Amiodarone-liposome interaction: a multinuclear NMR and X-ray diffraction study

Amiodarone, a potent antiarrhythmic drug, is widely used in cardiology. Its electrophysiological effects, as well as many of its side effects, seem to involve lipids. We report here a multinuclear NMR and X-ray diffraction study of amiodarone in egg phosphatidylcholine liposomes and lipid multilayers. In proton NMR experiments, amiodarone alters the signal from the lipid trimethyl ammonium group for pH values ranging from 3.2 to 8.4; cholesterol does not cause this alteration. The addition of SCN- changes both the proton and phosphorus NMR spectra of liposomes containing amiodarone. For both proton and carbon NMR, amiodarone modifies the signal from the lipid methylene groups, but to a far lesser extent than does cholesterol. Incorporation of amiodarone in EPC bilayers also modifies the low-angle X-ray diffraction patterns, decreasing the lamellar repeat period at low water contents, but swelling the fluid spaces between bilayers at high water contents. Electron density profiles and modeling studies using the X-ray data indicate that amiodarone decreases the bilayer thickness and adds electron density at the interfacial region of the bilayer. Our analysis of the NMR and X-ray data indicates that the iodine atoms of amiodarone are located near the hydrocarbon/water interface and that the tertiary amine of amiodarone is in the headgroup region of the bilayer.     

The relationship of serum vitamin A, cholesterol, and triglycerides to the incidence of ovarian cancer

Prospective and retrospective studies have suggested that serum vitamin A and total cholesterol levels may be associated with cancer. Our study showed that the mean (+/- SEM) concentrations of serum vitamin A 489 +/- 33.28 (mean +/- SEM micrograms/liter and serum total cholesterol 174.7 +/- 8.96 (mean +/- SEM) mg/dl from ovarian cancer patients in Singapore were significantly lower than the respective values of 668 +/- 25.10 (mean +/- SEM) microgram/liter and 210.7 4.48 (mean +/- SEM) mg/dl from noncancerous control subjects (P less than 0.0001 for both compounds). In addition, ovarian cancer patients did not show significantly lower serum triglyceride levels than the control subjects. Age did not significantly correlate the serum vitamin A and total cholesterol concentrations, but there was correlation with respect to the serum triglyceride levels. There were moderate correlations between vitamin A and cholesterol levels (r = 0.36, P less than 0.0027) and between cholesterol and triglyceride levels (r = 0.37, P less than 0.0024) in the control subjects but not in the cancer patients. Vitamin A levels correlated moderately with triglyceride levels in both the cancer patients (r = 0.42, P less than 0.0258) and the control subjects (r = 0.33, P less than 0.0069). The inverse relationship between the incidence of ovarian cancer and serum vitamin A and serum total cholesterol concentrations may have distinct implications for preventive medicine and public health.     

Effect of long-term administration of AY-9944, an inhibitor of 7-dehydrocholesterol delta 7-reductase, on serum and tissue lipids in the rat

The effect of long-term administration of AY-9944, a specific inhibitor of cholesterol biosynthesis, was examined in rats maintained on diets with low and high cholesterol and fat content. Sterol and phospholipid levels were determined in the serum, liver, adrenals, lungs, and brain after 6 and 12 months of feeding AY-9944 at several dose levels. In all the tissues examined, the cholesterol content was lowered and the cholesterol was partly replaced by 7-dehydrocholesterol biosynthesized instead of cholesterol in the presence of AY-9944. Cholesterol levels were particularly low in the serum and adrenals, while 7-dehydrocholesterol accumulated in the lungs. The fall in cholesterol and appearance of 7-dehydrocholesterol were reversible. Alterations of this type in the brain indicated that sterol metabolism is active in the adult rat brain. Addition of cholesterol to the diet reduced the effect of the inhibitor by eliminating the liver as a site of sterol synthesis.     

Alpha-asarone inhibits HMG-CoA reductase, lowers serum LDL-cholesterol levels and reduces biliary CSI in hypercholesterolemic rats.

