A comparative study of serum selenium and vitamin E levels in a population of male risk drinkers and abstainers

Depressed selenium and Vitamin E levels may contribute to hepatic injury through lipid peroxidation. To study the effect of moderate alcohol drinking (32.4±23.6 g ethanol/d) on serum selenium and serum vitamin E concentrations, we conducted a matched-pair study of 73 healthy, well-nourished risk drinkers and healthy controls with little or no alcohol consumption. Among risk drinkers, serum selenium was significantly lowered (1.49 vs 1.67 μmol/L;p<0.001) compared with controls. Difference in α-tocopherol concentrations did not, however, reach statistical significance (22.8 vs 24.9 μmol/L;p=0.06). Nutritional and life-style factors differed very little between the two groups. We conclude that even moderate alcohol consumption lowers selenium status. Selenium may thus represent a link joining the hepatotoxic and nutritional backgrounds of alcoholic liver disease.     

Serum selenium versus lymphocyte subsets and markers of disease progression and inflammatory response in human immunodeficiency virus-1 infection

Serum selenium levels were determined cross-sectionally in 57 HIV-infected patients who were classified according to the Centers for Disease Control (CDC) 1993 classification system. Mean serum selenium levels were lower in CDC stage II (58.7±12.2 μg/L;p<0.01;n=18) and stage III (47.6±11.3 μg/L;p<0.01;n=19) HIV-infected patients, than in healthy subjects (80.6±9.6 μg/L;n=48) and stage I patients (73.6±16.5 μg/L;n=20). Serum selenium levels were positively correlated with CD4 count, CD4/8 ratio, hematocrit, and serum albumin (r=0.42;r=0.39;r=0.48; andr=0.45;p<0.01, respectively) and inversely with serum levels of thymidine kinase (r=−0.49;p<0.01;n=49) and β2-microglobulin (r=−0.46;p<0.001;n=49). In addition, serum selenium levels in 20 randomly selected AIDS-free individuals (CDC I:n=10; CDC II:n=10) were inversely correlated with serum concentrations of interleukin-8 (IL-8) and soluble tumor necrosis factor receptors (sTNFR) types I and II. There was no correlation with serum immuneglobulin A and total serum protein levels. The results show that the progressive deprivation of serum selenium in HIV-infection is associated with loss of CD4⁺-cells and with increased levels of markers of disease progression and inflammatory response.     

Relationship among serum selenium levels,lipid peroxidation,and acute bronchiolitis in infancy

Thirty-four infants with acute bronchiolitis and 25 age-matched healthy controls were enrolled to investigate the possible relationship between serum malondialdehyde (MDA) and selenium (Se) levels and the occurrence and severity of acute bronchiolitis in children. Serum samples were taken for serum Se and MDA measurements, and the clinical score was assessed at admission. Blood was taken again from the children with bronchiolitis at 2 mo after discharge from the hospital. Mean serum MDA levels were significantly higher in patients with acute bronchiolitis than at the postbronchiolitis stage and the controls (4.2±2.5nmol./L, 1.4±0.8 nmol/L, and 0.7±0.2 nmol/L, respectively [p<0.001]). Infants with bronchiolitis had lower mean serum Se levels at the acute stage than after 2 mo (31.7±28.9μg/L versus 68.4±26.4 μg/L, p<0.05, respectively); both of which were significantly lower than the control group measurements (145.0±21.9 μg/L) (p<0.001). There was a negative correlation between serum MDA and Se levels in the patient group (=−0.85, p<0.001). The age of the patient, child's immunization status, parental smoking habit, and family crowding index were not correlated with serum Se, MDA levels, or clinical score at admission. In conclusion, increased MDA levels and impaired Se status demonstrate the presence of possible relationship of these parameters with pathogenesis of acute bronchiolitis, and antioxidant supplementation with Se might be thought to supply a beneficial effect against bronchiolitis.     

