Fatty acid composition in chronic heart failure: low circulating levels of eicosatetraenoic acid and high levels of vaccenic acid are associated with disease severity and mortality.

OBJECTIVES: Free fatty acids (FFAs) are the major energy sources of the heart, and fatty acids (FAs) are active components of biological membranes. Data indicate that levels of FAs and their composition may influence myocardial function and inflammation. The aim of this study was to investigate whether total levels and composition of FAs and FFAs in plasma are altered in clinical heart failure (HF) and whether any alterations in these parameters are correlated with the severity of HF. SUBJECTS: Plasma from 183 patients with stable HF was compared with plasma from 44 healthy control subjects. RESULTS: Our main findings are as follows: (i) patients with HF had decreased levels of several lipid parameters and increased levels of FFAs in plasma, compared with controls, which were significantly correlated with clinical disease severity. (ii) Patients with HF also had a decreased proportion in the plasma of several n-3 polyunsaturated FAs, an increased proportion of several monounsaturated FAs, and a decreased proportion of some readily oxidized long-chain saturated FAs. (iii) These changes in FA composition were significantly associated with functional class, impaired cardiac function (i.e., decreased cardiac index and increased plasma N-terminal pro-B-type natriuretic peptide levels) and enhanced systemic inflammation (i.e., increased high-sensitivity C-reactive protein levels). (iv) Low levels of C20:4n-3 (eicosatetraenoic acid) and in particular high levels of C18:1n-7 (vaccenic acid) were significantly associated with total mortality in this HF population. CONCLUSIONS: Our data demonstrate that patients with HF are characterized by a certain FA phenotype and may support a link between disturbed FA composition and the progression of HF.

Tetradecylthioacetic acid attenuates dyslipidaemia in male patients with type 2 diabetes mellitus, possibly by dual PPAR-alpha/delta activation and increased mitochondrial fatty acid oxidation.

AIM: We previously demonstrated that a modified fatty acid, tetradecylthioacetic acid (TTA), improves transport and utilization of lipids and increases mitochondrial fatty acid oxidation in animal and cell studies. We conducted an exploratory study of safety and effects of this novel drug in patients with type 2 diabetes mellitus and investigated the mechanism of action in human cell lines. METHODS: Sixteen male patients with type 2 diabetes mellitus received 1 g TTA daily for 28 days in an open-labelled study, with measurement of parameters of lipid metabolism, glucose metabolism and safety (ClinicalTrials.gov NCT00605787). The mechanism of action was further investigated in a human liver cell line (HepG2) and in cultured human skeletal muscle cells (myotubes). RESULTS: Mean LDL cholesterol level declined from 4.2 to 3.7 mmol/l (p < 0.001), accompanied by increased levels of the HDL apolipoproteins A1 and A2, and a decline in LDL/HDL ratio from 4.00 to 3.66 (p = 0.008). Total fatty acid levels declined, especially the fraction of the polyunsaturated n-3 fatty acids docosahexaenoic acid (-13%, p = 0.002) and eicosapentaenoic acid (-10%, p = 0.07). Glucose metabolism was not altered and the drug was well tolerated. In cultured liver cells, TTA acted as a pan-PPAR agonist with predominant PPAR-alpha and PPAR-delta activation at low TTA concentrations. In myotubes, TTA and a PPAR-delta agonist, but not the PPAR-alpha or PPAR-gamma agonists, increased the fatty acid oxidation. CONCLUSIONS: We demonstrate for the first time that TTA attenuates dyslipidaemia in patients with type 2 diabetes mellitus. These effects may occur through mechanisms involving PPAR-alpha and PPAR-delta activation, resulting in increased mitochondrial fatty acid oxidation.

Regulation of gene expression for lipogenic enzymes in the liver and adipose tissue of hereditary hypertriglyceridemic, insulin-resistant rats: effect of dietary sucrose and marine fish oil.

