Sławomir Tubek

Role of zinc in regulation of arterial blood pressure and in the etiopathogenesis of arterial hypertension.

Increased gastrointestinal absorption and urinary excretion of zinc has been confirmed in experimental and clinical studies on primary arterial hypertension as a result from changes of intracellular and extracellular zinc content. In arterial hypertension, the levels of zinc in serum, lymphocyte, and bone decrease while increasing in heart, erythrocytes, kidney, liver, suprarenal glands and spleen. These changes result in the loss of zinc homeostasis that leads to various degrees of deficiency, not entirely compensated by nutritional factors or increased absorption in the gastrointestinal tract. Loss of zinc homeostasis can be both cause and effect of high blood pressure. In the present review, the role of zinc metabolism changes and its mechanisms in arterial hypertension are discussed.

Role of Zinc in Hemostasis: A Review

Zinc is a multi-functional element that is found in almost 300 enzymes where it performs catalytic, co-catalytic, and/or structural functions. In 1982, Gordon et al. (Am J Clin Ntr 35:849–857, 1982) found that a low zinc diet caused poor platelet aggregation and increased bleeding tendency in adult males. This fact drew interest to the role of zinc in blood clotting. It has been shown that hyperzincemia predisposes to increased coagulability, and hypozincemia to poor platelet aggregation and increased bleeding time. The blood clotting disturbances can be regressed by appropriate zinc intake management. Considering the importance of zinc as an essential element, its participation in regulation of the equilibrium between pro- and anti-thrombotic factors originating in platelets and endothelium prompted further investigations.

Zinc Supplementation or Regulation of its Homeostasis: Advantages and Threats

To accomplish its multifunctional biological roles, zinc requires precise homeostatic mechanisms. There are efficient mechanisms that regulate zinc absorption from the alimentary tract and its excretion by the kidney depending on the organism demands. The regulatory mechanisms of cellular zinc inflow, distribution, and zinc outflow are so efficient that symptoms of zinc deficiency are rare, and symptoms connected with its massive accumulation are even more rare. The efficiency of homeostatic mechanisms that prevent zinc deficiency or excessive zinc accumulation in the organism is genetically conditioned. It seems that an essential element of zinc homeostasis is the efficiency of zinc transmembrane exchange mechanisms. Intracellular free zinc concentration is higher than in extracellular space. Physiologically, the active outflow of zinc ions from the cell depends on the increase of its concentration in extracellular space. The ion pumps activity depends on the efficiency by which the cell manages energy. Considering the fact that zinc deficiency accelerates apoptosis and that excessive zinc accumulation inside cells results in a toxic effect that forces its death brings about several questions: Is intensification and acceleration of changes in zinc metabolism with age meaningful? Is there a real zinc deficiency occurring with age or in connection with the aforementioned pathological processes, or is it just a case of tissue and cell redistribution? When discussing factors that influence zinc homeostasis, can we consider zinc supplementation or regulation of zinc balance in the area of its redistribution? To clarify these aspects, an essential element will also be the clear understanding of the nomenclature used to describe changes in zinc balance. Zinc homeostasis can be different in different age groups and depends on sex, thus zinc dyshomeostasisrefers to changes in its metabolism that deviate from the normal rates for a particular age group and sex. This concept is very ample and implies that zinc deficiency may result from a low-zinc diet, poor absorption, excessive loss of zinc, zinc redistribution in intra- and extracellular compartments, or a combination of these factors that is inadequate for the given age and sex group. Such factor or factors need to be considered for preventing particular homeostasis disorders (or dyshomeostasis). Regulation of zinc metabolism by influencing reversal of redistribution processes ought to be the main point of pharmacologic and nonpharmacologic actions to reestablish zinc homeostasis. Supplementation and chelation are of marginal importance and can be used to correct long-term dietary zinc deficiency or zinc poisoning or in some cases in therapeutic interventions. In view of its biological importance, the problem posed by the influence of zinc metabolism requires further investigation. To date, one cannot consider, for example, routine zinc supplementation in old age, because changes of metabolism with age are not necessarily a cause of zinc deficiency. Supplementation is warranted only in cases in which deficiency has been established unambiguously. An essential element is to prevent sudden changes in zinc metabolism, which lead to dyshomeostasis in the terms defined here. The primary prophylaxes, regular physical activity, efficient treatment of chronic diseases, are all elements of such prevention.

