Suppression of Non-Esterified Fatty Acids and Triacylglycerol in Experimental Animals by the Adenosine Analogue GR79236

1993 ◽  
Vol 84 (6) ◽  
pp. 663-669 ◽  
Author(s):  
P. Strong ◽  
R. Anderson ◽  
J. Coates ◽  
F. Elus ◽  
B. Evans ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Oral Administration ◽  
Dose Range ◽  
Blood Concentrations ◽  
Esterified Fatty Acids ◽  
Pithed Rats ◽  
A1 Receptor ◽  
Isolated Adipocytes ◽  
Dose Dependent

1. This is the first description of the metabolic activity of a novel adenosine A1-receptor agonist, GR79236. GR79236 inhibited catecholamine-induced lipolysis in human, rat and dog isolated adipocytes. 2. Oral administration of GR79236 (0.1-10 mg/kg) to fed rats induced minimal changes in the plasma concentration of non-esterified fatty acids and in the blood concentrations of glucose and lactate. 3. Intravenous infusion of GR79236 to fasted pithed rats, or oral administration of GR79236 to fasted conscious rats and dogs, produced time- and dose-dependent decreases in the plasma non-esterified fatty acid concentration. In the fasted rats, doses of GR79236 that lowered plasma levels of non-esterified fatty acids also produced hypotriglyceridaemia and anti-ketotic effects. 4. Only in the pithed rats were acute effects on the plasma glucose and lactate concentrations observed. Hypoglycaemia and hyperlactataemia occurred over the dose range studied (1 × 10−11-1 × 10−8 mol min−1 kg−1). 5. This profile of activity suggests that compounds such as GR79236 might be agents which can be used to define the role of excessive lipolysis in experimental (and human) pathophysiology.

Pharmacokinetics of the Antimalarial Drug, AQ-13, in Rats and Cynomolgus Macaques

2004 ◽  
Vol 23 (3) ◽  
pp. 179-189 ◽  
Author(s):  
Sandhya Ramanathan-Girish ◽  
Paul Catz ◽  
Moire R. Creek ◽  
Benjamin Wu ◽  
David Thomas ◽  
...  
Keyword(s):  
Oral Dose ◽  
Oral Administration ◽  
Antimalarial Drug ◽  
Dose Range ◽  
Plasmodium Species ◽  
Repeat Dose ◽  
Nonlinear Kinetics ◽  
Dose Administration ◽  
Blood Concentrations ◽  
Cynomolgus Macaques

The purpose of this study was to evaluate the bioavailability and pharmacokinetics of a new antimalarial drug, AQ-13, a structural analog of chloroquine (CQ) that is active against CQ-resistant Plasmodium species, in rats and cynomolgus macaques. Sprague-Dawley rats ( n = 4 /sex) were administered a single dose of AQ-13 intravenously (i.v.) (10 mg/kg) or orally (20 or 102 mg/kg). Blood and plasma samples were collected at several timepoints. AQ-13 achieved Cmax after oral administration at approximately 3 to 4 h and could be detected in blood for 2 to 5 days after oral administration. The ratio of area under the curve (AUC) values at the high and low dose for AQ-13 deviated from an expected ratio of 5.0, indicating nonlinear kinetics. A metabolite peak was noted in the chromatograms that was identified as monodesethyl AQ-13. Oral bioavailability of AQ-13 was good, approximately 70%. The pharmacokinetics of AQ-13 was also determined in cynomolgus macaques after single (i.v., 10 mg/kg; oral, 20 or 100 mg/kg) and multiple doses (oral loading dose of 50, 100, or 200 mg/kg on first day followed by oral maintenance dose of 25, 50, or 100 mg/kg, respectively, for 6 days). The AUC and Cmax values following single oral dose administration were not dose proportional; the Cmax value for AQ-13 was 15-fold higher following an oral dose of 100 mg/kg compared to 20 mg/kg. MonodesethylAQ-13 was a significant metabolite formed by cynomolgus macaques and the corresponding Cmax values for this metabolite increased only 3.8-fold over the dose range, suggesting that the formation of monodesethyl AQ-13 is saturable in this species. The bioavailability of AQ-13 in cynomolgus macaques following oral administration was 23.8% for the 20-mg/kg group and 47.6% for the 100-mg/kg group. Following repeat dose administration, high concentrations of monodesethyl AQ-13 were observed in the blood by day 4, exceeding the AQ-13 blood concentrations through day 22. Saturation of metabolic pathways and reduced metabolite elimination after higher doses are suggested to play a key role in AQ-13 pharmacokinetics in macaques. In summary, the pharmacokinetic profile and metabolism ofAQ-13 are very similar to that reported in the literature for chloroquine, suggesting that this new agent is a promising candidate for further development for the treatment of chloroquine-resistant malaria.