Our results showed that alpha-asarone was an inhibitor of hepatic HMG-CoA reductase and that the administration of alpha-asarone at 80 mg/kg body wt. for 8 days decreased serum cholesterol by 38% (p < 0.001) in hypercholesterolemic rats. This alpha-asarone treatment affected mainly the serum LDL-cholesterol levels, leaving serum HDL-cholesterol lipoproteins unaffected, with a consequent decrease of 74% in the LDL/HDL ratio. In addition, alpha-asarone especially stimulated bile flow in hypercholesterolemic rats (60%), increasing the secretion of bile salts, phospholipids and bile cholesterol. The drug also reduced the cholesterol levels of gallbladder bile, whereas the concentration of phospholipids and bile salts increased only slightly, leading to a decrease in the cholesterol saturation index (CSI) of bile in the hypercholesterolemic rats. This CSI decrease and the increase in bile flow induced by alpha-asarone may account for the cholelitholytic effect of alpha-asarone. It seems that alpha-asarone induced clearance of cholesterol from the bloodstream and that the excess of hepatic cholesterol provided by LDL-cholesterol is diverted to bile sterol secretion via a bile choleresis process. The inhibition of HMG-CoA reductase and the increase in bile flow induced by alpha-asarone, as well as the decrease in the CSI, could then explain the hypocholesterolemic and cholelitholytic effects of alpha-asarone.     

Influence of zinc on cardiac and serum biochemical parameters in rabbits

The pattern of lipid profiles and organic constituents of cardiac and serum tissues of rabbits were studied on treatment with cholesterol, zinc and zinc + cholesterol. Total carbohydrate and total protein levels were decreased with elevated lipid levels in cholesterol fed rabbits. However, the zinc and cholesterol + zinc fed rabbits showed decreased lipid fractions in cardiac and serum tissues leading to reduced atherosclerotic process in rabbits. These results suggest that the zinc is acting as a hypolipidaemic and anti atherogenic agent in experimental rabbits.     

ABO associations with blood pressure, serum lipids and lipoproteins, and anthropometric measures

Discriminant analysis was used to explore multivariate associations with ABO blood types in a biracial sample of 898 Bogalusa youths. Dependent variables included blood pressure (systolic and diastolic), serum lipid and lipoprotein levels (total cholesterol, alpha-, beta-, and pre-beta-lipoprotein cholesterol, and triglycerides), and anthropometric variables (height, weight, right arm length, triceps skinfold thickness, and a computed ponderal index). Analyses performed within race showed that several variables including beta-lipoprotein cholesterol, systolic blood pressure, and the ponderal index were sufficient to discriminate between individuals possessing the B antigen (B and AB) and those not possessing the B antigen (A and O) in the White subsample. However, height in itself can account for the detected difference, B individuals being taller than non-B individuals by a mean value of 2.4 cm. A concordant, but not significant effect was found in the Black subsample. Further tests support the conclusion that the strongest association is between ABO blood type and height.     

Copper supplementation effects on indicators of copper status and serum cholesterol in adult males

Two 6-wk double-blind studies evaluated the effects of supplements of 2 or 3 mg Cu/d on serum copper, ceruloplasmin, red-blood-cell super oxide dismutase (RBC-SOD), total serum cholesterol, and serum lipoprotein-cholesterol fractions in adult males. Study I had 6 supplemented and 8 placebo subjects, whereas study II had 7 and 6, respectively. Copper supplementation did not appear to affect serum copper levels, RBC-SOD, hematocrit, and ceruloplasmin levels when assayed by radial immunoassay diffusion. Supplementation with 2 mg Cu/d produced an increase in LDL cholesterol and the percentage of cholesterol as LDL at wk 4 compared to the placebo group, and a concomitant decline in VLDL-cholesterol levels and the percentage of cholesterol as VLDL. At wk 6, the percentage of cholesterol as LDL increased and that of cholesterol as VLDL decreased compared to baseline values in the supplemented group. Supplements of 3 mg Cu/d increased hemoglobin levels, ceruloplasmin activity, and serum total-cholesterol levels at wk 6 compared to placebos. Differences in cholesterol may be partly explained by variability in the placebo groups in both studies. Copper supplementation effects on cholesterol deserves further investigation.     