Hypertriglyceridemia is closely linked to insulin resistance. Increased dietary intake of n-3 polyunsaturated fatty acids reverses both hypertriglyceridemia and insulin resistance. To evaluate molecular mechanisms responsible for the hypotriglyceridemic effects of n-3 polyunsaturated fatty acids, the expression of genes for lipogenic enzymes in liver and white and brown adipose tissue was estimated in hereditary hypertriglyceridemic rats which underwent an euglycemic hyperinsulinemic clamp. Before the clamp, animals were fed a basal or a high (63%) sucrose diet with or without fish oil for two weeks. Results were compared to data obtained from control animals subjected to the identical protocol. In hereditary hypertriglyceridemic rats, gene expression for malic enzyme was increased in liver and in brown adipose tissue but not in white adipose tissue. The high sucrose diet raised malic enzyme mRNA levels in liver of both hereditary hypertriglyceridemic and control rats, and this effect was more pronounced in brown adipose tissue. Supplementing the high sucrose diet with fish oil led to a suppression of malic enzyme gene expression in liver and brown adipose tissue of control rats. However, this inhibitory effect was not as pronounced in the hereditary hypertriglyceridemic rats. Raised levels of fatty acid synthase mRNA in liver and brown adipose tissue of control rats fed high sucrose diet were suppressed by consumption of diet high in n-3 fatty acids. On the other hand, in hereditary hypertriglyceridemic rats fed high sucrose diet, fish oil supplementation failed to suppress increased levels of fatty acid synthase mRNA in liver and in brown adipose tissue. It appears that hereditary hypertriglyceridemic rats have elevated levels of mRNA for lipogenic enzymes in liver and brown adipose tissue and dietary control leading to an alteration of hypertriglyceridemia influences gene expression of lipogenic enzymes only under special dietary circumstances.

Effect of illuminated nifedipine, a potent antioxidant, on intestinal and vascular smooth muscles.

1. The effects of nifedipine (Nif) and its illuminated nitroso product nitrosopine (NTP) were investigated on lipid peroxidation, KCl elevated smooth muscle tension, and ionic currents of single smooth muscle cells. 2. Illumination of Nif at 400-700 nm within 24-48 h changed it completely to a potent antioxidant, NTP. 3. Nif relaxed the KCl-induced contractions of guinea-pig taenia caeci and rat aorta and reduced the amplitude of the evoked inward Ca2+ current of taenia caeci cells in a concentration-dependent manner. NTP (up to 100 microM) was ineffective in this respect. Pretreatment by NTP (10 microM) did not affect the actions of Nif. 4. The evidence suggests that NTP, generated by day-light illumination from Nif, exerts antioxidant activity but is devoid of voltage-dependent Ca2+ channel (VDC) blocking property and does not interfere with the action of Nif on the smooth muscle cell membrane VDC.

Increased thyroid volume and prevalence of thyroid disorders in an area heavily polluted by polychlorinated biphenyls.