Zinc content in lymphocytes and the activity of zinc ion efflux from lymphocytes in primary arterial hypertension

Clinical observations and experimental data show that zinc (Zn) plays a role in regulating arterial blood pressure and in arterial hypertension etiopathogenesis. To determine the direction of changes in Zn metabolism in primary arterial hypertension, Zn absorption from the alimentary tract, Zn levels in blood serum, its content in lymphocytes, Zn efflux rate constants from lymphocytes, and urinary Zn excretion in patients with hypertension and in healthy subjects were studied. In this article, Zn levels in blood serum, its content in lymphocytes, and Zn efflux rate constants from lymphocytes are presented. In primary arterial hypertension, on the basis of this study, decreasing Zn levels in blood serum and its decreasing content in lymphocytes were found. The Zn efflux rate constants from lymphocytes increased at the initial stage of hypertension (mild arterial hypertension) and decreased in the late stage of the hypertension disease (severe arterial hypertension). Taking into consideration all of the directions of changes and the fact that Zn can be a factor that increases arterial blood pressure, the changes in Zn distribution can be regarded as having, to a certain extent, a protective character leading to weakening of the pressor reaction, assuming a genetic existence of relative or absolute Zn excess in the body. The changes of Zn distribution can lead, after some time, to Zn deficiency and the resulting metabolic changes (e.g., carbohydrate intolerance).

Increased absorption of zinc from alimentary tract in primary arterial hypertension.

Zinc absorption from the alimentary tract, as revealed by serum zinc concentration, was studied in a group of 10 patients (age 37.7±5.1 yr) with moderate and severe untreated primary arterial hypertension before and after a 30-d treatment with perindopril 4 mg/d. Blood pressure was 177.33±16.24/111.33±15.26 mm Hg before and 143.41±17.34/91.29±12.54 mm Hg after treatment (p<0.05/p<0.05). Nine persons (age 37±6.2 yr) with normal blood pressure (121.33±9.9/78±5.23 mm Hg) were the control group. Blood samples were taken from the ulnar vein at 8.00 am (0 h), before taking zinc orally (one tablet of Zincas (zinc aspartate), containing 5 mg Zn2+) and at 1, 3, and 6 h after the dose. Serum zinc concentration in control and hypertensive group (before treatment) were initially 15.47±6.26 versus 15.99±5.65 (NS), 19.37±6.40 versus 20.83±4.48 (NS) after 1 h, 17.91±4.76 versus 31.32±10.49 (p<0.003) after 3 h, and 15.32±5.47 versus 17.87±6.56 (NS) after 6 h. Maximal increase of Zn was 4.77±2.10 versus 17.53±4.13, respectively (p<0.001). In the hypertensive group, serum Zn before and after perindopril treatment was initially 15.98±5.65 versus 14.81±3.11 (NS), 20.83±4.48 versus 18.17±2.50 (NS) after 1 h, 31.32±10.49 versus 22.94±5.80 (NS) after 3 h, 17.53±4.13 (p<0.001) after 6 h. Maximal increase of Zn before treatment was 17.53±4.13 versus 9.17±4.67 (p<0.017) after treatment. The following conclusions were reached: (1) In patients with primary arterial hypertension, an increased zinc absorption from alimentary tract was found; (2) A 30-d perindopril treatment 4 mg/d orally decreased zinc absorption in these patients.

Role of trace elements in primary arterial hypertension: is mineral water style or prophylaxis?

A negative relationship between water hardness and cardiovascular mortality rate was demonstrated and became a source of interest regarding minerals and trace metals in the pathogenesis of atherosclerosis, cardiovascular diseases, and arterial hypertension. Higher incidences of sudden death, cerebrovascular diseases, arterial hypertension, and coronary heart disease have been reported in soft water areas. A major research effort has been devoted to the problem in an attempt to find a protective factor in hard water or a detrimental factor or element in soft water. The roles of calcium, magnesium, cobalt, lithium, vanadium, silicon, manganese, and copper have been considered potentially beneficial, whereas those of cadmium, lead, silver, zinc, and antimony have been considered potentially harmful. Cobalt and zinc have been attributed both roles. In the present article, the role of trace quantities of several elements in mineral water in the etiopathogenesis of primary arterial hypertension is reviewed.

Selected zinc metabolism parameters in relation to insulin, renin-angiotensin-aldosterone system, and blood pressure in healthy subjects: gender differences.

The relationship between the renin-angiotensin-aldosterone system and insulin concentration and selected zinc (Zn) metabolism parameters and arterial blood pressure in young healthy subjects of both sexes is presented in this study. The following parameters were measured: systolic and diastolic arterial blood pressure, total and ouabain-dependent efflux rate constants of Zn from lymphocytes, serum and lymphocyte Zn concentrations, serum aldosterone, angiotensin-converting enzyme, insulin, sodium and potassium concentrations, body mass index, and plasma rennin activity. The correlations among these parameters show gender-dependent differences, except for a negative correlation between serum Zn and ouabain-dependent Zn efflux rate constant and the serum level of angiotensin-converting enzyme, and a positive relationship between the total efflux rate constant of Zn from lymphocytes and the serum aldosterone levels, both of which were gender independent. The results led us to conclude that there is a gender-independent functional relation between Zn homeostasis and the renin-angiotensin-aldosterone system. Insulin does not appear to play a significant role in Zn homeostasis.