Effects of an alpha-glucosidase inhibitor, acarbose, on blood glucose and serum lipids in streptozotocin-induced diabetic rats

Effects of either a single dose or a long-term administration of an alpha-glucosidase inhibitor, acarbose, on blood glucose, cholesterol concentrations in serum lipoprotein fractions, triglycerides and free fatty acids were examined in streptozotocin-induced diabetic rats. In experiment 1, starch loading tests were performed with or without adding acarbose. The addition of acarbose (0.75 mg per kg of body weight or over) significantly reduced the elevation of blood glucose levels. In experiment 2, the animals were divided into three groups: Group A fed on a control diet, Group B fed on a diet containing 5 mg acarbose in 100 g of diet and Group C fed on a diet containing 20 mg acarbose in 100 g of diet. The food intake in Group C was significantly reduced by 22% as compared to Group A, while the food intake in Group B showed no change. The high dose of acarbose showed a tendency to lower fasting blood glucose levels, but the difference was statistically insignificant. However, postprandial glucose levels in Group C at each period examined and in Group B at 30 days were significantly lower than the counterparts in Group A. Acarbose caused a dose-dependent decrease in serum total cholesterol levels and HDL-cholesterol: total cholesterol ratios were elevated in Group B and C. Serum triglyceride levels in Group B and C were extremely lower than those in Group A on and after 20 days. These results indicate that the addition of acarbose to the diet induces a decrease in postprandial blood glucose levels and simultaneously causes an improvement in lipid metabolism of streptozotocin-induced diabetic rats.     

Rate-limiting, diurnal activity of hepatic microsomal cholesterol-7 alpha-hydroxylase in pigeons with high serum cholesterol

Efficiency of regulating serum cholesterol by cholesterol-7 alpha-hydroxylase was studied in pigeon strains hypo-(SR-39) and hypercholesterolemic (SR-37) with respect to dietary cholesterol. Diurnal hydroxylase activity in SR-37 was 10% of that in strain SR-39 adapted to a light-dark cycle and fed a non-cholesterol diet. Acrophase (6 p.m.) activity was 54-fold greater in SR-39 than in SR-37 pigeons. Dietary cholesterol elevated enzyme activity 2.8-fold in SR-37 pigeons. Dietary cholestyramine plus cholesterol increased hydroxylase activity 21-fold in SR-37 and 3-fold in SR-39 strain; yet, activity remained greater in SR-39. Cholestyramine feeding prevented elevated cholesterol levels in both groups. The circadian rhythms of hydroxylase and serum corticosterone were determined. The diurnal activity in SR-37 was 10% of that in SR-39 and acrophase activity was 34-fold greater in SR-39. Hormone levels were comparable. Programmed acrophase was asynchronous between strains. Hydroxylase activity was positively correlated with corticosterone levels and inversely correlated with serum cholesterol. A defect in the up-regulation of cholesterol-7 alpha-hydroxylase is proposed which limits the catabolism of cholesterol in strain SR-37.     

Dietary fat and cholesterol and serum cholesterol in the gerbil

Groups of gerbils were fed purified diets containing either 10 or 20% of safflower, olive, or coconut oil. Each diet was fed without cholesterol and with 0.1 and 0.2% of added cholesterol. The animals were bled after 2, 4, and 8 wk for the determination of the level of serum cholesterol. The major factors affecting the level of serum cholesterol were the kind of dietary oil, the amount of dietary cholesterol, and the length of time the diet was fed. The level of safflower oil had a statistically significant effect but the level of olive or coconut oil had no significant effect. Various other statistically significant interactions were observed which make simple interpretations of the data difficult. The levels of serum cholesterol achieved in the gerbils fed the different oils with no or very low levels of dietary cholesterol were similar to those seen in men fed the same oils. Although the gerbil is apparently resistant to the development of atherosclerosis, it may be a useful model for studying the effect of dietary fats upon cholesterol metabolism.     