OBJECTIVE: To evaluate whether long-term exposure to heavy environmental pollution with polychlorinated biphenyls (PCBs) could result in impairment of thyroid status as evaluated by an epidemiological field survey. METHODS: Thyroid volume (ThV) was measured by ultrasound in 238 employees of a factory (EMP) which previously produced PCBs and 454 adolescents from the surrounding area polluted by PCBs. Controls (C) were 572 adults and 965 adolescents from much less polluted areas. In the 238 EMP and various numbers (shown in parentheses) of adult C the levels of thyroid-stimulating hormone (TSH) (n = 498), thyroxine (n = 498), thyroglobulin (n = 278) and thyroid antibodies (anti-peroxidase (TPO Ab), n= 517; anti-thyroglobulin (Tg Ab), n=455; anti-TSH receptor (TSHR Ab), n=238) were estimated in serum, while only TSH and TPO Ab were measured in 269 and 171 adolescents from polluted and control areas respectively. In several subjects in whom thyroid disease was suspected, total tri-iodothyronine or free thyroxine and tri-iodothyronine were measured. In a total of 362 adults and adolescents the urinary iodine was estimated. RESULTS: Using the Mann-Whitney test, ThV in EMP (mean+/-S.E. = 18.85+/-0.69 ml, median= 17.3 ml, upper quartile=22.9 ml, n=238) was significantly higher (P< 0.001) than that in C (13.47+/-0.48 ml, 11.5 ml, 15.3 ml, n = 486 respectively). Similarly, ThV in adolescents from the polluted area (9.37+/-0.17 ml, 8.9 ml, 11.0 ml, n = 454 respectively) was significantly higher (P< 0.001) than that in C (8.07+/-0.10 ml, 7.6 ml, 9.6 ml, n = 965 respectively). In adults, a significantly increased prevalence of TPO Ab (P<0.05) was found (using the chi-square test) in EMP women of all ages (54/190) vs C women (70/282), in EMP women aged 31-50 years (40/117 vs 70/282 respectively) and those aged 41- 50 years (28/77 vs 54/215 respectively). Compared with C, there was also a higher prevalence of Tg Ab in EMP women aged 31-60 years (36/169 vs 50/342 respectively) and of TSHR Ab (P< 0.001) in the group of EMP men and women (25/238) vs sex- and age-matched C (6/238). No difference between EMP and C was found in the level of thyroxine (mean+/-S.D = 116.1+/-31.2 nmol/l, n = 238 vs 112.2+/-37.0 nmol/l, n = 460 respectively), TSH in the range 0.1-4.5 mU/l(1.56+/-0.86 mUl/l, n = 219 vs 1.51+/-0.84 mU/l, n = 460 respectively), prevalence of TSH >4.5 (14/238 vs 28/498 respectively) and <0.1 mU/l(5/238 vs 10/498 respectively). The prevalence of individuals without any defined clinical or laboratory signs of thyroid disorders among EMP who had worked in the factory for 21-35 years (43/128, 33.6%) was significantly lower than that in twice as many matched C (118/256, 46.1%, P< 0.025) or in EMP who had worked for only 11-20 years (36/73, 49.3%, P< 0.05). In adolescents, no difference was found in the prevalence of TPO Ab or TSH >4.5 mU/l between the polluted (17/269, 6.3%, and 2/243, 0.8% respectively) and C areas (15/171, 8.5% and 4/140, 2.8% respectively). The median values of urinary iodine were in the optimal range (microg per dl/number of cases) and about the same in polluted (12.6/90 and 11.4/55) and C areas (14.1/80, 13.2/82 and 13.4/55). CONCLUSIONS: Since iodine intake in Slovakia is considered sufficient as a result of 45 years of well-monitored iodine prophylaxis, the increased ThVand prevalence of thyroid disorders in the polluted areas presumably results from long-term exposure to toxic substances rather than from a difference in life-long iodine intake. The increased prevalence of some thyroid antibodies may be related to the known immunomodulatory effects of PCBs.

The effect of hyperlipidemia on serum fatty acid composition in type 2 diabetics.

Fatty acid (FA) profiles of total serum lipids were determined by capillary gas chromatography in Type 2 diabetic patients (NIDDM) with diverse types of hyperlipidemia. In patients with hypertriglyceridemia (DM-HTG) and combined hypertriglyceridemia and hypercholesterolemia (DM-HLP), a significantly different total FA composition was found compared with healthy controls or diabetics with normal serum lipids. In particular, the proportions of saturated and monounsaturated FA were increased and the proportions of n-6 polyunsaturated FA were decreased. In DM-HLP patients, PUFA n-6 metabolites and C20-C22 PUFA were also decreased. Thus, hyperlipidemia shifts significantly the serum FA composition in NIDDM patients into an atherogenic profile. More study is needed, however, to understand if serum FA changes may contribute to the increased atherogenesis commonly found in these patients.

Fatty acid composition in fractions of structural and storage lipids in liver and skeletal muscle of hereditary hypertriglyceridemic rats.

The fatty acid (FA) compositions of liver and skeletal muscle structural lipids, overall phospholipids and phosphatidylcholine, and triglycerides (TG) were determined in the hereditary hypertriglyceridemic (HTG) rat, a nonobese animal model of the insulin resistance syndrome. Four groups of HTG rats and four groups of control animals were fed equal-energy diets for two weeks: basal (B), high-sucrose (HS), or fish oil-supplemented basal (BFO) or high-sucrose (HSFO) diets. In the liver of HTG rats, a decrease of n-6 long-chain polyunsaturated FA (PUFA), especially in 20:4n-6, in comparison with controls was found. Moreover, a concomitant accumulation of 18:2n-6 in structural lipids was observed. These differences were more pronounced in liver than in skeletal muscle. HS feeding raised the proportion of 18:1n-9 and decreased 18:2n-6 in lipid fractions. In both tissues and in both strains, the amounts of long-chain n-3 PUFA, as well as the level of total C20-22 PUFA, went up after fish oil feeding. However, the effects were somewhat less pronounced in the HTG rats. The increase in n-3 PUFA occurred mainly at the expense of reduced levels of 18:2n-6 in structural lipids and of 18:1n-9 in triglycerides. These changes were associated, in companion studies reported in this volume, with improved insulin action in HTG rats. In conclusion, the FA composition in lipid subclasses of HTG rats differs significantly from the controls mainly in liver structural lipids, suggesting the impairment of PUFA desaturation. Dietary change effected a similar modulation of FA profile across both strains, with fish oil increasing the levels of long-chain PUFA toward control values in the NTG rats. The HTG rat thus provides an interesting animal model for the study of impaired fatty acid metabolism.

