase (40 meq KCl powder/day), (3) KCit phase (40 meq K 3 Cit powder/day diluted in water), and KMg citrate phase (KMgCit, 40 meq K, 20 meq Mg, and 74 meq citrate powder/day, IND 116,208). Subjects were instructed to take study drugs in 2 divided doses twice daily after dissolution in 250 ml of water. Each phase was followed by at least 1 week of washout. All study drugs were prepared in a similar powder sachets form to ensure double blinding. All subjects were maintained on their customary diet throughout the study. During the study, participants were seen every 2 weeks in the research clinic. During each clinic visit, BP was measured by nursing staff, using the same validated oscillometric device (Vital Signs; Welch Allyn, Skaneateles Falls, NY), after the patient had been in rest quietly for 5 minutes as recommended by the guidelines. BP measurement during a single visit was repeated 3 times separated by 1 minute, and these BP values were averaged.
Twenty-four–hour ambulatory BP monitoring was performed at baseline and after 4 weeks of each study drug, using a SpaceLabs model 90,207 (SpaceLabs Inc., Issaquah, Washington) as previously described. Measurement of arterial stiffness was performed during the fourth week of treatment in each phase after an overnight fast, using arterial tonometry technique. Arterial tonometry and simultaneous electrocardiogram were obtained from the brachial, radial, femoral, and carotid arteries using a pulse transducer device (Cardiovascular Engineering, Inc. Waltham, Massachusettes) as previously described ; 24-hour urine sample were collected during the last week of treatment for K, pH, citrate, Mg, sodium (Na), calcium (Ca), phosphorus (Pi), sulfate (S), creatinine (Cr), and total volume. Similarly, blood samples were collected after 4 weeks of treatment after an overnight fast for K, Na, Cl, carbon dioxide (CO 2 ), Mg, Cr, Ca, Pi, parathyroid, and 1,25-dihydroxyvitamin D (1,25-(OH) 2 D).
Urinary 8-isoprostane (8-isoP) was measured using an enzyme immunoassay kit (Cayman Chemical, Ann Arbor, Michigan) based on competitive binding between 8-isoP and 8-isoprostane-acetylcholinesterase (AChE) conjugate (8-isoprostane tracer) for limited specific binding sites compared against a standard curve at 412 nm as previously described.
Plasma and urinary electrolytes including Pi, Ca, Mg, and Na were determined with methods presented as previously described.
Mixed-effects linear models were used to conduct the repeated-measures analysis to assess differences between KCl, KCit, KMgCit, and placebo phases. Contrasts from these models were used for pairwise comparisons. Treatment order was also assessed in our mixed-effects models and was included as a fixed effect to test for interactions between study drug and treatment order; no effect of treatment order on any outcome variables was found. The 0.05 level of significance was used for model main effects and the 0.01 level of significance was used for pairwise tests to adjust for multiple testing. Statistical analyses were conducted using SAS, version 9.4 (SAS Institute, Cary, North Carolina). All tests were 2 sided, and a p value <0.05 was considered statistically significant. Augmented pressure was presented as median and interquartile range. Other variables are presented as means ± SD.
Results
Baseline characteristics of all subjects are listed in Table 1 . There were 6 prehypertensive subjects and 24 subjects with stage I hypertension. Among hypertensive subjects, 17 of 24 received antihypertensive treatment before study participation. All treated subjects received single-drug regimen before participation in the study (6 were on β blockers, 11 on angiotensin receptor blockers, or angiotensin-converting enzyme inhibitors, or calcium channel blockers), which was continued at the same dose throughout the study. Serum electrolytes at baseline and at 4 weeks during each treatment phase are presented in Supplemental Table 1 .
| Variables | |
|---|---|
| Age (years) | 54±12 |
| Black | 12 (40%) |
| Female | 16 (53%) |
| Weight (kg) | 90±18 |
| Body Mass Index (kg/m 2 ) | 31± 5 |
| Office Systolic Blood Pressure (mmHg) | 125±11 |
| Office Diastolic Blood Pressure (mmHg) | 81±8 |
| Office Heart Rate (bpm) | 72±11 |
| 24-hr Systolic Blood Pressure Average (mmHg) | 126±10 |
| 24-hr Diastolic Blood Pressure Average (mmHg)) | 79±10 |
| 24-hr Heart Rate Average (bpm) | 76±11 |
| 24-hr Daytime Systolic blood pressure (mmHg) | 129±10 |
| 24-hr Daytime diastolic blood pressure (mmHg) | 81±11 |
| 24-hr Daytime Heart Rate (bpm) | 77±11 |
| 24-hr Nighttime Systolic Blood Pressure (mmHg) | 117±12 |
| 24-hr Nighttime Diastolic Blood Pressure (mmHg) | 71±10 |
| 24-hr Nighttime Heart Rate (bpm) | 70±11 |
| Calcium (mg/dl) | 9.5±-0.5 |
| Phosphorus (mg/dl) | 3.6±0.1 |
| Magnesium (mg/dl) | 2.2±0.3 |
| Sodium (meq/L) | 139±2 |
| Potassium (meq/L) | 4.2±0.3 |
| Chloride (meq/L) | 105±2 |
| Bicarbonate (meq/L) | 23±2 |
| Urea nitrogen (mg/dl) | 13.7±3.5 |
| Creatinine (mg/dl) | 0.9±0.2 |
| Albumin (g/dl) | 4.2±0.6 |
| Parathyroid hormone (g/ml) | 59±31 |
| 1,25-dihydroxyvitamin D (pg/ml) | 73±34 |
Serum K and 24-hour urinary K excretion were increased during KCl, KCit, and KMgCit phases compared with placebo phase (p <0.01 vs placebo, Table 2 ). Serum Mg was increased during KMgCit phase compared with placebo and KCl phases (both p <0.01); 24-hour urinary Mg excretion was increased during KMgCit phase compared with placebo and KCit (both p <0.01). There was a tendency for 24-hour urinary Mg excretion to be higher during KMgCit compared with KCl, but the difference did not reach statistical significance (p = 0.017).