Sodium selenite therapy and thyroid-hormone status in cystic fibrosis and congenital hypothyroidism

The effectiveness of a peroral sodium selenite therapy (115 μg Se/m² BSA/d) administered to cystic fibrosis patients (n=32) could after three months be identified in a significant serum selenium increase (0.69→0.96 μmol/L), a significant malondialdehyde decrease (2.72→1.64 μmol/L), as well as in a significant serum vitamin E increase (4.31→5.72 μg/mL) Parallel to that, a serum T₃ increase as well as a highly significant decrease in the serum T₄/T₃-ratio were found, too, which point to improved peripheral T₄→T₃ conversion during selenium medication. Type-I-iodothyronine-5′-deiodinase has recently been identified as a specific selenoenzyme. In the case of congenital hypothyroidism (n=37) application of sodium selenite in the above specified dosage yielded a mean serum selenium increase (0.87→1.12 μmol/L), a not significant T₃ increase (2.57→2.61 nmol/L) as well as a not significant TSH decrease (5.34→4.49 mIU/L) without an expected T₄ decrease. With the serum lipids, however, a lowering of total cholesterol (4.85→4.53 mmol/L) simultaneous with a mean increase in HDL-cholesterol (1.52→1.66 mmol/L) as well as a decrease in LDL-cholesterol (2.93→2.52) could be observed. We view the reduction of the atherogenic serum lipid constellation in the course of selenium medication as an expression of increased thyroid-hormone efficacy.     

Selenium Levels in First-Degree Relatives of Diabetic Patients

The present study was conducted to evaluate the serum selenium levels in first-degree relatives of diabetic patients (FDR) according to controls. Insulin resistance, serum lipid levels, inflammation markers, and blood pressure were also studied in these patients. Serum levels of selenium in FDR were significantly lower than control group (74.65 ± 5.9 vs 88.7 ± 8.7 μg/dl, p < 0.0001). HsCRP, HOMA-IR, insulin, homocysteine levels were significantly higher in FDR according to the control group (1.32 ± 0.9 vs 0.63 ± 0.4 mg/dL, p < 0.0001; 2.07 ± 0.84 vs 1.51 ± 0.69, p < 0.0001; 9.26 ± 3.8 vs 6.8 ± 2.98 μU/MI, p < 0.0001; 15.7 ± 7.4 vs 11.5 ± 5.1 μmol/L, p < 0.0001, respectively). There was significant correlation between selenium levels and hsCRP (r = − 0.450, p < 0.0001). There was also weak significant correlation also between HOMA-IR and selenium levels (r = −0.227, p = 0.003). There was a correlation between systolic blood pressure and BMI (r = 0.365, p < 0.0001). But there was no correlation between selenium levels and blood pressure or other parameters. HsCRP, HOMA-IR, homocysteine levels in individuals with selenium levels < 80 μg/L (n = 78) was significantly higher than hsCRP HOMA-IR, homocysteine levels in individuals with selenium levels ≥ 80 (n = 91; 1.23 ± 0.98 vs 0.81 ± 0.76 mg/dL, p < 0.003; 1.99 ± 0.88 vs 1.64 ± 0.74, p < 0.005; 15.0 ± 7.6 vs 12.9 ± 5.7 μmol/L, p < 0.049, respectively). Selenium deficiency may contribute to cardiovascular disease risk in FDR.     

Significance of serum trace element status in patients with rheumatic heart disease

It is known that certain trace elements can affect various heart diseases. In this study, we aimed to evaluate the changes in concentrations of certain serum trace elements in patients with chronic rheumatic heart disease (RHD). Serum analysis of selenium (Se), zinc (Zn), and copper (Cu) trace elements was assayed by atomic absorption spectrophotometry. RHD patients had significantly lower serum concentrations of Se and Zn than control subjects (p<0.05 and p<0.001, respectively). However, the serum Cu concentration was significantly higher in RHD patients than in controls (1.93±0.59 μg/L vs 1.06±0.29 μg/L; p<0.001). Similarly, the Cu/Zn ratio in RHD patients was higher than in control subjects (4.70±0.92 vs 1.68±0.45; p<0.001). Additionally, no significant correlation was found among these trace element concentrations and the functional capacity classes (p>0.05). RHD patients had decreased serum Se and Zn element concentrations and increased serum Cu element concentration. We suggest that Se and Zn deficiency might be contributory factors in the development of rheumatic heart disease, and a high Cu concentration and a high Cu/Zn ratio might reflect an ongoing inflammatory process in this disease.     