Central sympathetic outflow to skeletal muscle: the major link between non-esterified fatty acids and elevated blood pressure?

2009 ◽  
Vol 118 (1) ◽  
pp. 43-45 ◽  
Author(s):  
Markus Schlaich
Keyword(s):  
Blood Pressure ◽  
Fatty Acids ◽  
Pressor Response ◽  
The Metabolic Syndrome ◽  
Arterial Blood ◽  
Esterified Fatty Acids ◽  
System Activation ◽  
Central Sympathetic Outflow ◽  
Sympathetic Nervous System Activation

Sympathetic nervous system activation is a hallmark of several conditions associated with an adverse prognosis, including hypertension and the metabolic syndrome. Proposed mediators of increased sympathetic drive include hyperinsulinaemia, leptin, NEFAs (non-esterified fatty acids), pro-inflammatory cytokines, baroreflex impairment and others. The role of NEFAs appears to be of particular importance given the increased levels observed in human obesity and the experimental results linking the NEFA-induced pressor response to sympathetic activation. Findings from human studies have yielded conflicting results with regards to a sympathetically mediated association between NEFAs and elevated arterial blood pressure. In the present issue of Clinical Science, Florian and Pawelczyk present some interesting results obtained from a small number of healthy normotensive lean volunteers who were exposed to NEFA infusion and cardiovascular and sympathetic monitoring using state of the art methodology that appears to be in support of such a link. However, several methodological and conceptual considerations need to be taken into account when interpreting the results from this study. Put into perspective, the case for a substantial sympathetically mediated pressor response to NEFA infusion does not appear to be a very strong one.

PLASMA NON-ESTERIFIED FATTY ACID LEVELS IN HYPOPITUITARY SUBJECTS

1966 ◽  
Vol 35 (1) ◽  
pp. 107-115 ◽  
Author(s):  
T. C. B. STAMP
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Oral Administration ◽  
Normal Subjects ◽  
Control Group ◽  
Insulin Administration ◽  
Plasma Nefa ◽  
Prolonged Fasting ◽  
Fat Mobilization ◽  
Esterified Fatty Acids

SUMMARY Changes in the plasma levels of non-esterified fatty acids (NEFA) in a group of patients with proven hypopituitarism have been compared with those found in control subjects during prolonged fasting, after the injection of insulin and after the oral administration of glucose with and without the previous administration of insulin. During a 4 hr. prolongation of an overnight fast plasma NEFA levels increased at a significantly slower rate in the patients with hypopituitarism. The intravenous injection of insulin was followed by a prompt fall in NEFA levels in the control group, and by a rapid return to or above original values. The recovery was consistently and markedly impaired in the patients with hypopituitarism and this abnormality differentiated them more clearly from the normal subjects than the abnormality in their plasma sugar response to insulin. The patients with pituitary hypofunction had a flat plasma sugar curve after the oral administration of glucose, but there were only minor differences from the normal plasma NEFA levels. Previous insulin administration impaired glucose tolerance in normal subjects and resulted in a more rapid late return of NEFA levels than after the administration of glucose alone. This late rise in NEFA did not occur in the hypopituitary group. The results obtained support the concept that pituitary integrity is required for normal fat mobilization. The consistency of the changes suggests that tests based on plasma NEFA measurements may provide a useful indirect means of diagnosing pituitary hypofunction.

The effects of non-esterified fatty acids and β-hydroxybutyrate on the hepatic CYP2E1 in cows with clinical ketosis

2019 ◽  
Vol 86 (1) ◽  
pp. 68-72
Author(s):  
Zhicheng Peng ◽  
Xiaobing Li ◽  
Zhe Wang ◽  
Guowen Liu ◽  
Xinwei Li
Keyword(s):  
Oxidative Stress ◽  
Fatty Acids ◽  
Dairy Cows ◽  
Blood Concentrations ◽  
Cytochrome P4502e1 ◽  
Esterified Fatty Acids ◽  
Cyp2e1 Expression ◽  
Expression And Activity

AbstractDairy cows with ketosis display severe oxidative stress as well as high blood concentrations of non-esterified fatty acids (NEFA) and β-hydroxybutyrate (BHB). Cytochrome P4502E1 (CYP2E1) plays an important role in the induction of oxidative stress. The aim of this study was to investigate CYP2E1 expression and activity in the liver of clinically ketotic cows (in vivo) and the effects of NEFA and BHB on CYP2E1 expression and activity in hepatocytes (in vitro). Dairy cows with clinical ketosis exhibited a low blood concentration of glucose but high concentrations of NEFA and BHB. Hepatic mRNA, protein expression, and activity of CYP2E1 were significantly higher in cows with clinical ketosis than in control cows. In vitro, both NEFA and BHB treatment markedly up-regulated the mRNA and protein expressions as well as activity of CYP2E1 in cow hepatocytes. Taken together, these results indicate that high levels of NEFA and BHB significantly up-regulate the expression and activity of hepatic CYP2E1, and may be influential in the induction of oxidative stress in cows with clinical ketosis.