Possible role of genetic factors in thyroid growth rate and in the assessment of upper limit of normal thyroid volume in iodine-replete adolescents.

The objective of this study was to answer the question whether thyroid volume in adolescent siblings of similar age and a life-long sufficient iodine intake is uniform. If different, it would indicate that genetic or environmental factors unrelated to iodine intake can influence thyroid growth. We measured thyroid volume by ultrasound in: (1) 251 sibling pairs (SP) and 19 sibling triads 10 to 18 years of age. The age range of each SP was less than 24 months and of each triad less than 42 months; (2) 28 monozygotic and 13 dizygotic sets of twins 7 to 18 years of age. The sibling pairs were retrospectively divided into 3 groups irrespective of age (thyroid volume as means+/-S.E. mL/m2). Group 1: 159 pairs with low thyroid volume in both siblings; mean thyroid volume of each pair less than 5.00 mL/m2 (3.96+/-0.05, median 4.08, range 2.07-4.98); group 2: 69 pairs with high thyroid volume in both siblings; mean thyroid volume greater than 5.00 mL/m2 (5.85+/-0.12, median 5.57, range 5.03-11.02); group 3: 23 pairs with low thyroid volume in 1 sibling (3.53+/-0.15, median 3.53, range 1.71-4.91) and high thyroid volume in another (7.36+/-0.23, median 7.18, range 5.96-10.30). The majority of triads, monozygotic, and dizygotic twins resembled group 1, a few resembled group 2, and only 3 triads and 1 set of dizygotic twins resembled group 3. Among monozygotic twins, there was no pair with a strikingly discordant thyroid volume and only 1 such pair was found among dizygotic twins. In monozygotic twins, the thyroid volume was almost identical (mean difference 0.34+/-0.06 mL/m2) and significantly less (p < 0.012) than in dizygotic twins (0.9+/-0.25 mL/m2). Among 502 children of 251 sibling pairs the frequency of high thyroid volume (>5.00 mL/m2) was greater in girls (103/279, 36.9%, p < 0.01) than in boys (49/223, 22.0%). The same was true for the frequency of hypoechogenicity (42/279 or 15.0% in girls vs. 12/223 or 5.4% in boys; p < 0.01). The frequency of hypoechogenicity in both sexes of the combined groups 2 and 3 (40/186, 21.5%) was higher (p < 0.001) than in group 1 (14/316, 4.4%). All siblings examined lived in a common household with their parents, eating the same daily meals at home and school. Our results suggest that the observed differences in thyroid volume of siblings were not related to iodine intake, but to other factors, eg, genetic and environmental. It is not clear whether the children with high thyroid volume and increased frequency of hypoechogenicity should be included into the recently recommended range of normal thyroid volume for adolescents.

Pharmacokinetic study of stobadine.

The aim of this paper is to provide a brief overview of most important results of stobadine kinetic studies in rats, dogs, and human volunteers. In these studies, stobadine dihydrochloride and stobadine dipalmitate was used for intravenous and oral administration, respectively. To evaluate kinetic properties of stobadine and its metabolites, TLC, HPLC, GLC, GC-MS, radiometric, and fluorometric methods were developed and used.

Further studies of blood levels of some tumor markers in the area polluted by polychlorinated biphenyls and control population.

