Effect of hypotensive therapy combined with modified diet or zinc supplementation on biochemical parameters and mineral status in hypertensive patients

Journal of Trace Elements in Medicine and Biology 47 (2018) 140–148

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Clinical studies

Effect of hypotensive therapy combined with modified diet or zinc supplementation on biochemical parameters and mineral status in hypertensive patients☆

T

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Joanna Suliburskaa, , Katarzyna Skrypnika, Monika Szulińskab, Justyna Kupszc, Paweł Bogdańskib Instytut Żywienia Człowieka i Dietetyki, Uniwersytet Przyrodniczy w Poznaniu (Institute of Human Nutrition and Dietetics, Poznan University of Life Sciences), ul. Wojska Polskiego 31, 60-624 Poznań, Poland b Zakład Edukacji i Leczenia Otyłości oraz Zaburzeń Metabolicznych, Uniwersytet Medyczny w Poznaniu (Department of Education and Obesity Treatment and Metabolic Disorders, University of Medical Sciences, Poznan, Poland), ul. Szamarzewskiego 82/84, 60-569 Poznan, Poland c Katedra i Zakład Fizjologii, Uniwersytet Medyczny w Poznaniu (Department of Physiology, University of Medical Sciences, Poznan, Poland), ul. Święcickiego 6, 61-781 Poznan, Poland a

A R T I C L E I N F O

A B S T R A C T

Keywords: Hypertension Antihypertensive monotherapy Mineral status Zinc Zinc supplementation

Background: Hypotensive therapy leads to a number of trace elements metabolism disturbances. Zinc balance is frequently affected by antihypertensive treatment. Aim: To evaluate the effect of a hypotensive treatment, modified diet and zinc supplementation on mineral status and selected biochemical parameters in newly diagnosed hypertensive patients on monotherapy. Methods: In the first stage, arterial hypertension in ninety-eight human subjects was diagnosed. In the second stage, antihypertensive monopharmacotherapy was implemented. In the third stage, patients were randomized into three groups and continued antihypertensive monotherapy: group D received an optimal-mineral-content diet, group S received zinc supplementation, and group C had no changes in diet or zinc supplementation. Iron, zinc, and copper concentrations in serum, erythrocytes, urine, and hair were determined. Lipids, glucose, ceruloplasmin, ferritin, albumin, C-reactive protein (CRP), tumor necrosis factor α (TNF-α), nitric oxide (NO), superoxide dismutase (SOD) and catalase (CAT) were assayed in serum. Results: Antihypertensive monotherapy decreased zinc concentration in serum and erythrocytes and increased the level of zinc in urine, decreased CAT and SOD activity, TNF-α concentration in serum, and increased the level of NO in the serum. Zinc supply led to an increase in zinc concentration in serum, erythrocytes, and hair (in group S only). In the groups with higher zinc intake, decreased glucose concentration in the serum was observed. Significant correlation was seen between the zinc and glucose serum concentrations. Conclusion: Hypotensive drugs disturb zinc status in newly diagnosed hypertensive patients. Antihypertensive monotherapy combined with increased zinc supply in the diet or supplementation favorably modify zinc homeostasis and regulate glucose status without blood pressure affecting in patients with hypertension.

1. Introduction A high number of trials have provided data on the disorders of trace elements metabolism resulting from hypotensive therapy [1–4]. Treatment with angiotensin-converting enzyme inhibitors (ACE-Is) and

some diuretics leads to deficits of zinc, magnesium, and potassium [5]. Disturbances in macroelement and microelement status can additionally be a reason for unfavorable changes in the metabolism of carbohydrates and lipids, and may affect enzyme activity of enzymes such as superoxide dismutase (SOD), catalase (CAT), and carbonic

Abbreviations: ACE-Is, angiotensin-converting enzyme inhibitors; AH, arterial hypertension; ARBs, angiotensin II receptor antagonists; BMI, body mass index; BP, blood pressure; CA, carbonic anhydrase; cAMP, cyclic adenosine monophosphate; CAT, catalase; CRP, C-reactive protein; ELISA, enzyme-linked immunosorbent assay; ESR, erythrocyte sedimentation rate; GLU, glucose; HDL, high-density lipoprotein; IL-6, interleukin 6; iNOS, inducible nitric oxide synthase; LDL, low-density lipoprotein; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide; SDs, standard deviations; SHR, spontaneously hypertensive rats; SOD, superoxide dismutase; TCH, total cholesterol; TG, triglycerides; TIBC, total iron binding capacity; TNF-α, tumor necrosis factor α; ZnT8, zinc efflux transporter 8 ☆ Laboratory of Institute of Human Nutrition and Dietetics, Poznan University of Life Sciences, ul. Wojska Polskiego 31, 60–624 Poznań, Poland. ⁎ Corresponding author at: Institute of Human Nutrition and Dietetics, Poznan University of Life Sciences, ul. Wojska Polskiego 31, 60–624, Poznań, Poland. E-mail addresses: [email protected] (J. Suliburska), [email protected] (K. Skrypnik), [email protected] (M. Szulińska), [email protected] (J. Kupsz), [email protected] (P. Bogdański). https://doi.org/10.1016/j.jtemb.2018.02.016 Received 16 November 2017; Received in revised form 13 February 2018; Accepted 14 February 2018 0946-672X/ © 2018 Elsevier GmbH. All rights reserved.