Copper modifies the activity of sodium-transporting systems in erythrocyte membrane in patients with essential hypertension

The aim of the study was to verify the hypothesis if copper could influence the activity of sodium-transporting systems in erythrocyte membrane that could be related to essential hypertension. The examined group of patients consisted of 15 men with hypertension. The control group was 11 healthy male volunteers. The Na⁺/H⁺ exchanger (NHE) activity in erythrocytes was determined according to Orlov et al. The activity of transporting systems (ATP-Na⁺/K⁺; co-Na⁺/K⁺/Cl⁻; ex-Na⁺/Li⁺; free Na⁺ and K⁺ outflow [Na⁺, K⁺-outflow]) was determined according to Garay's method. The concentration of copper in plasma was assessed using atomic absorption spectrometry. The activity of ATP-Na⁺/K⁺ (μmol/L red blood cells [RBCs]/h) in hypertensive patients was 2231.5±657.6 vs 1750.5±291 in the control (p<0.05), the activity of co-Na⁺/K⁺/Cl⁻ (μmol/L RBCs/h) in hypertensives was 171.3±77.9 vs 150.7±53.9 in the control (NS). Na⁺-outflow (μmol/L RBCs/h) in hypertensives was 118.3±51.6 vs 113.3±24.4 in the control (NS). The K⁺-outflow (μmol/L RBCs/h) in hypertensives was 1361.7±545.4 vs 1035.6±188.3 in the control (NS). The activity of ex-Na⁺/Li⁺ (μmol/L RBCs/h) in hypertensive patients was 266.1±76.1 vs 204.1±71.6 in the control (p<0.05). NHE activity (mmol/L RBCs/h) in hypertensives was 9.7±2.96 vs 7.7±1.33 in the control (p<0.05). In hypertensive patients, negative correlation was found between the activity of Na⁺/K⁺/Cl⁻ co-transport and plasma copper concentration (R _s=−0.579, p <0.05) and between the activity of ex-Na⁺/Li⁺ and plasma copper concentration (R _s=−0.508, p<0.05). Plasma copper concentration significantly influences the activity of sodium transporting systems in erythrocyte membrane. Copper supplementation could be expected to provide therapeutic benefits for hypertensive patients.     

Serum Total Selenium Status in Greek Adults and Its Relation to Age. The ATTICA Study Cohort

The trace element selenium is an essential micronutrient for human health and its low levels in serum are implicated in the pathogenesis of several chronic diseases. Therefore, the determination of total selenium in serum may contribute to the assessment of the health and nutritional status of certain populations. The objective of the present work was to determine total selenium in the serum of 506 healthy volunteers that participated in the ATTICA study. Selenium was determined in serum by using the technique of inductively coupled plasma mass spectrometry. The mean serum selenium concentration was determined to be 91.8 ± 33.7 μg/L (N = 506); 87.6% of women and 88.5% of men had serum selenium concentration below 125 μg/L, the cutoff considered to be required for optimal glutathione peroxidase activity. No association was found between serum selenium levels and the gender of the participants while a significant decline of selenium with age (p < 0.0001) was observed. According to our results, no anthropometric, lifestyle, nutritional, or biochemical indices were able to affect the association between serum selenium and age. This result may indicate that other factors such as selenium distribution as well as retention may be affecting the relationship between serum selenium and age.     

Effects of diabetes type and treatment on zinc status in diabetes mellitus

Zinc status was assessed in 53 diabetic patients: 18 insulin-dependent diabetic patients (IDDM), 22 noninsulin-dependent diabetic patients (NIDDM) treated with oral antidiabetic agents, and 13 insulin-treated, noninsulin-dependent diabetic patients (IRDM). Plasma zinc concentrations were in the usual range for healthy subjects in these three groups (15.3±0.9 μmol/L). Urinary zinc excretions were elevated in the IDDM group (18.3±4.1 μmol/24 h;p<0.01 vs normal) and in the NIDDM group (17.5±3.5 μmol/24 h;p<0.01 vs normal), but normal in the IRDM group (11.3±2.4 μmol/24 h). In 14 NIDDM patients treated with transient continuous sc insulin injections, urinary zinc decreased from 16.5±2.2 μmol/24 h before insulin treatment to 11.5±0.3 μmol/24 h after insulin treatment without any modification in plasma zinc concentrations.     