Effect of alfalfa meal in diets of laying quails on performance, egg quality and some serum parameters

This study was conducted to investigate the effects of increasing levels of alfalfa meal in the diet of laying quails on egg production, feed consumption, feed efficiency, egg quality, egg yolk cholesterol and selected serum parameters. In this study, 192, 10-week old quails (Coturnix coturnix japonica) were evenly distributed to four groups with four replicates of 12 quails each. The control group was fed a basal diet containing 0% alfalfa meal and the remaining groups received 3, 6 or 9% alfalfa meal for 12 weeks. Live weight, feed consumption, and egg production were recorded and feed efficiency were calculated. Eggs were examined for interior and exterior quality and egg yolk cholesterol content. At the end of the experiment, blood samples were collected and sera were analysed for serum Ca, inorganic P (P(i)), Mg, triglycerides and total cholesterol. Any level of alfalfa meal had no effect on live weight, egg production, feed consumption, feed efficiency, egg weight, and egg yolk index. Six percent and 9% alfalfa meal increased specific gravity of whole egg and eggshell thickness as well as serum P(i) levels. Nine percent alfalfa meal reduced serum triglycerides, total cholesterol levels and egg yolk cholesterol content. The results of this experiment indicated that addition of 9% alfalfa meal into the laying quail diet may improve eggshell quality and reduced serum triglycerides and serum and egg yolk cholesterol without any adverse effect on performance.     

Comparison of demography, diet, lifestyle, and serum lipid levels between the Guangxi Bai Ku Yao and Han populations

Bai Ku Yao is an isolated subgroup of the Yao minority in China. Little is known about dyslipidemia in this population. The aim of this study was to compare the effects of demography, diet, and lifestyle on serum lipid levels between the Bai Ku Yao and Han populations. A total of 1,170 subjects of Bai Ku Yao and 1,173 subjects of Han Chinese aged 15-89 years were surveyed by a stratified randomized cluster sampling. The levels of total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, apolipoprotein A-I (apoA-I), and apoB were significantly lower in Bai Ku Yao than in Han. Physical activity level and total dietary fiber intake were higher, whereas body mass index (BMI), waist circumference, total energy intake, and total fat intake were lower in Bai Ku Yao than in Han. Hyperlipidemia was positively correlated with BMI, waist circumference, and total energy and total fat intakes and negatively associated with physical activity level and total dietary fiber intake in both populations, but it was positively associated with age and alcohol consumption only in Han. The differences in the lipid profiles between the two ethnic groups were associated with different dietary habits, lifestyle choices, and levels of physical activities.     

Lamotrigine and phenytoin, but not amiodarone, impair peripheral chemoreceptor responses to hypoxia.

Amiodarone, lamotrigine, and phenytoin, common antiarrhythmic and antiepileptic drugs, inhibit a persistent sodium current in neurons (I(NaP)). Previous results from our laboratory suggested that I(NaP) is critical for functionality of peripheral chemoreceptors. In this study, we determined the effects of therapeutic levels of amiodarone, lamotrigine, and phenytoin on peripheral chemoreceptor and ventilatory responses to hypoxia. Action potentials (APs) of single chemoreceptor afferents were recorded using suction electrodes advanced into the petrosal ganglion of an in vitro rat peripheral chemoreceptor complex. AP frequency (at Po(2) approximately 150 Torr and Po(2) approximately 90 Torr), conduction time, duration, and amplitude were measured before and during perfusion with therapeutic dosages of the drug or vehicle. Hypoxia-induced catecholamine secretion within the carotid body was measured using amperometry. With the use of whole body plethysmography, respiration was measured in unanesthesized rats while breathing room air, 12% O(2), and 5% CO(2), before and after intraperitoneal administration of amiodarone, lamotrigine, phenytoin, or vehicle. Lamotrigine (10 microM) and phenytoin (5 microM), but not amiodarone (5 microM), decreased chemoreceptor AP frequency without affecting other AP parameters or magnitude of catecholamine secretion. Similarly, lamotrigine (5 mg/kg) and phenytoin (10 mg/kg) blunted the hypoxic but not the hypercapnic ventilatory response. In contrast, amiodarone (2.5 mg/kg) did not alter the ventilatory response to hypoxia or hypercapnia. We conclude that lamotrigine and phenytoin at therapeutic levels impair peripheral chemoreceptor function and ventilatory response to acute hypoxia. These are consistent with I(NaP) serving an important function in AP generation and may be clinically important in the care of patients using these drugs.     