Journal of Trace Elements in Medicine and Biology 47 (2018) 140–148

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anhydrase (CA) [6]. Beneficial effects of a diet enriched in minerals on the homeostasis of macroelement and microelement, along with hypotensive monotherapy, have been reported in some studies [1,7,8]. However, there are still only a limited number of studies that provide data on the effect of antihypertensive monotherapy on mineral status, and also on the effects of combining mineral supplementation with pharmacotherapy on biochemical parameters in patients with arterial hypertension (AH). A combination of antihypertensive pharmacotherapy with mineral supplementation or dietary intervention seems to be more effective and beneficial to the health of patients. Zinc is a microelement frequently affected by commonly recommended antihypertensive drugs [9]. Studies on antihypertensive treatment and zinc metabolism have presented inconsistent results on correlation between serum zinc concentration and blood pressure (BP) [7,8,10–14]. Some studies have shown that high serum zinc concentration is associated with incident hypertension, however with no association between zinc intake in diet and risk of hypertension [11]. Contrary, other studies registered inverse correlation between serum Zn and blood pressure [8]. Moreover, it has been documented that zinc deficiency is the risk factor of elevated blood pressure and dietary zinc intake is inversely correlated with systolic blood pressure independently from body mass, energy intake and sodium intake [14]. Zinc regulates blood pressure and takes part in vascular tone modulation by inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transactivation activity. Thus, Zn controls inducible nitric oxide synthase (iNOS) endothelial expression and activity [15]. The aim of our study was to evaluate the effects of hypotensive treatment combined with a higher zinc supply in the diet and supplements on the mineral status and selected biochemical parameters of newly diagnosed hypertensive patients on monotherapy. To the best of our knowledge, our study is the first human study to compare these two models of zinc supply in such a homogenous group of patients. So far, there has been an evident lack of convincing scientific evidence, which might serve as a basis for revising the recommendations regarding mineral supplementation during hypotensive pharmacotherapy.

month prior to enrollment, having an pacemaker implanted; alcohol, nicotine or drug abuse; mental disorders; pregnancy, childbirth or lactation at enrollment or in the three months prior to enrollment; or any other condition that, in the opinion of investigators, would make participation in the study not in the best interest of the subject, or could prevent, limit, or confound the efficacy of the study. The occurrence of any of the exclusion criteria during the study resulted in withdrawal of the subject from the trial. Of 425 patients examined at the outpatient clinic of the Department of Internal Medicine, Metabolic Disorders and Hypertension, Poznań University of Medical Sciences, 320 individuals were excluded from the trial due to secondary forms of hypertension (5); the use of mineral supplements within the three months prior to enrollment (22); lipid disorders requiring treatment in the three month prior to the trial (15); history of ischemic heart disease (55), stroke (18), congestive heart failure (21), clinically significant arrhythmia or conduction disorders (19), peripheral artery or vein disease (9), diabetes mellitus (44), abnormal renal (8), liver (7) or thyroid gland (11) function, clinically significant chronic or acute inflammatory process within the respiratory (2), genitourinary (3), or digestive tract (3), or in the oral cavity, larynx, pharynx, or paranasal sinuses (9), connective tissue diseases (3), arthritis (2), or malignancy (1); infection in the month prior to enrollment (26), having a pacemaker implanted (14); alcohol, nicotine or drug abuse (19); mental disorders (2); pregnancy, childbirth or lactation at enrollment or in the three months prior to enrollment (2). The 105 subjects who fulfilled all inclusion criteria and had no exclusion criteria were randomized into three groups C, D, and S of 35 subjects each. Seven subjects (5 from group C and 2 from group D) were excluded from the trial due to acute inflammatory processes within the genitourinary (2) or digestive (3) tract, and infection (2). A total of 98 subjects (61 women and 37 men) completed all three stages of the trial and were included in the statistical analysis: 30 from group C (19 women and 11 men), 33 from group D (20 women and 13 men), and 35 from group S (22 women and 13 men).

2. Material and methods

The study was designed as a prospective randomized trial and was performed in three stages. In the first stage, primary hypertension was diagnosed and antihypertensive monotherapy was begun. In the second stage, patients underwent antihypertensive monotherapy lasting three months. The subjects received diuretics; calcium antagonists (Ca-antagonists); ACE-Is; angiotensin II receptor antagonists (ARBs); or βblockers. After three months of monotherapy, patients were divided using a randomization list into three equinumerous groups: C (control group), D (diet group) and S (supplementation group). In the third stage, which lasted 30 days, subjects from all groups received the same antihypertensive drug as in the second stage and either an optimalmineral-content diet (group D), zinc supplementation (group S), or continued drug use with no change in diet and no mineral supplementation (group C). Patients from group D received an optimal-mineral-content properly balanced diet enriched in food with high zinc content prepared individually for each patient by a qualified dietician. Patients from group S received zinc supplementation as one capsule containing 15 mg of Zn taken orally once a day in the morning, two hours after antihypertensive drug administration with no change in diet, through all 30 days of the third stage of the trial. Zinc supplementation was chosen in group S due to significantly lower serum, erythrocyte, and urine zinc concentration in stage II of the study, and in account of the results of our previous study, [17] which showed disturbed zinc homeostasis after antihypertensive monotherapy. Antihypertensive drug administration was comparable between groups and between stages II and III. The number of patients receiving particular antihypertensive monotherapy is shown in Table 1. During the study, patients were asked to not use dietary supplements and not to change their lifestyle or level of physical activity. All patients consulted

2.2. Study design

2.1. Study patients The study protocol was approved by the Ethics Committee at Poznań University of Medical Sciences, approval no. 86/09. The study complies with the ethical standards of the Declaration of Helsinki and its amendments. All subjects gave their written informed consent prior to their inclusion in the study. Four hundred and twenty-five patients with no antihypertensive therapy were screened at the outpatient clinic of the Department of Internal Medicine, Metabolic Disorders and Hypertension, Poznań University of Medical Sciences, and 105 were enrolled in the study. The inclusion criteria were informed written consent; age 18–65 years; primary arterial hypertension diagnosed in accordance with the guidelines of the European Society of Hypertension 2013 and the European Society of Cardiology 2013; [16] beginning monotherapy with an antihypertensive drug; stable body weight (less than 3 kg selfreported change during the three months prior to enrollment). The exclusion criteria were any secondary form of hypertension; the use of mineral supplements within the three months prior to enrollment; lipid disorders requiring treatment in the three months prior to the trial; a history of ischemic heart disease, stroke, congestive heart failure, clinically significant arrhythmia or conduction disorders, peripheral artery or vein disease, diabetes mellitus, abnormal renal, liver or thyroid gland function, clinically significant chronic or acute inflammatory process within the respiratory, genitourinary, or digestive tract, or in the oral cavity, larynx, pharynx, or in the paranasal sinuses, or connective tissue diseases, arthritis, or malignancy; infection in the 141