Concentrations of cadmium,lead, selenium,and zinc in human blood and seminal plasma

The concentrations of cadmium, lead, selenium, and zinc in blood and seminal plasma were determined in 76 Singapore males. Except for zinc, the concentrations were generally higher in blood than in seminal plasma (cadmium, 1.31 μg/L vs 0.61 μg/L; lead, 82.6 μg/L vs 12.4 μg/L, and selenium, 163.6 μg/L vs 71.5 μg/L). The mean concentration of zinc in seminal plasma was more than 30 times higher than in blood (202 mg/L vs 6.2 mg/L). Significant positive correlations were found between the concentrations in blood and seminal plasma for the two essential trace elements: selenium (r=0.45,p<0.001) and zinc (r=0.25,p<0.05). However, no relationships were found between the concentrations in blood and seminal plasma for two toxic metals (cadmium and lead). Significant inverse correlations were observed between Cd and Zn (r=−0.40,p<0.01), and Pb and Se (r=−0.32,p<0.05) in blood, whereas significant positive correlations were noted between Cd and Se (r=0.45,p<0.01), Cd and Zn (r=0.35,p<0.05), and Se and Zn (r=0.57,p<0.001) in seminal plasma. The physiological significance of these relationships are also discussed in this paper.     

Serum extracellular superoxide dismutase activity as an indicator of zinc status in humans

The present study focused on whether serum extracellular superoxide dimutase (EC-SOD) activity can be used as a functional indicator of marginal zinc deficiency in humans. Subjects in this study were 444 healthy adults over 30 yr of age living a normal rural life in Kyunggi province, Korea. The mean dietary zinc intake of subjects obtained from one 24-h recall was 6.41 ± 4.35 mg and the average serum zinc concentration of the subjects was 11.06 ± 2.44 (μmol/L. Subjects were divided into three groups by serum zinc concentrations: adequate (serum zinc >10.7 (μmol/L), low (serum zinc 9.0–10.7 μmol/L), and very low (serum zinc <9.0 μmol/L) groups. A total of 50 subjects were selected from the three groups for analysis of EC-SOD activities. The EC-SOD activity of subjects increased with increasing serum zinc concentrations, and the activities of the three groups were significantly different as indicated by the Kruskal-Wallis test (p = 0.0239). Also, serum EC-SOD activities were significantly correlated with serum zinc concentrations (r = 0.289,p = 0.04). Serum EC-SOD activities, however, were not significantly correlated to the dietary zinc intakes. In conclusion, these results show that EC-SOD activities are decreased in subjects with low serum zinc concentrations and suggest that EC-SOD activity may be a functional indicator of zinc nutritional status in humans.     

Selenium levels in blood of Upper Silesian population

The selenium status and the relationship of whole-blood selenium and plasma homocysteine are reported for healthy human subjects living in Upper Silesia. A total of 1063 individuals (627 male and 436 female) examined for whole-blood selenium were subdivided into six groups according to age; the youngest included adolescents (n=143) aged 10–15 yr, and the oldest were centenarians (n=132). The mean Se content was relatively low (62.5±18.4 μg/L), and it tended to be higher in men (65.9±17.2 μg/L) than in women (57.5±18.9 μg/L). Selenium levels appeared to be age dependent, as the highest values were observed in young and middle-age adults (21–40 yr), whereas they were significantly lower in adolescents and in the elderly. In more than 40% of apparently healthy adults (aged 21–69 yr), the Se concentration was within the range 60–80 μg/L (i.e., below the lower limit of the nutritional adequacy range [80 μg/L]). A significant inverse correlation between whole-blood selenium and plasma total homocysteine was detected in a smaller population sample of middle-aged and elderly persons (n=204).     