The levels of beta2-microglobulin (beta2-m), alpha-fetoprotein (AFP) and thyroglobulin (TG) were measured in the serum of 245 employees of chemical factory formerly producing polychlorinated biphenyls (PCB) consisting of 54 males (age range 24-65 years, median 45) and 191 females (age range 20-69 years, median 45). The control population consisted of 636 adults from control areas of northwest and east Slovakia. The frequency of beta2-microglobulin levels lower than 1.6 microg/ml in 242 employees of chemical factory was 76.8% (186/242) which was three times higher (P<0.001) than 24.4% (155/635) in 636 controls. Still more remarkable difference was obtained when using the cut/off level of 1.2 microg/ml, the frequency of such values in the employees being 45.4% (110/242) vs. 4.4% (28/635) in the controls. In contrast, no difference in alpha-fetoprotein levels was observed between the employees and the controls, the respective frequency of these < 5.0 ng/ml being 87.6% (212/242) vs. 86.2% (389/451) and these < 10.0 ng/ml being 100.0% (242/242) vs. 97.8% (441/451). Similarly, the frequency of normal thyroglobulin levels < 50.0 ng/ml) did not differ, being 95.6% (174/182) in the employees and 87.9% (87/99) in the controls. Most of a total of 20 cases with thyroglobulin level > 50.0 ng/ml showed sonographicaly enlarged and multinodular thyroid with focal or diffuse hypoechogenicity, three of them showed solitary nodule with a diameter > 10 mm. Although the decreased levels of beta2-microglobulin might be somehow related to the modulation of immune system, more plausible explanation appears to be the possible impairment of renal tubules by PCB similar to that caused by heavy metals resulting in increased urinary excretion of beta2-microglobulin and decrease of its blood level.

Hepatobiliary disposition of 3'-azido-3'-deoxythymidine (AZT) in the rat: effect of phenobarbitone induction.

Isolated liver with a recirculating perfusate was used to study 3'-azido-3'-deoxythymidine (AZT) disposition in phenobarbitone-pretreated rats at 68 microM AZT concentration in the reservoir. Clearance of AZT in the livers obtained from control animals was 0.42 +/- 0.01 (mean +/- s.d.) mL min-1/10 g liver. Over the study period of 105 min, 12.7 +/- 2.6% of the dose was excreted in bile and of this 95% was recovered as 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranuronosylthymidine (GAZT). The amount of GAZT found in the perfusate after 105 min of liver perfusion was < 1% of the AZT dose introduced into the reservoir. Phenobarbitone pretreatment of rats resulted in a 5.5-fold increase of AZT clearance. In addition, the area under the perfusate concentration-time curve (AUC0-105 min) for 3'-amino-3'-deoxythymidine (AMT) and for a catabolite of unknown structure was increased 3- and 10-fold, respectively, and the amount of AZT dose excreted in the bile was nearly doubled. Thus phenobarbitone was capable of stimulating both detoxification of AZT to GAZT and bioactivation of AZT to AMT, a catabolite known to be highly toxic to human bone marrow cells. This induction was the result of enhancement of AZT catabolism rather than its transport into the cells, since on incubation of AZT (0-250 microM) with rat isolated hepatocytes, a linear relationship between concentration and amount taken up by the cells was shown. In addition, the rate of AZT uptake was not influenced by KCN, dinitrophenol, or temperature, which is consistent with a simple diffusion of AZT through the hepatocellular membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased glucose transporter protein (GLUT4) in skeletal muscle of hypertriglyceridaemic insulin-resistant rat.

Protein levels (Western blot) of the major glucose transporter isoform (GLUT4) were measured in skeletal muscles (quadriceps femoris) of an animal model of human metabolic syndrome X, i.e. the hereditary hypertriglyceridaemic (HTG) insulin-resistant rats fed various diets. The results were compared with the data obtained in normal Wistar rats which underwent the identical protocol. In HTG rats fed the basal diet (B) or high-sucrose diet (HS) (known to induce hypertriglyceridaemia and to impair insulin action), a decrease of GLUT4 protein levels (B: Control 100 +/- 3 vs HTG 46 +/- 5%, p < 0.005; HS: Control 80 +/- 9 vs HTG 49 +/- 3%, p < 0.005) was observed. Furthermore, marine fish oil (FO) rich in n-3 polyunsaturated fatty acids (PUFA), added to the basal diet (30 wt % of n-3 PUFA) reduced the GLUT4 protein levels (B: 100 +/- 3 vs B+FO: 42 +/- 4%, p < 0.005) in control rats to values similar to those found in HTG rats (B: 46 +/- 4%). However, dietary FO did not have any effect in HTG rats (49 +/- 3%). Feeding the high-sucrose diet supplemented with FO to both the control and HTG rats was followed by a further decrement of GLUT4 protein (Control 15 +/- 5 vs HTG 14 +/- 4%). In conclusions, a) the hereditary HTG rats had by about 50% lower GLUT4 protein levels in the quadriceps femoris muscle in comparison to normal Wistar rats; b) high-sucrose diet or raised dietary intake of n-3 PUFA did not further alter the number of glucose carriers in quadriceps femoris muscle in HTG rats and c) feeding the high-sucrose diet with higher proportion of n-3 PUFA was associated with an additional reduction of the GLUT4 protein level in this muscle.