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Table 1 The characteristic of patients. Parameter

I stage

II stage

III stage Control

Diet

Supplement

n Gender (F/M) Age (year) mean ± SD BMI (kg/m2) mean ± SD WHR mean ± SD

98 61/37 53.6 ± 13.7 33.3 ± 8.7 0.9 ± 0.1

98 61/37 – 33.2 ± 8.3 0.9 ± 0.1

30 19/11 – 33.4 ± 7.3 0.9 ± 0.1

33 20/13 – 32.8 ± 7.9 0.9 ± 0.1

35 22/13 – 33.6 ± 8.8 0.9 ± 0.1

Monotherapy (n) Diuretic Calcium antagonist β-blocker Angiotensin-converting enzyme inhibitor Angiotensin II receptor antagonist

– – – – –

36 18 18 14 12

11 6 7 6 4

13 6 5 4 4

12 6 6 4 4

n-number of subjects; F- female; M- male; BMI-body mass index; SD-standard deviation; WHR-waist-hip-ratio. Table 2 The daily energy and nutrients intake in the diet. Parameter

n Gender (F/M) Energy (kcal) Fat (% energy) Protein (% energy) Carbohydrate (% energy) Fe (mg) Zn (mg) Cu (mg)

I stage

98 61/37 2006.7 ± 750.6 37.2 ± 9.2 14.0 ± 5.5 48.8 ± 13.4 9.8 ± 3.0 9.5 ± 2.5 1.1 ± 0.4

II stage

98 61/37 1988.6 ± 761.9 36.5 ± 10.2 13.9 ± 5.1 49.6 ± 12.5 9.7 ± 2.9 9.3 ± 2.5 1.0 ± 0.4

III stage

98 61/37 2016.3 ± 741.9 35.5 ± 9.9 14.1 ± 4.8 50.7 ± 13.6 10.2 ± 2.4 10.3 ± 2.4 1.1 ± 0.4

III stage Control

Diet

Supplement

30 19/11 1978.5 ± 935.5 36.1 ± 10.0 14.2 ± 5.7 49.7 ± 12.8 9.8 ± 3.3 9.1 ± 2.8 1.0 ± 0.3

33 20/13 1957.1 ± 668.4 34.1 ± 9.8 14.1 ± 4.0 51.8 ± 13.4 10.5 ± 1.2 11.5 ± 1.1* 1.1 ± 0.2

35 22/13 2064.5 ± 649.3 35.5 ± 10.2 14.2 ± 5.1 50.3 ± 14.5 10.2 ± 2.3 9.7 ± 2.3 1.1 ± 0.4

Data are presented as mean ± SD. SD- standard deviation; n- number of subjects; F- female; M- male. * significant difference vs. control group.

after a night’s rest, twelve hours after consuming the last meal. Patients were measured wearing light clothes, without shoes. Weight was measured to the nearest 0.1 kg and height to the nearest 1 cm. The body mass index (BMI) was calculated by dividing the weight (kg) by the height (m) squared.

with a dietician and were instructed to maintain the diet they had followed hitherto, except for group D during the third stage of the trial, for which dietary recommendations were prepared by a qualified dietician. On the last day of each stage of the study, blood, urine, and hair samples were collected from the subjects, and blood pressure and anthropometric parameters were measured. Three days before the collection of blood samples, in all three stages of the study, dietary intake was determined by obtaining 24 h dietary recalls from the subjects. The dietary recall used in the study is recommended by the Polish National Food and Nutrition Institute. In the first stage, the dietary recall was retrospective, in the second and the third stage, a food diary was used. A standard album of meal and portion sizes was employed. Nutrient content was determined by a dietician using a computer program (Dietetyk 3.0, Alpha-Net Software). The daily energy and nutrient intake in the diet is presented in Table 2. Except for the significantly higher consumption of Zn in group D in the third stage of the study, compared to the control group, there were no significant differences in energy, nutrient, Fe, Zn, or Cu consumption between the stages of the trial or between study groups in the third stage. To maintain patient compliance on the last day of the second and third stages of the study, all packages of antihypertensive drugs and all packages of zinc supplement (for the S group) were collected, and the antihypertensive drugs tablets and zinc supplement capsules were counted. Patients were additionally asked to record the date and time of antihypertensive drug and zinc supplement administration every day of the study in a special drug/supplement diary. The compliance rate of patients was 80%–100%.

2.4. Blood pressure measurement Blood pressure was measured according to the guidelines of the European Society of Hypertension [16]. A digital electronic tensiometer (705IT, Omron Corporation, Kyoto, Japan) was used. Large or regular cuffs were used, depending on subject’s arm circumference. Blood pressure measurements were performed in the morning, after a night’s rest, twelve hours after consuming the last meal, after a 15-minut rest, in the sitting position, with legs uncrossed and the back and arm supported. Blood pressure was taken as a mean of three measurements on the left arm. 2.5. Blood sampling Blood samples were collected in the morning, after 30 min in the supine position, following a 12 h fast and a night’s rest. The blood was taken from an ulnar vein in serum-separated tubes, and in another tube with heparin sodium to obtain erythrocytes. The coagulated blood was left to clot at room temperature, and then centrifuged. The supernatant fluid was separated. Serum samples were frozen and stored at −20 °C until analysis. To separate the erythrocytes, the total blood was centrifuged at 4 °C for 15 min at 2000 × g. Blood cells were washed three times with 5 ml of 0.9% saline solution and centrifuged at 2000 × g for 10 min at 4 °C. Following centrifuging, the saline solution was separated and the

2.3. Anthropometry Anthropometric measurements were performed in the morning, 142

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2.8. Hair sample collection

erythrocyte mass was placed in demineralized Eppendorf tubes. The separated erythrocytes were stored at −20 °C for mineral analysis. The blood sample collection procedure has been described in our previous paper [1].