A contribution to the world selenium map

Atomic absorption spectrophotometric method was used to determine the serum selenium levels of 86 healthy individuals. Variations in age, sex, and geographically different urban regions of Yugoslavia were investigated. A group of 63 healthy children, ages 8–15 yr, were examined. Mean±standard deviation of the serum selenium concentration was 57±9 μg/L; age and geographic area had no effect on the Se status of children, but the difference between boys and girls was significant (P<0.05). A group of 23 men from Zagreb, ages 22–37 yr, were examined. The group was divided into three age subgroups and no difference was found among these groups. The mean Se concentration was 69±18 μg/L, and a statistically significant difference was found only between the group of adults and the group of children (P<0.05).     

The time-trend and the relation between smoking and circulating selenium concentrations in Norway

ObjectivesThe objectives of this study were to investigate biomarkers of selenium status in relation to smoking habits and to analyze the time-trend of selenium in serum (S-Se) in Norway during the time period 1995–2006.MethodsThe impact of smoking habits was investigated in a population recruited to a cross-sectional study of blue-collar workers in the southern part of the country (n=98). The time-trend was studied in all subjects who delivered blood samples for the determination of S-Se to a large commercial clinical chemistry laboratory in Norway.ResultsSmokers had 0.14 and 0.20 μmol/L lower concentrations of selenium in whole blood (B-Se) and serum, respectively, than non-smokers. The amount of smoking, as assessed by the serum cotinine concentration, was negatively associated with the B-Se concentration (Pearson's r=?0.43). The 1/3 of the blue-collar workers with the lowest concentrations of B-Se or S-Se had lower activity of glutathione peroxidase in serum (S-GSHpx) than the remaining subjects. Snuff users had about the same levels of B-Se and S-Se as the non-smokers, although they had about the same amount of nicotine metabolites in urine and serum as the smokers. A decreasing trend of S-Se was observed during the observation period from 1995 to 2006. The mean concentration was 1.26 μmol/L in 1995, while the lowest mean concentration was measured in 2003 (1.01 μmol/L).ConclusionSmoking, but not snuffing, is associated with lower concentrations of B-Se and S-Se. The reduction of B-Se is negatively associated with the nicotine biomarker cotinine in serum. A substantial proportion of blue-collar workers had not maximized the activity of S-GSHpx. Selenium status may have become poorer since 1995.     

Nuclear all-trans retinoic acid receptors

The present study was undertaken to investigate the effects of selenite (Se^IV) and selenate (Se^VI) on the all-trans retinoic acid (RA)-nuclear retinoic acid receptor (RAR) complex formation in rat liver. We also present the data on the in vitro effects of Se^IV on the RARα and the type I iodothyronine 5′-deiodinase gene expression in the GH₄C₁ rat pituitary tumor cells. Se^IV at 1.0 μmol/L was found to reduce (p<0.05) the RA specific binding to RAR in rat liver. Dithiothreitol (DTT), a protective agent for sulfhydryl groups, was found to be slightly effective in protecting the RAR binding properties when affected by Se^IV. Se^VI at 0.1 μmol/L reduced (p<0.05) the RA specific binding to RAR in liver, as well. Seleno-l-methionine (Se-^II) when compared tol-methionine did not exert any inhibitory effect on the formation of the RA-RAR complex. Se^IV (up to 2.5 μmol/L) has no inhibitory effect on GH₄C₁ cell proliferation as well as the prolactin secretion. Se^IV at 1.0 μmol/L significantly decreases the rate of mRNA synthesis and/or degradation of the α form of the RAR and causes the enhancement of the type I iodothyronine 5′-deiodinase gene expression in GH₄C₁ cells. The results based on in vitro experiments suggest that inorganic selenium may affect the RA specific binding to their cognate receptor molecules, and it may reduce expression of the gene encoding the RARα, with the cell vitality and the cell growth remaining unchanged.     