Effect of Alfalfa Meal in diets of laying quails on performance,egg quality and some serum parameters

This study was conducted to investigate the effects of increasing levels of alfalfa meal in the diet of laying quails on egg production, feed consumption, feed efficiency, egg quality, egg yolk cholesterol and selected serum parameters. In this study, 192, 10-week old quails (Coturnix coturnix japonica) were evenly distributed to four groups with four replicates of 12 quails each. The control group was fed a basal diet containing 0% alfalfa meal and the remaining groups received 3, 6 or 9% alfalfa meal for 12 weeks. Live weight, feed consumption, and egg production were recorded and feed efficiency were calculated. Eggs were examined for interior and exterior quality and egg yolk cholesterol content. At the end of the experiment, blood samples were collected and sera were analysed for serum Ca, inorganic P (P_i), Mg, triglycerides and total cholesterol. Any level of alfalfa meal had no effect on live weight, egg production, feed consumption, feed efficiency, egg weight, and egg yolk index. Six percent and 9% alfalfa meal increased specific gravity of whole egg and eggshell thickness as well as serum P_i levels. Nine percent alfalfa meal reduced serum triglycerides, total cholesterol levels and egg yolk cholesterol content. The results of this experiment indicated that addition of 9% alfalfa meal into the laying quail diet may improve eggshell quality and reduced serum triglycerides and serum and egg yolk cholesterol without any adverse effect on performance.     

Amiodarone-induced changes in lipid metabolism

Hypothyroidism is a major cause of secondary hypercholesterolemia. Amiodarone treatment alters both the levels of serum lipids and thyroid hormones. We investigated whether the amiodarone-induced changes in lipid metabolism are related to the changes in thyroid hormone levels. Eighteen patients received amiodarone (31 +/- 3 g cumulative dose) for six weeks. Serum triglyceride, total-cholesterol, high density lipoprotein-cholesterol and its subfractions, apolipoproteins B and AI, and plasma post-heparin lipoprotein lipase and hepatic triglyceride lipase activities were determined. Amiodarone treatment caused significant increases in serum total-cholesterol (baseline 4.4 +/- 0.21 (SE), 6 weeks 5.12 +/- 0.26 mmol/l, P less than 0.01), in low density lipoprotein cholesterol (baseline 2.61 +/- 0.26, 6 weeks 3.36 +/- 0.21 mmol/l, P less than 0.05) and in apolipoprotein B (baseline 1.95 +/- 0.15, 6 weeks 2.26 +/- 0.13 mmol/l, P less than 0.01) concentrations. Serum high density lipoprotein and its subfractions, or apolipoprotein AI levels did not change. Plasma post-heparin lipoprotein lipase activity increased (baseline 137 +/- 21, 6 weeks 168 +/- 21 U/ml, P less than 0.01) while hepatic triglyceride lipase did not change. Amiodarone also caused an increase in serum thyroxine (baseline 110 +/- 8, 6 weeks 136 +/- 6 mmol/l, P less than 0.05), although values remained in euthyroid range. In summary, amiodarone therapy increased the concentrations of atherogenic lipoproteins in the serum similar to that seen in hypothyroidism. On the other hand the effect of amiodarone on lipoprotein lipase was opposite to that seen in hypothyroidism. Therefore, amiodarone-induced changes in lipid metabolism cannot be explained solely on the basis of the changes in circulating thyroid hormone levels.     

Relationship between exercise-induced changes in serum and hepatic cholesterol metabolism in rats

The purpose of the present study was to determine the effects of exercise training on serum cholesterol level and hepatic cholesterol metabolism in rats. Twenty-four male Wistar strain rats, aged 6 weeks, were assigned to one of three experimental groups; control (n = 8), exercised 20 minutes a day (E20, n = 8), and exercised 60 minutes a day (E60, n = 8). Rats were sacrificed after ten weeks exercise. The levels of serum total cholesterol and HDL-cholesterol in the group E20 and group E60 were lower than that of control, 8% and 24% (p less than 0.01) for the total cholesterol and 10% and 24% (p less than 0.05) for the HDL-cholesterol, respectively. The activity of HMG-CoA reductase in liver microsome was significantly higher in the group E60 than that of control. The hepatic microsomal HMG-CoA reductase activity was negatively related to serum total (r = -0.62, p less than 0.01) and HDL (r = -0.58, p less than 0.01) cholesterol levels. From these results, we concluded that the enhancement of the cholesterol metabolism in the liver by exercise is a major course of the exercise-induced change in serum cholesterol of Wistar rats.     