A 1 cm-long hair strand from the occipital scalp was collected into separate labeled paper bags. The hair sample was taken by the investigator shortly after the hair had been washed with a shampoo containing no functional components. Subjects were instructed about the hair-washing procedure and explained that only by complying with the procedure could reliable results be obtained. Patients were instructed not to use hair spray or hair dye during the study. Hair samples were washed in acetone and deionised water, before being dried at 105–110 °C. They were then dried and weighed. Dyed or permed hair was not used.

2.6. Biochemical analysis The serum levels of total cholesterol (TCH), high-density lipoprotein cholesterol (HDL), and triglycerides (TG) were assayed by routine enzymatic methods. Measurements were performed using commercial kits (Abcam, Cambridge, United Kingdom). The concentration of low-density lipoprotein cholesterol (LDL) in the serum was calculated using the Friedwald formula: LDL (mmol/L) = TCH (mmol/L) – HDL (mmol/L) k TG (mmol/L)/2.2 [18]. Glucose (GLU) serum concentration was estimated using the radioimmunological method with commercial kits (Abcam, Cambridge, United Kingdom). Erythrocyte catalase (CAT) and superoxide dismutase (SOD) activity were determined using a spectrophotometric method using commercial kits (Oxis International Inc., CA, USA). Serum C-reactive protein (CRP) concentration was determined using the turbidimetric immunoassay commercial kit (R&D System, Minneapolis, MN, USA). Nitric oxide (NO) serum concentration was measured using an enzyme immunoassay commercial kit (R&D System, Minneapolis, MN, USA). Carbonic anhydrase (CA), tumor necrosis factor α (TNF-α) and albumin serum concentrations were determined by enzyme-linked immunosorbent assay (ELISA) using commercial kits (R&D System, Minneapolis, MN, USA). Serum ceruloplasmin and ferritin concentrations were determined by the ELISA method using commercial kits (Abcam, Cambridge, United Kingdom). The total iron binding capacity (TIBC) in serum was determined by the ELISA method using a commercial kit (MyBioSource, San Diego, CA, USA). Spectrometric measurements were performed using an Advia 1800 device (Siemens, Berlin, Germany). Hemoglobin concentration (mg/mL) was measured using the cyanmethemoglobin method (Merck, Darmstadt, Germany). The complete blood count was performed using a hematology analyzer (Cell-Dyn 3700, Abbott Laboratories, Lake Bluff, IL, USA). The precision and accuracy of the techniques used to assay the biochemical parameters were validated. Reproducibility was checked with a human serum control (Randox Laboratories, Crumlin, United Kingdom). Accuracy was assessed by means of the recovery value, which ranged between 95% and 109%. The variability coefficient did not exceed 10%.

2.9. Mineral determination The zinc, iron, and copper contents of serum, urine, erythrocytes, and hair were determined after digestion in 65% (w/w) spectra pure HNO3 (Merck, Kenilworth, NJ, USA) in the Microwave Digestion system (Mars 5, CEM, Matthews, NC, USA). After digestion, the concentrations of zinc, iron, and copper in the mineral solutions were determined using flame atomic absorption spectrometry (AAS-3, Carl Zeiss, Jena, Germany). The mineral contents of samples were measured at wavelengths of 213.9 nm for zinc, 248.3 nm for iron, and 324.8 nm for copper. The accuracy of the method was verified with certified reference materials (HUM ASY CONTROL 2 and URN ASY CONTROL 2, Seronorm Trace Elements Whole Blood L-2, Sero, Billingstad, Norway) and was 95%–96% for zinc, 95%–98% for iron, and 99%–103% for copper. 2.10. Statistical analysis The statistical analysis was carried out using Statistica for Windows 10.0 (StatSoft, Kraków, Poland). The results are shown as arithmetic means ± standard deviations (SDs). The Shapiro–Wilk test was used to check for normal distribution of the data. Comparisons between groups were performed using the Wilcoxon rank–sum test. Associations between variables were calculated as the Spearmen coefficient of correlation. A p-value of less than 0.05 was regarded as significant. It was calculated that a sample size of at least 30 subjects in each group would yield at least 80% power of detecting an intervention effect that was statistically significant at the 0.05 α level. 3. Results There were no significant differences in quantity, gender, age, or BMI at any stage of the trial or between groups in the third stage. The baseline characteristics of the statistically analyzed population are presented in Table 1. Systolic and diastolic blood pressure significantly decreased following three months of hypotensive therapy. In the third stage, systolic and diastolic arterial pressure remained decreased, with no differences between the study groups (Table 3). Three months hypotensive monotherapy led to significant decreases in serum TNF-α concentration (5%), significant decreases in CAT (17%)

2.7. Urine sample collection The 24 h urine collection was performed on the final day of each stage of the study. The urine was collected following a 12 h fast and a night’s rest. The urine was collected into sterilized vessels and stored at 4 °C. The volume of urine was measured. A representative sample of the urine was taken and stored at −20 °C for analysis.

Table 3 Blood pressure in three stages of the study. Parameters

SBP (mmHg) DBP (mmHg)

I stage

160.9 ± 17.4 92.8 ± 9.3

II stage

III stage

*

140.3 ± 17.5 82.3 ± 9.2*

III stage

*

138.1 ± 17.7 80.9 ± 8.5*

Control

Diet

Supplement

139.4 ± 10.8 80.1 ± 8.9

137.5 ± 28.1 84.2 ± 8.4

137.5 ± 7.9 78.4 ± 7.7

Data are presented as mean ± SD; DBP- diastolic blood pressure; SBP- systolic blood pressure; SD- standard deviation. * significance differences vs. stage I.