The response of trout and zebrafish embryos to low and high boron concentrations is U-shaped

Fish in the embryo-larval stage of development have been shown to be sensitive to boron (B) at both ends of the dose-response curve (1,2). The present study evaluated the health effects of low and high B concentrations on rainbow trout (Oncorhynchus mykiss), a cold water species, and zebrafish (Danio rerio), a warm water species. Rainbow trout embryos were incubated from day 1 until 2 wk posthatch in Type 1 ASTM ultrapure-grade water (12.5°C) supplemented with only B (0-500 μM) as boric acid, or together with CaCO₃ (0–2 mM) to increase water hardness. Embryonic growth was stimulated by B in a dose-dependent manner at all Ca concentrations (p < 0.001). Chronic exposures below 9 μmol B/L impaired embryonic growth and above 10 mmol B/L caused death (p < 0.001). Thus, the safe range of exposure for the rainbow trout was between the adverse effect concentrations of 9 μmol B/L and 10 mmol B/L. Zebrafish were maintained for 6 mo in ultrapure water containing <0.2 μmol B/L to determine the effect of low-level exposure. High-level exposure was assessed by exposing zygotes, derived from parents maintained at 46 μmol B/L, to graded concentrations of boric acid up to a concentration of 75 mmol B/L from fertilization until they were free feeding (96 h). Fertilization occurred, but zygotes failed to survive when water contained <0.2 umol B/L (p < 0.001). Death occurred at and above 9.2 mmol B/L. Thus, the safe range of B exposure for zebrafish was between the adverse effect concentrations of 0.2 μmol B/L and 9.2 mmol B/L. The dose-response for both species was thus U-shaped. Part of this work was previously published in abstract form and presented at Experimental Biology 97, April 6–9, New Orleans, LA (Eckhert, C. [1997] Embryonic trout growth and boron exposure,FASEB J. 11, A406 [abstract]).     

Bioavailability of enterai yeast—selenium in preterm infants

There is no data or literature on the effects of supplementing infants with yeast selenium, although its intestinal absorption and bioavailability are higher in adults compared with other selenium compounds. The aim of the present investigation was to study the impact of selenium enriched yeast on the serum selenium concentration of preterm infants living in a low selenium area (Hungary). Twenty-eight preterm infants with mean ± SD birth weight of 962 ± 129 g and gestational age 27 ± 1 wk were randomized into two groups at birth with respect to selenium supplementation. In the supplemented group (n = 14) infants received 4.8 mg yeast selenium containing 5 μg selenium daily via nasogastric drip during the first 14 postnatal days. The nonsupplemented infants were used as a reference group. In the supplemented group, the serum selenium concentration increased from 32.1 ± 8.5 μg/L to 41.5 ± 6.5 μg/L and in the nonsupplemented group it decreased from 25.9 ± 6.8 μg/L to 18.2 ± 6.4 μg/L from birth in two weeks time. Compared with previous studies, our results suggest that the bioavailability of selenium in the form of yeast selenium is higher than that of other selenium compounds used for preterm infants. We did not observe any complications or side-effects owing to enterai yeast selenium supplementation. We conclude that selenium enriched yeast is a safe and an effective form of short-term enterai selenium supplementation for infants.     

Plasma zinc and copper in Paris area preschool children with growth impairment

Plasma zinc, copper, and parameters of growth were measured in a group of 116 French preschool children, 2–5 yr-old from low-income households. Participants were selected on the basis of Z-scores of weight for height (WHZ) and height for age (HAZ). Zinc and copper concentrations of children with growth impairment (GI), defined by a WHZ and/or HAZ< −1 Z-score, were compared to those of age, sex, and ethnic origin matched controls (WHZ and HAZ >−1 Z-score). Mean (±SD) plasma zinc concentration was 12.58±1.84 μmol/L in the GI group, and 13.27±1.98 μmol/L in the controls. The difference of the means of paired samples was 0.69±2.34, and by pairedt-test the significance reachedp=0.028. This effect was primarily a result of the weight retarded group (WHZ <−1 Z-score,p<0.009) and to the girls (p<0.05). There were no significant differences in plasma copper concentrations between groups. These results suggest the presence of marginal zinc deficiency in French preschool children with low weight for height Z-scores.     