The Content of Elements in Rainwater and its Relation to the Frequency of Hospitalization for Arterial Hypertension, Chronic Obstructive Pulmonary Disease, and Psoriasis in Opole Voivodship, Poland During 2000–2002

The content of chemical elements in rainwater is a suitable indirect indicator of its presence in airborne dust, sometimes referred to as rain fallout. Rainwater is considered a suitable monitor for environmental or natural pollution. The yearly content of chemical elements in rainwater may be considered as a good indicator for determining the influence of these environmental factors on the human body. We decided to investigate the relationship between chemical elements in rainwater and the frequency of hospitalizations for arterial hypertension, chronic obstructive pulmonary disease, and psoriasis. There is a mild correlation between zinc and cadmium and cases of arterial hypertension. For obstructive pulmonary disease, there is a strong correlation with the content of potassium, calcium, iron, manganese, lead and nickel, and with chloride, sulfide, total nitrogen, and nitrites. There is also a mild correlation with magnesium, zinc, copper, cadmium and chromium, and with ammonium nitrogen. In cases of hospitalization for psoriasis, a correlation was revealed with such elements as potassium, ammonium nitrogen, and phosphorus.

Correlations between serum zinc concentrations and oxygen balance parameters in patients with primary arterial hypertension.

It has been postulated that increased blood pressure is related to hypersensitivity of arterial chemoreceptors and increased tissue oxygen supply. Arterial blood pressure has been found to be negatively correlated to serum zinc and positively correlated to age, body mass index, and hemoglobin concentrations. The aim of the present investigation was to further explore the relationship between blood pressure and zinc concentrations in serum and blood morphology parameters, iron concentrations, and venous blood gasometry parameters. The study was carried out in two groups. Group Aconsisted of 23 subjects of both sexes suffering from moderate to severe arterial blood pressure. Their mean age was 53.13±10.45 yr (range: 23–74 yr). Group B included 48 subjects of mean age 36.7±10.0 yr (range: 26–60 yr). This group included 5 patients with arterial hypotension, 37 with hypertension, and the remaining 6 with normal blood pressure.Significant positive correlations between serum zinc and red blood cell count (r = 0.51) and negative with age (r = −0.52) were found. By multiple regression, negative correlations were also found between serum zinc and the diastolic blood pressure and with hemoglobin (r = −0.5). Age was positively correlated to systolic (r = 0.49) and diastolic (r = 0.45) blood pressure parameters and to hemoglobin concentrations (r = 0.33 and r = 0.38, respectively). Buffered and excess bases in blood were negatively correlated to zinc (r = −0.29 in both cases) and to systolic and diastolic blood pressure (r = −0.31 and r = −0.40, respectively). In turn, the systolic and diastolic blood pressure also correlated negatively to the partial pressure of carbon dioxide and positively to venous blood oxygen saturation and to the partial pressure of oxygen. The role of zinc and acid-balance realtionships in blood pressure regulation and in arterial hypertension ethiopatogenesis is disscused.

Zinc balance normalization : An important mechanism of angiotensin-converting enzyme inhibitors and other drugs decreasing the activity of the rennin-angiotensin-aldosterone system

: Imbalances of zinc (Zn) metabolism in arterial hypertension are related to increased urinary Zn excretion, Zn transfer between extracellular and intracellular spaces, and redistribution of this element inside the cells. The changes include an increase of the absorption of Zn in the gastrointestinal tract and decreases of its concentration in lymphocytes, bone, and arterial walls. The Zn content of erythrocytes, cardiac muscle, and kidneys also increases. The condition eventually leads to Zn deficiency (1-5). Zinc plays many roles in biological systems. It is a component of over 300 enzymes, performing catalytic, cocatalytic, and/or structural functions. Among others, it conditions the activities of carbonic anhydrase (CA) and the angiotensin-I converting (ACE) and endothelin-converting (EC) enzymes. Zn is essential for forming the quaternary structure of numerous regulatory proteins and hormone receptors that conditions binding with DNA, such as zinc-fingers, zinc-twists, or zinc-clusters. It is a structural element of the nucleic acids and takes part in its metabolism. Zn stabilizes and regulates cell membrane functions. Cellular growth and division depends on the content of Zn inside the cell and on its transport inside the cells compartments (6-11).