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Table 4 Serum concentrations of investigated parameters and blood count in three stages of the study. Parameters

TCH (mmol/l) LDL (mmol/l) HDL (mmol/l) TG (mmol/l) GLU (mmol/l) Albumin (g/l) CRP (mg/l) TNF-α (pg/ml) Ferritin (μg/l) Ceruloplasmin (g/l) TIBC (μmol/l) NO (μmol/l) CA (U/ml) CAT (U/gHg) SOD (U/gHg) RBC (106/μl) HGB (g/dl) HCT (%)

I stage

5.5 ± 1.2 3.1 ± 0.8 1.4 ± 0.4 1.9 ± 0.8 5.6 ± 1.2 42.4 ± 4.6 5.2 ± 2.4 4.5 ± 0.8 132.7 ± 111.1 0.3 ± 0.1 62.8 ± 11.3 10.7 ± 2.4 4.6 ± 0.3 75.3 ± 9.1 2271.0 ± 198.0 4.7 ± 0.4 9.2 ± 1.7 41.5 ± 3.1

II stage

5.2 ± 1.1 3.1 ± 1.0 1.4 ± 0.4 1.8 ± 0.8 5.6 ± 1.1 42.6 ± 4.9 4.9 ± 2.2 4.3 ± 0.8* 135.1 ± 115.2 0.4 ± 0.2 56.6 ± 11.2 14.9 ± 2.8* 4.4 ± 0.4 62.7 ± 4.7* 1812.7 ± 221.9* 4.7 ± 0.4 8.7 ± 1.0 41.5 ± 2.7

III stage

III stage

5.0 ± 1.0 2.9 ± 1.0 1.4 ± 0.5 1.6 ± 0.6* 5.2 ± 0.6* 42.4 ± 4.8 4.8 ± 2.3* 4.2 ± 0.8* 134.0 ± 120.3 0.4 ± 0.2 57.8 ± 9.2 11.4 ± 3.4* 4.4 ± 0.3 67.7 ± 6.2* 2119.2 ± 202.8* 4.6 ± 0.3 8.7 ± 1.2 40.8 ± 6.4

Control

Diet

Supplement

5.2 ± 0.8 2.8 ± 0.8 1.4 ± 0.4 1.5 ± 0.6 5.3 ± 0.7 42.0 ± 4.5 4.6 ± 2.3 4.2 ± 0.7 129.7 ± 95.6 0.4 ± 0.2 55.8 ± 8.9 12.2 ± 2.8 4.4 ± 0.4 66.7 ± 5.0 2072.6 ± 233.2 4.6 ± 0.3 8.4 ± 0.6 41.0 ± 1.3

5.1 ± 1.4 3.0 ± 1.3 1.5 ± 0.5 1.6 ± 0.7 4.8 ± 0.5** 42.6 ± 5.1 4.9 ± 2.3 4.2 ± 0.8 134.7 ± 105.5 0.5 ± 0.2 61.2 ± 11.1 11.2 ± 3.4 4.5 ± 0.2 68.7 ± 8.7 2129.3 ± 187.1 4.7 ± 0.2 9.1 ± 1.7 42.7 ± 2.1

4.7 ± 0.7 2.8 ± 0.6 1.3 ± 0.5 1.6 ± 0.6 4.9 ± 0.4** 42.7 ± 4.7 4.8 ± 2.2 4.2 ± 0.8 142.1 ± 116.6 0.5 ± 0.3 57.1 ± 8.9 10.6 ± 3.8 4.4 ± 0.3 68.7 ± 5.8 2181.9 ± 182.3 4.6 ± 0.5 8.5 ± 0.8 38.2 ± 5.0

Data are presented as mean ± SD; CA- carbonic anhydrase; CAT- catalase; CRP- C-reactive protein; GLU- glucose; HCT- hematocrit; HDL- high-density lipioprotein; HGB- hemoglobin; LDL- low-density lipioprotein; NO- nitric oxide; RBC- red blood cell; SD- standard deviation; SOD- superoxide dismutase; TCH- total cholesterol; TG- triglycerides; TIBC- total iron binding capacity; TNF-α- tumor necrosis factor α. * significant difference vs. stage I. ** significant difference vs. control group.

concentration (above 9% in D group and 7.5% in S group) compared to the control group (Table 4). Moreover, a markedly lower hair copper concentration was seen in group D (above 35%) than in group C (Table 5). The analysis of the parameters of all patients in the third stage found a significant reverse correlation between zinc and glucose concentration in serum (R = − 0.37), shown in Fig. 1.

and SOD (20%) activity, and significant increases by nearly 40% in NO serum concentration compared to the baseline (Table 4). Antihypertensive therapy significantly decreased zinc concentration by 10% in serum and by around 20% in erythrocytes and also increased the level of zinc by around 30% in the urine. The modified diet and zinc supplementation increased zinc concentration in the serum (10% and 19% respectively), erythrocytes (around 20%), and hair (above 38% in group S only; Table 5). In the third stage of the study, a significant decrease in the average serum concentrations of TG (nearly 16%), GLU (7%), CRP (nearly 8%), and TNF-α (nearly 7%), a significant decrease in average CAT (10%) and SOD (nearly 7%) activities, and a significant increase by 6.5% in mean serum NO concentration were seen in comparison to the first stage. Increased zinc intake caused a significant decrease in serum GLU

4. Discussion The influence of antihypertensive monotherapy on disturbing zinc homeostasis in newly diagnosed hypertensive patients is a new finding in this study. Furthermore in this study it was assessed nutritional strategy to prevent adverse effect of hypotensive treatment. Increased zinc supply in the diet and as supplements favorably modifies zinc