Influence of high density lipoprotein (HDL), prepared from human blood, on prostanoid formation, serum and tissue lipids and development of arteriosclerosis in cholesterol rich fed rabbits

The i.v. administration of high density lipoprotein (HDL) into cholesterol fed rabbits decreased statistically significantly the serum level of total cholesterol and of low density lipoprotein cholesterol after a feeding period of 8 weeks. These diminished levels of cholesterol were associated with a statistically significant reduction in the levels of cholesterol esters in kidneys and platelets but not in hepatic tissue or in aorta. Macroscopically detectable arteriosclerosis was not statistically significantly diminished. The formation of prostanoids by the aorta remained unchanged. The atherogenic role of immunologic factors acting against the heterologous HDL may have compensated for the antiatherogenic HDL action on plasma and tissue lipids.     

The serum apo B and apo E in rats following cholesterol diet and thymus treatment

The serum levels of apo B and apo E in rats fed on a diet rich in cholesterol before and after thymus treatment were determined by the authors. The diet enriched with cholesterol increases the serum levels of apo E and of the large and small species of apo B. After treatment the large apo B and the small one strongly decrease, while apo E increases further. These data support the hypothesis that the dropping of total cholesterol, after thymus treatment, cannot be ascribed to apo E decrease but possibly to B-apoproteins.     

Associations between serum cholesterol and immunophenotypical characteristics of circulatory B cells and Tregs

Blood lipids play a major role in the manifestation of cardiovascular diseases. Recent research suggested that there are connections between cholesterol levels and immunological alterations. We investigated whether there is an association between serum cholesterol levels (total, HDL, and LDL) and immune cells (B cell and regulatory T cells [Tregs]). The analysis was based on data from 231 participants of the MEGA study in Augsburg, Germany, recruited between 2018 and 2021. Most participants were examined two different times within a period of 9 months. At every visit, fasting venous blood samples were taken. Immune cells were analyzed immediately afterward using flow cytometry. Using multivariable-adjusted linear regression models, the associations between blood cholesterol concentrations and the relative quantity of several B-cell and Treg subsets were analyzed. We found that particularly HDL cholesterol concentrations were significantly associated to some immune cell subpopulations: HDL cholesterol showed significant positive associations with the relative frequency of CD25++ Tregs (as proportion of all CD4+CD25++ T cells) and conventional Tregs (defined as the proportion of CD25+CD127− cells on all CD45RA−CD4+ T cells). Regarding B cells, HDL cholesterol values were inversely associated with the cell surface expression of IgD and with naïve B cells (CD27−IgD+ B cells). In conclusion, HDL cholesterol levels were associated with modifications in the composition of B-cell and Treg subsets demonstrating an important interconnection between lipid metabolism and immune system. Knowledge about this association might be crucial for a deeper and more comprehensive understanding of the pathophysiology of atherosclerosis.     

Dietary influences on serum lipids and lipoproteins

Substantial data are available to indicate that the diet influences serum levels of cholesterol and lipoproteins. These data are derived from studies in laboratory animals, from epidemiologic studies, and from human investigations. Most research has focused on effects of diet on serum total cholesterol concentrations. In recent years, however, attention has shifted to individual lipoproteins, i.e., low density lipoproteins (LDL), high density lipoproteins (HDL), and very low density lipoproteins (VLDL). Three nutritional factors have been identified that raise serum LDL levels; these are saturated fatty acids, cholesterol itself, and excess caloric intake leading to obesity. The major cholesterol-raising saturated fatty acid in the diet is palmitic acid. Several nutrients can be substituted for saturated fatty acids to produce a reduction in LDL-cholesterol levels. These are polyunsaturated fatty acids, monounsaturated fatty acids, carbohydrates, and even one saturated fatty acid, stearic acid. The latter appears to be converted rapidly into a monounsaturated fatty acid in the body. Any of these nutrients can be used for replacement of cholesterol-raising saturated fatty acids in the diet. However, their relative effects on other metabolic processes remain to be determined fully. At present it appears that carbohydrates and monounsaturated fatty acids represent the preferred replacements for saturated fatty acids, although modest increases in polyunsaturated fatty acids and stearic acid, at the expense of cholesterol-raising saturates, probably are safe and may provide for greater variety in the diet.