| Variable | Placebo | Potassium Chloride | Potassium Citrate | Potassium Magnesium Citrate | Mixed Model |
|---|---|---|---|---|---|
| n = 30 | n = 30 | n = 30 | n = 30 | p value | |
| Weight (kg) | 89±18 | 89±18 | 90±18 | 89±17 | 0.40 |
| Body Mass Index (kg/m 2 ) | 30±12 | 31±5 | 31±5 | 31±5 | 0.37 |
| Office Systolic Blood Pressure (mmHg) | 129±12 | 127±11 | 125±13 | 124±11 | 0.16 |
| Office Diastolic Blood Pressure (mmHg) | 81±9 | 80±9 | 81±8 | 81±9 | 0.70 |
| Office Heart Rate (bpm) | 70±12 | 68±9 | 70±10 | 70±11 | 0.17 |
| 24-hr Average Systolic Blood Pressure (mmHg) | 129±13 | 126±9 ∗ | 127±10 | 127±11 | 0.07 |
| 24-hr Average Diastolic Blood Pressure (mmHg) | 80±11 | 78±9 | 78±9 | 79±10 | 0.20 |
| 24-hr Average Heart Rate (bpm) | 76±15 | 74±10 | 76±11 | 75±10 | 0.43 |
| 24-hr Daytime Systolic Blood Pressure (mmHg) | 132±13 | 129±10 | 130±12 | 130±12 | 0.21 |
| 24-hr Daytime Diastolic Blood Pressure (mmHg) | 82±12 | 81±10 | 81±10 | 81±11 | 0.37 |
| 24-hr Daytime Heart rate (bpm) | 76±11 | 76±10 | 78±11 | 76±10 | 0.48 |
| 24-hr Nighttime Systolic Blood Pressure (mmHg) | 121±15 | 116±12 ∗ | 118±11 | 119±13 | 0.03 |
| 24-hr Nighttime Diastolic Blood Pressure (mmHg) | 73±10 | 70±9 | 71±9 | 73±10 | 0.05 |
| 24-hr Nighttime Heart Rate (bpm) | 70±11 | 68±10 | 71±10 | 71±10 † | 0.04 |
| Calcium (mg/dl) | 9.5±0.4 | 9.5±0.4 | 9.4±0.7 | 9.6±0.4 | 0.23 |
| Phosphorus (mg/dl) | 3.5±0.6 | 3.5±0.5 | 3.6±0.5 | 3.4±0.5 | 0.30 |
| Magnesium (mg/dl) | 2.1±0.2 | 2.1±0.2 | 2.2±0.2 | 2.3±0.3 ∗ † | 0.001 |
| Sodium (meq/L) | 138±1 | 138±2 | 137±2 | 138±2 | 0.22 |
| Potassium (meq/L) | 4.2±0.3 | 4.4±0.3 ∗ | 4.3±0.3 ∗ | 4.4±0.3 ∗ | 0.0001 |
| Chloride (meq/L) | 105±2 | 105±2 | 104±2 † | 104±2 † | 0.01 |
| Bicarbonate (meq/L) | 23±2 | 22±2 | 23±2 | 23±2 | 0.55 |
| Urea nitrogen (mg/dl) | 12.9±3.4 | 13.6±3.4 | 13.9±3.5 | 14.1±3.5 | 0.13 |
| Creatinine (mg/dl) | 0.9±1.1 | 0.9±0.2 | 0.9±0.2 | 0.9±0.2 | 0.96 |
| Albumin (g/dl) | 4.4±0.3 | 4.3±0.6 | 4.4±0.2 | 4.4±0.2 | 0.31 |
| Parathyroid hormone (g/ml) | 58±30 | 65±43 | 66±37 | 61±28 | 0.46 |
| 1,25- dihydroxyvitamin D (pg/ml) | 71±29 | 76±31 | 82±37 ∗ | 77±32 | 0.09 |
| Klotho (%) | 19±9 | 19±11 | 19 ±12 | 21±12 | 0.71 |
| 24 hour Urine Data | |||||
| Total Volume (L/day) | 2.0±0.6 | 1.9±0.7 | 2.0±0.5 | 2.0±0.7 | 0.95 |
| pH | 6.0±0.4 | 6.0±0.6 | 6.4±0.6 ∗ † | 6.7±0.4 ∗ † ‡ | <0.0001 |
| Calcium (mg/day) | 181±101 | 160±92 | 148±78 | 158±94 | 0.10 |
| Magnesium (mg/day) | 97±40 | 104±52 | 100±43 | 121±44 ∗ ‡ | 0.01 |
| Phosphorus (mg/day) | 842±301 | 868±364 | 858±306 | 764±278 | 0.32 |
| Creatinine (mg/day) | 1451±389 | 1477±492 | 1501±474 | 1393±436 | 0.59 |
| Sodium (meq/day) | 173±61 | 184±65 | 190±100 | 187±78 | 0.64 |
| Potassium (meq/day) | 58±30 | 95±34 ∗ | 84±31 ∗ | 91±37 ∗ | <0.0001 |
| Citrate (mg/day) | 668±262 | 753±308 | 908±385 ∗ † | 995±407 ∗ † | <0.0001 |
| Sulphate (mmol/day) | 16.8 ±5.6 | 17.6±7.6 | 17.4±5.0 | 16.5±5.1 | 0.77 |
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