Table 5 Mineral content in three stages of the study. Parameter

Serum (μmol/l) Fe Zn Cu

I stage

17.3 ± 4.7 10.1 ± 1.5 15.8 ± 3.1

II stage

III stage

III stage Control

Diet

Supplement

17.7 ± 4.7 9.1 ± 1.3* 15.8 ± 2.7

17.4 ± 4.9 9.8 ± 1.4 15.9 ± 3.0

16.5 ± 6.6 8.9 ± 1.2 15.8 ± 2.3

16.8 ± 6.2 9.8 ± 1.5** 16.1 ± 3.1

18.8 ± 7.8 10.6 ± 1.9** 15.8 ± 2.1

Erythrocytes (μmol/g Hgb) Fe 49.3 ± 8.0 Zn 0.5 ± 0.1 Cu 43.2 ± 10.3

51.6 ± 9.6 0.4 ± 0.1* 44.5 ± 10.2

49.9 ± 10.2 0.5 ± 0.1 42.4 ± 11.3

47.9 ± 10.4 0.4 ± 0.1 44.1 ± 10.7

47.4 ± 9.0 0.5 ± 0.1** 42.1 ± 10.1

49.4 ± 10.5 0.5 ± 0.1** 41.6 ± 10.6

Urine (μmol/24 h) Fe Zn Cu

2.0 ± 0.8 5.3 ± 2.0 0.8 ± 0.3

2.4 ± 0.9 6.9 ± 2.0* 0.8 ± 0.3

2.4 ± 0.9 6.7 ± 2.0* 0.8 ± 0.2

2.5 ± 1.1 6.5 ± 2.0 0.7 ± 0.1

2.4 ± 1.2 6.6 ± 2.0 0.8 ± 0.2

2.4 ± 0.7 6.9 ± 2.0 0.8 ± 0.2

Hair (μg/g) Fe Zn Cu

15.1 ± 4.2 129.9 ± 26.7 16.4 ± 8.4

15.3 ± 4.6 125.3 ± 25.5 17.4 ± 9.4

15.8 ± 5.2 140.1 ± 32.4 15.7 ± 7.4

12.4 ± 2.8 111.9 ± 27.9 19.3 ± 8.0

15.6 ± 5.7 143.9 ± 28.2 12.4 ± 5.1**

17.9 ± 12.3 154.6 ± 31.6** 16.5 ± 8.2

Data are presented as mean ± SD. Hgb-hemoglobin; SD- standard deviation. * significant difference vs. stage I. ** significant difference vs. control group.

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Fig. 1. Correlation between zinc and glucose serum concentration in the third stage of the study (n = 98); R = − 0.37; p < 0.05.

adversely affecting blood pressure. In the third stage of the study, the serum and erythrocyte zinc content was increased both in the zinc supply with the diet and supplements, as compared to the control group. In the third stage of the experiment, the control, diet, and supplementation groups showed no significant differences in urine zinc concentration. This shows the effectiveness of zinc in the diet and zinc in supplements in restoring zinc levels in the body with no influence of the source of the zinc on the elevated zinc removed with the urine. Similar results were obtained by Suliburska et al. [1] in a study of 45 hypertensive patients on zinc supply in modified diet, though there were no significant changes in erythrocyte zinc content after the supply of zinc in the diet. Interestingly, in our study, only zinc supplementation, and not the zinc in the diet, led to increased zinc levels in hair, as compared to the control group, with no differences in overall hair zinc content between the first, second, and third stages of the study. The decreased level of zinc in the body affects iron and copper homeostasis on account of the many metabolic relationships between these elements [25,26]. Our study did not register any significant changes in copper content in serum, erythrocytes, urine, or hair after antihypertensive treatment implementation, which is in line with the results of clinical trials [27]. The copper content of serum, red blood cells, and urine also remained stable in response to the high-zinc supply. However, we observed significantly decreased copper levels in the hair in the group with zinc in the diet following the third stage of the study, which was not seen in the group receiving zinc supplementation. The potential role of copper in hypertension promotion through oxidative stress and inflammation has been shown in some studies [28]. It has been documented that Cu/Zn ratio is associated with markers of inflammation such as CRP, erythrocyte sedimentation rate (ESR) and interleukin 6 (IL-6) and increased all-cause mortality, hypertension-cause mortality in this range [28]. Moreover, Zn/Cu ratio is shown to be lower in patients with essential hypertension compared to normotensive controls [29]. Our study revealed no changes in iron content following hypotensive treatment with or without the higher Zn supply. Hypotensive drugs that cause unfavorable alterations in zinc and copper turnover lead to a number of biochemical changes in the body [4,30]. Copper deficiency produces hypercholesterolemia and impaired arterial relaxation dependent on the endothelium. Zinc deficiency can results in insulin resistance and glucose intolerance [30]. This study showed decreased triglycerides and glucose serum concentration after the third stage of the experiment. These results are in line with previous observations of Suliburska et al., [17] who showed a decreased concentration of serum glucose and triglycerides upon treatment with indapamide in spontaneously hypertensive rats (SHR) with simultaneous zinc and copper supplementation. However, in the present study, while

homeostasis and glucose metabolism in hypertensive patients on hypotensive monotherapy. It is worth pointing out that, in this study, we found that increased zinc intake in the diet and as supplements had similar effectiveness on zinc status and glucose metabolism in hypertensive patients being treated with pharmacotherapy. It seems that increased zinc intake, should be recommended in this group of the patients. The unfavorable influence of hypotensive drugs on zinc homeostasis has been observed in previous studies [1,4,17]. Diuretics and calcium channel blockers show the greatest negative impact on zinc turnover. The interaction between antihypertensive drugs and zinc has mainly a pharmacokinetic nature. Hypotensive drugs lead to inhibition of zinc reabsorption in renal tubules, leading to increased excretion of zinc with the urine [1,9,19]. This effect is observed even in patients receiving zinc supplementation [20]. Intestinal mineral reabsorption is also affected by hypotensive drugs. Moreover, this group of drugs shows mineral chelating ability and disturbs the transport of minerals from the blood to tissues [1,9,19]. Increased urine concentration of zinc, accompanied by decreased serum and erythrocyte zinc concentration, was also observed in the second stage of our experiment following antihypertensive monotherapy. Furthermore, the elevated urine zinc content persisted despite the high-zinc diet and zinc supplementation in the third stage of the study, although in serum and in red blood cells, the zinc content increased to a level comparable to this in the first stage. This observation reveals that hypotensive drug-derived zincuria is independent of the oral zinc supply. These results indicate that there is an urgent need to find an effective way to treat zinc disturbances caused by antihypertensive treatment. In our study, the improvement in zinc homeostasis after the modified diet and zinc supplementation was accompanied by decreased blood pressure in hypertensive patients with antihypertensive monotherapy. A number of studies have shown a role of zinc in blood pressure regulation. Both zinc deficiency and zinc excess lead to hypotensive mechanism dysfunction and blood pressure elevation [21–23]. Tubek [22] showed that a decrease in the blocking of calcium channels is correlated with low extracellular zinc concentration. In consequence, calcium ions move inside the cells and accumulate, which elevates the blood pressure. In our previous study, [17] we showed that hypotensive treatment with indapamide and amlodipine—which are correlated with lower zinc serum concentration—is less effective than treatment with perindopril and metoprolol, which do not cause zinc disturbances. In experimental studies it was observed that excessive zinc intake reduced renal function and increased blood pressure [23,24]. In this study zinc intervention did not change blood pressure and effectiveness of hypotensive drugs in patients. The nutrition strategy proposed in this study to prevent zinc imbalance in the treatment patients seems to have beneficial effect on mineral status and glucose metabolism without 145