Decreased blood level of beta 2-microglobulin in the employees of a factory which produced polychlorinated biphenyls.

Under the project of evaluating the health status of the employees of CHEMKO factory (East Slovakia) which produced PCBs between 1955 and 1985, the level of beta 2-microglobulin (beta 2-m) was measured in the serum of 242 subjects from CHEMKO (Group A) and two control groups from much less polluted areas: 1,277 females from a small mountainous village (Group B), 2,179 adults from the area of a large city of Kosice (Group C). The level of thymidine kinase (TK) was measured in the groups A and B only. In addition, age-matched groups of 155 women each from all areas were evaluated. In both the whole group and the age-matched group from CHEMKO the level of beta 2-m was significantly lower (P < 0.001) than that in the respective control groups, while no difference was found in the level of TK. In conclusion, it is suggested that the decrease of beta 2-m in CHEMKO employees might be related to the immunotoxic effects of organochlorines.

Bioavailability and pharmacokinetic studies in the development of an oral formulation of stobadine dipalmitate.

The pyridoindole stobadine is a novel drug with antioxidant and cardioprotective properties. The objective of this study was to compare the bioavailability and the main pharmacokinetic parameters of two different stobadine dosage forms, STBtest and STBref, after single oral dosing in the form of gelatine capsules to 6 dogs. The dose ranged from 2.9 to 4.7 mg/kg and a randomized two-period crossover design was applied. To quantify the drug in plasma, a GC/MS method was developed with a quantification limit of 1 ng/ml. The time profiles of stobadine plasma concentrations were fitted by pharmacokinetic models. The extent of relative bioavailability ranged between 0.71 and 1.56. Practically no difference was found between the bioavailability rate of the two capsules, expressed as Cmax/AUC, with values ranging from 0.0022-0.0047 min-1 for STBtest and 0.0022-0.0045 min-1 for STBref. In conclusion, the technological difference of the capsules investigated did not yield deviations in either their extent or rate of absorption. Therefore the two stobadine formulations were concluded to be bioequivalent.

The effect of the new oral hypoglycemic agent A-4166 on glucose turnover in the high fat diet-induced and/or in the hereditary insulin resistance of rats.