Urinary zinc excretion is normalized in primary arterial hypertension after perindopril treatment

Increased or unchanged urinary zinc excretion has been reported in hypertension. In the present article, this observation was confirmed in a group of 10 untreated hypertensive patients of both sexes that had no diabetes or obesity. The 24-h zinc excretion was significantly different between the patients: 7.46±3.01 μmol and healthy controls: 5.19±2.19 μmol (p<0.025). After a 1-mo treatment with 4 mg perindopril per day, a decrease of urinary zinc was observed until it reached levels not significantly different from those of the healthy controls (5.98±2.13 μmol). The decrease was significantly different from that of the pretreatment values (p<0.05).     

Myocardial energy metabolism in ischemic preconditioning and cardioplegia: A metabolic control analysis

For both, cardioplegia (CP) and ischemic preconditioning (IP), increased ischemic tolerance with reduction in infarct size is well documented. These cardioprotective effects are related to a limitation of high energy phosphate (HEP) depletion. As CP and IP have to be assumed to act by different mechanisms, their effects on myocardial HEP metabolism cannot be assumed to be identical. Therefore, a systematic analysis of myocardial HEP metabolism for both procedures and their combination was performed, addressing the question whether there are different effects on myocardial HEP metabolism by IP and CP. In this study, metabolic control analysis was used to analyze the regulation of HEP metabolism. In open chest pigs subjected to 45 min LAD occlusion (index ischemia), CP and IP preserved myocardial ATP (control (C) 0.14 ± 0.05 μmol/g wwt; CP: 0.95 ± 0.14, IP: 0.61 ± 0.12; p<0.05 C vs. CP and IP) and reduced myocardial necrosis (infarct size IA/RA: C: 90.0 ± 3.0%; CP: 0.0 ± 0.0% but patchy necroses; IP: 5.05 ± 2.1%; p<0.05 C vs. CP and IP). The effects on HEP metabolism, however, were different: CP acted predominantly by slowing down the breakdown of phosphocreatine (PCr) during early phases of ischemia (C: ΔPCr 0–2 min: 5.24 ± 0.32 μmol/g wwt; CP: ΔPCr 0–2 min: 3.38 ± 0.23 μmol/g wwt, p<0.05 vs. C), leaving ATP breakdown during later stages unaffected (C: ΔATP 5–45 min: 1.77 ± 0.11 μmol/g wwt CP: ΔATP 5–45 min: 1.59 ± 0.28 μmol/g wwt, n.s. vs. C). In contrast to CP, in IP PCr breakdown was even increased (IP: ΔPCr 0–2 min: 7.06 ± 0.34 μmol/g wwt, p<0.05 vs. C), but ATP depletion greatly attenuated (IP: ΔATP 5–45 min: 0.48 ± 0.10 μmol/g wwt, p<0.05 vs. C and CP). Combining IP and CP yielded an additive effect with slowing down the breakdown of both PCr (IP+CP: ΔPCr 0–2 min: 5.09± 0.35 μmol/g wwt, p<0.05 vs. C and IP) and ATP (IP+CP: ΔATP 5–45 min: 0.56 ± 0.48 μmol/g wwt, p<0.05 vs. C and CP), resulting in a higher ATP content at the end of index ischemia (1.86 ± 0.46 μmol/g wwt, p<0.05 vs. C, CP and IP). Compared to IP, combining IP+CP achieved also a further reduction in infarct size (IA/RA: 0.0 ± 0.0%, p<0.05 vs IP) and—compared to CP—a disappearance of the patchy necroses. {The concept of major differences in myocardial HEP metabolism during CP and IP is further supported at a molecular level by metabolic control analysis. CP but not IP slowed down the CK reaction velocity at high PCr levels. In contrast to CP exerting a continuous decline in vATPase for any given ATP level, in IP myocardium ATPase reaction velocity was even increased at higher ATP contents, whereas a marked decrease in ATPase reaction velocity was found if ATP levels decreased. The equilibrium of the CK-reaction remained unchanged following CP, whereas IP induced a changing CK equilibrium, which was the more shifted towards PCr the more myocardial HEP content decreased. The data demonstrate different effects of CP and IP on myocardial HEP metabolism, i.e. PCr and ATP breakdown as well as the apparent equilibrium of the creatine kinase (CK)-reaction. For these reasons the combination of the two protective interventions has an additive effect. (Mol Cell Biochem 278: 222–232, 2005)