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inflammatory parameters. Our study demonstrated a significant decrease in serum SOD concentration and serum CAT concentration in patients with monotherapy, with no change being found after higher zinc intake in the diet or as a supplement. Our observations regarding SOD contradict these of Suliburska et al., [17] who registered a tendency for SOD to increase in SHRs with zinc and copper supplementation after treatment with indapamide. Zinc has well-documented antioxidative properties [49,50]. In humans, zinc supplementation leads to a decrease in plasma lipid peroxidation which is not accompanied by an increase in SOD concentration [51]. It thus remains unclear whether the favorable effects of zinc on oxidative stress and lipid peroxidation are mediated by SOD [47]. Zinc treatment causes a significant increase in serum and hepatic catalase in diabetic rats [52]. There is a dearth of studies investigating the effect of zinc supply on catalase in humans, and it is seems that further studies are needed to explain this relation. Hypotensive therapy and zinc supplementation were not found to have any effect on hemoglobin, hematocrit, or red blood cells in this study. In our previous experimental study, we observed that treatment with indapamide and amlodipine was associated with increased red blood cell count and hematocrit values in the serum of SHRs [53]. Our study has shown comparable effects of high zinc intake both in the diet and as supplements on selected biochemical parameters in hypertensive patients treated with antihypertensive monotherapy. To the best of our knowledge, no such comparative study in this type of group of human subjects has been performed so far. In one study, Dimitrova [54] examined the effect of diets containing zinc (100 mg Zn/kg of diet vs. 160 mg Zn/kg of diet) on blood pressure, activity of superoxide dismutase in erythrocytes, and serum lipid concentrations (total cholesterol, LDL, HDL, and triglycerides) in male spontaneously hypertensive rats. A diet containing 160 mg Zn/kg of diet led to a significant increase in superoxide dismutase activity, significant decrease in systolic blood pressure, and significant decrease in hydroperoxide concentration. Moreover, zinc supplements caused a decrease in serum LDL and an increase in serum HDL concentration. However, no antihypertensive intervention was undertaken in Dimitrova’s study [54].

glucose serum concentration was significantly lower in the zinc diet and zinc supplementation groups than in the control group, there were no differences between these three groups in terms of triglyceride serum concentration. Zinc is involved in the synthesis of insulin, its storage, and its release [31]. It has been documented that zinc has a significant role in signaling processes connected with insulin-mediated metabolism. Zn action as signaling molecule in extracellular signal recognition, protein kinase activity, second messenger activity, protein phosphorylation and transcription factor regulation has been shown so far. In adipocytes Zn is involved in cyclic adenosine monophosphate (cAMP) phosphodiesterase activity and the mobilization of glucose transporters to the plasma membrane, which is independent from insulin receptor kinase activity [32]. Zn demonstrates insulin-mimetic action in a range of mechanisms preventing from insulin resistance or even increasing insulin sensitivity. One of the most important is the inhibition of protein tyrosine phosphatase 1B, which is a negative regulator of insulin and leptin signaling transduction pathways. As a result the insulin signal through the insulin receptor is prolonged [33]. Moreover, Zn modulates glucose transport, glycogen synthesis, lipogenesis, inhibits gluconeogenesis and lipolysis, and regulates key points of the insulin signaling pathway [34]. Zn plays also important role in insulin secretion, secretory granule maturation, and exocytosis. Zinc efflux transporter 8 (ZnT8) localized on insulin secretory vesicles of beta cells acts as the primary Zn transporter that moves Zn from the cytoplasm into these organelles, where Zn takes part in insulin crystallization and proper secretion [35]. The association between zinc status and glucose and insulin sensitivity has been also found in other studies [36,37]. Elevated supply of Zn in the third stage of the study could favorably modify insulin production and signaling pathway and led to observed favorable changes in glucose serum content. These relations are confirmed by the reverse correlation between zinc and glucose concentration in serum observed in the third stage of this study. Hyperglycemia presents significant additional cardiovascular risk factor in patients with hypertension increasing the occurrence of cardiovascular diseases. Thus, normalization of serum insulin and glucose levels should be considered as therapeutic aim leading to decrease in cardiovascular events prevalence and mortality rate reduction in this group of patients [38,39]. Antihypertensive drugs affect NO, TNF-α, and CRP serum concentration. Some β-blockers, such as nebivolol, increase the serum NO concentration by stimulating endothelial-derived nitric oxide synthase [40]. ACE-Is like enalapril, ramipril, perindopril, and quinapril reduce serum CRP concentration [41]. TNF-α serum concentration is decreased by the ACE-I quinapril [42]. The calcium antagonist amlodipine significantly inhibits TNF-α production [43]. In our previous experimental study, we found that amlodipine decreased TNF-α in SHRs [44]. This study showed a significant increase in serum NO concentration in the second and third stages of the study, with no differences between groups in the third stage of the experiment. Thus, an increase in serum NO concentration in the second and third stages of the study was the effect of antihypertensive treatment, not of zinc supply. The increase in NO serum concentration following antihypertensive treatment is a welldocumented cause of blood pressure decreases, [45] and was also observed in this study. The decreased serum concentration of zinc promotes inflammation by increasing production of IL-1β, TNF-α, and other proinflammatory cytokines [46]. The anti-inflammatory properties of zinc have been well demonstrated [36,47]. Zinc supplementation causes a drop in proinflammatory cytokines synthesis; the effect is best understood in the case of IL-1β [48]. In our study, a significant decrease in serum TNF-α concentration in the second and third stages of the study and a significant decrease in serum CRP concentration following the third stage of the trial were noted; however, there were no differences between the groups in the third stage of the experiment. Our study thus managed to confirm the beneficial effect of antihypertensive treatment on inflammation, showing no influence of zinc supply on the investigated