A-4166, a phenylalanine derivative, is a hypoglycemic agent, which has been shown to improve blood glucose levels mainly due to the rapid and short term stimulation of insulin release. Nevertheless, a possible extrapancreatic action of A-4166 has not yet been investigated. Therefore, insulin action (euglycemic hyperinsulinemic 6.4 mU.kg-1.min-1 clamp plus 3H-2-deoxyglucose tracer administration) was studied after 3 weeks on either standard (BD) or high fat (HF) diet in normal control (C) or in hereditary insulin resistant (hHTg) rats which were given a single dose of A-4166 (10 mg per kg BW, i.v.) 60 min after clamp commencement. HF feeding reduced the glucose infusion rate (GIR) required to maintain euglycemia to about 50% of C (p < 0.001). In hHTg rats, HF did not further pronounce the pre-existing decrease of GIR of hHTg animals fed BD. A-4166 changed GIR neither in C, nor in the hHTg group. The estimated glucose disposal (Rd) (C-BD: 32.3 +/- 1.9 vs C-HF: 25.5 +/- 1.9 mg.kg-1.min-1, p < 0.001) and glucose metabolic index (Rg') in skeletal muscles (Q. femoris: C-BD: 25.6 +/- 1.5 vs C-HF: 12.3 +/- 1.1 mmol.100 g-1.min-1, p < 0.001) were reduced by HF in control rats but were not restored by a concomitant bolus of A-4166. Nevertheless, in hHTg rats fed the HF diet a single dose of A-4166 brought back their Rd (hHTg-HF: 23.5 +/- 1.3 vs hHTg-HF plus A-4166: 31.0 +/- 3.5 p < 0.03) and Rg' (Soleus muscle: hHTg-HF: 29.2 +/- 3.2 vs hHTg-HF plus A-4166: 41.3 +/- 4.0) to values of the control group on BD. In summary, a) a single bolus administration of A-4166 to the control or to the insulin resistant hHTg rats, fed either the BD or HF diets, did not abolish the reduction of GIR required to maintain euglycemia during hyperinsulinemic clamps; b) nevertheless, A-4166 caused a significant increase of the estimated plasma glucose disposal (Rd) and skeletal muscle glucose metabolic index (Rg') of hHTG rats fed the HF diet; c) we suggest that A-4166 may have an extrapancreatic action but this needs to be proven using a long-term administration plan of A-4166.

Influence of methylfenpropidine on growth, sterol content and fatty acid composition of Candida albicans.

The effect of methylfenpropidine on growth, lipid contents, sterol and fatty acid composition was investigated in 5 strains of Candida albicans. The sensitivity of the strains decreased in the order: wild strains > erg+ ade nysR > ade nysR erg (defective delta (8-7)-isomerase) > ade nysR erg (defective delta 5-desaturase). The presence of the inhibitor influenced fecosterol isomerization, episterol dehydrogenation, zymosterol transmethylation, ignosterol reduction and squalene epoxidation. Methylfenpropidine also induced changes in fatty acid composition, causing a reduction of the palmitic and oleic acid content with a concomitant elevation of stearic, linoleic and linolenic acid levels. The lipid unsaturation index slightly increased. Morphological changes of wild strains were observed after the fungicide treatment.

[Determination of functional "lipid age" on the basis of analysis of serum fatty acids]. / Urcovanie funkcného "lipidového veku" na základe analýzy mastných kyselín séra.

The composition of total fatty acids was analyzed in the serum of subjects with normal lipid and glycide metabolism, aged 20 to 89 years. A mathematico-empirical procedure was applied and on using the method of multiple linear regression the formulas of biological function age, designated as lipid age, were established, with individual serum fatty acids and their ratios in relation to characteristic attributes of markers of aging as independent variable parameters. Further correction of lipid age to the chosen level of 60 years was described and the thus corrected lipid age was expressed in percentages. Application of the obtained formulas of lipid age in the series studied showed that the increase rate of lipid age was higher in men by an average of 5.5% compared to women, which represents a difference of 3.8 years. The obtained results demonstrate a significant relationship of fatty acids to the process of aging and their potential use in evaluating processes affecting lipid metabolism.

[Comparison of the effect of nifedipine and verapamil on lipid metabolism in experimental atherosclerosis in rabbits]. / Porovnanie vplyvu nifedipínu a verapamilu na metabolizmus lipidov pocas experimentálnej aterosklerózy u králikov.

The aim of the work was to study the effect of 8-week treatment with two calcium channel blockers on some parameters of lipid metabolism in rabbits. Experimental atherosclerosis was induced by 1% cholesterol diet. The calcium channel blockers were administered twice daily in the following doses: nifedipine 1.0 mg.kg-1 and verapamil 2.0 mg/kg-1 x day-1. The treatment with calcium channel blockers enhanced the level of total cholesterol as well as of triglycerides and decreased the HDL: total cholesterol ratio in all the experimental groups. The changes induced by nifedipine were, however, less significant compared to the effect of verapamil. The absolute amount of fatty acids determined by gas chromatography was lower after nifedipine administration in comparison to the verapamil treated group. Nifedipine induced a more favorable proportion in the composition of fatty acids. The increase in the level of monounsaturated fatty acids (palmitoleic and oleic acid) as well as the decrease in the level of polyunsaturated fatty acids (especially linoleic acid) was the lowest in the nifedipine treated group. (Fig. 6, Ref. 30.).