4.1. Study strong points This study is the first in the world showing a positive result for glycemia in response to increased zinc supply in the diet and in supplements in patients with hypertension treated with antihypertensive monotherapy. The study has revealed some unique results, such as the predominance of zinc supplementation in hair zinc content, the decreased copper hair content after increased zinc intake in the diet in hypertensive patients on monotherapy. Furthermore, this study compared the effectiveness of a diet with high zinc content with zinc supplements in hypertensive patients with monotherapy. The group of patients was also very homogenous, with very restrictive inclusion and exclusion criteria eliminating a wide range of disrupting factors, allowing a precise conclusion to be to drawn. Our study can serve as a basis for revising recommendations regarding mineral supplementation during hypotensive pharmacotherapy.

4.2. Study limitations The main limitation of this study is the relatively small study group consisting of 98 subjects and a female:male ratio not close to 1:1. The main reasons for this were the strict inclusion and exclusion criteria. However, such criteria enabled us to avoid many disturbing factors, which could have prevented clear and unambiguous results been obtained. Another limitation was the both the first and the second stage were relatively short. 146

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5. Conclusions

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Antihypertensive monotherapy disturbs zinc homeostasis in newly diagnosed hypertensive patients. Furthermore, hypotensive monotherapy combined with zinc supplementation has beneficial influence on zinc balance and also is essential for reduction of the risk of hyperglycemia in hypertensive on monotherapy without adversely affecting blood pressure. From a practical point of view obtained results suggest that antihypertensive treatment should include monitoring zinc and glucose status and patients may benefit from combined that therapy with increased zinc supply in the diet or supplementation. It is important finding for physicians and also for patients. Ethics Study has been approved by Ethics Committee of Poznań University of Medical Sciences (approval no. 86/09) and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All subjects gave their written informed consent prior to their inclusion in the study. Declarations of interest None. Funding This work was supported by the National Science Center, Poland [grant number 2669/B/P01/2011/40]. The funding source had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; nor in the decision to submit the article for publication. References [1] J. Suliburska, P. Bogdanski, M. Szulińska, D. Pupek-Musialik, The influence of antihypertensive drugs on mineral status in hypertensive patients, Eur. Rev. Med. Pharmacol. Sci. 18 (2014) 58–65. [2] W.E. Carpenter, D. Lam, G.M. Toney, N.L. Weintraub, Z. Qin, Zinc, copper, and blood pressure: human population studies, Med. Sci. Monit. 19 (2013) 1–8, http:// dx.doi.org/10.12659/MSM.883708. [3] M.M. Joosten, R.T. Gansevoort, K.J. Mukamal, J.E. Kootstra-Ros, E.J.M. Feskens, J.M. Geleijnse, G. Navis, S.J.L. Bakker, PREVEND study group, Urinary magnesium excretion and risk of hypertension: the prevention of renal and vascular end-Stage disease study, Hypertension 61 (2013) 1161–1167, http://dx.doi.org/10.1161/ HYPERTENSIONAHA.113.01333. [4] J. Suliburska, P. Bogdański, D. Pupek-Musialik, Z. Krejpcio, Dietary intake and serum and hair concentrations of minerals and their relationship with serum lipids and glucose levels in hypertensive and obese patients with insulin resistance, Biol. Trace Elem. Res. 139 (2011) 137–150, http://dx.doi.org/10.1007/s12011-0108650-0. [5] E. Trasobares, A. Corbaton, M. Gonzalez-Estecha, J.L. Lopez-Colon, P. Prats, P. Olivan, J.A. Sánchez, M. Arroyo, Effects of angiotensin-converting enzyme inhibitors (ACEi) on zinc metabolism in patients with heart failure, J. Trace Elem. Med. Biol. 21 (2007) 53–55, http://dx.doi.org/10.1016/j.jtemb.2007.09.018. [6] X.L. Zuo, J.M. Chen, X. Zhou, X.Z. Li, G.Y. Mei, Levels of selenium, zinc, copper, and antioxidant enzyme activity in patients with leukemia, Biol. Trace Elem. Res. 114 (2006) 41–54, http://dx.doi.org/10.1385/BTER:114:1:41. [7] R.B. Singh, M.A. Niaz, S.S. Rastogi, S. Bajaj, Z. Gaoli, Z. Shoumin, Current zinc intake and risk of diabetes and coronary artery disease and factors associated with insulin resistance in rural and urban populations of North India, J. Am. Coll. Nutr. 17 (1998) 564–570 http://www.ncbi.nlm.nih.gov/pubmed/9853535 (Accessed 30 June 2017). [8] M. Bergomi, S. Rovesti, M. Vinceti, R. Vivoli, E. Caselgrandi, G. Vivoli, Zinc and copper status and blood pressure, J. Trace Elem. Med. Biol. 11 (1997) 166–169, http://dx.doi.org/10.1016/S0946-672X(97)80047-8. [9] L.A. Braun, F. Rosenfeldt, Pharmaco-nutrient interactions – a systematic review of zinc and antihypertensive therapy, Int. J. Clin. Pract. 67 (2013) 717–725, http://dx. doi.org/10.1111/ijcp.12040. [10] W.R. Harlan, J.R. Landis, R.L. Schmouder, N.G. Goldstein, L.C. Harlan, Blood lead and blood pressure, JAMA 253 (1985) 530, http://dx.doi.org/10.1001/jama.1985. 03350280086025. [11] S.K. Kunutsor, J.A. Laukkanen, Serum zinc concentrations and incident hypertension, J. Hypertens. 34 (2016) 1055–1061, http://dx.doi.org/10.1097/HJH. 0000000000000923.

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