Vasodilation induced by endothelin: role of EDRF and prostanoids in rat hindquarters

1990 ◽  
Vol 259 (6) ◽  
pp. H1835-H1841 ◽  
Author(s):  
E. H. Ohlstein ◽  
L. Vickery ◽  
C. Sauermelch ◽  
R. N. Willette
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Perfusion Pressure ◽  
Microvascular Perfusion ◽  
Hemodynamic Effects ◽  
Hemodynamic Responses ◽  
Pithed Rats ◽  
Dose Dependent

Hemodynamic responses to endothelin (ET-1) were studied in hindquarters of anesthetized rats and also in isolated buffer-perfused hindquarters of pithed rats. ET-1 (10-100 pmol ia) produced brief dose-related increases in hindquarter blood flow. Acetylcholine (ACh. 0.3-1 micrograms ia) produced similar vasodilator responses. Hemodynamic responses elicited by either ET-1 or ACh were not significantly altered by pretreatment with indomethacin. ET-1 produced dose-dependent increases in skeletal muscle microvascular perfusion, whereas ET-1 had no effect on cutaneous microvascular perfusion, suggesting that vasodilation in the skeletal muscle of the hindlimb contributes to the increase in hindquarter blood flow induced by ET-1. Hemodynamic effects of ET-1 and ACh were studied in the isolated in situ buffer-perfused hindquarters of pithed rats. ET-1 (0.01-300 pmol ia) produced only dose-dependent increases in hindquarter perfusion pressure under basal conditions or when the vascular preparation was precontracted with methoxamine. ET-1 induced vasorelaxation was not observed. ACh (3 microgram ia) produced a 64% reduction in hindquarter perfusion pressure; indicative of endothelium-dependent relaxation. ET-3 (0.1-300 pmol) produced only dose-dependent increases in hindquarter perfusion pressure. When hemodynamic effects of ET-1 were studied under conditions of constant pressure, results were similar to those obtained under constant flow. This study demonstrates that in the rat hindquarters endothelium-derived relaxing factors and prostanoids do not appear to be mediators of endothelin-induced vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Fatty acids regulate the expression of lipoprotein lipase gene and activity in preadipose and adipose cells

1996 ◽  
Vol 314 (2) ◽  
pp. 541-546 ◽  
Author(s):  
Ez-Zoubir AMRI ◽  
Lydia TEBOUL ◽  
Christian VANNIER ◽  
Paul-André GRIMALDI ◽  
Gérard AILHAUD
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Lipoprotein Lipase ◽  
Fine Tuning ◽  
Lipase Gene ◽  
Lpl Gene ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Adipose Cells

During fasting, a reduction in lipoprotein lipase (LPL) activity has been observed in rat fat pad with no change in enzyme mass, whereas LPL mRNA and synthesis are increased, suggesting that insulin and/or fatty acids (FA) regulate LPL activity post-translationaly [Doolittle, Ben-Zeev, Elovson, Martin and Kirchgessner (1990) J. Biol. Chem. 265, 4570–4577]. To examine the role of FA, either preadipose Ob1771 cells or Ob1771 and 3T3-F442A adipose cells were exposed to long-chain FA and to 2-bromopalmitate, a non-metabolized FA. A rapid (2–8 h) and dose-dependent increase (up to 6-fold) in LPL mRNA occurred, primarily due to increased transcription, which is accompanied by a decrease (down to 4-fold) in LPL cellular activity. Under these conditions, secretion of active LPL was nearly abolished. Removal of FA led to full recovery of LPL activity. LPL gene expression in 3T3-C2 fibroblasts was not affected by FA treatment. However fatty acid-activated receptor transfected-3T3-C2 cells, which show FA responsiveness, had increased LPL gene expression upon FA addition. LPL synthesis and cellular content appeared unaffected by FA treatment, whereas secretion of LPL was inhibited. These results indicate that FA regulate the post-translational processing of LPL. It is proposed that the regulation of LPL activity by FA is important with regard to the fine-tuning of FA entry into adipocytes during fasting/feeding periods.

Prostanoids in regulation of postprandial jejunal hyperemia and oxygen uptake

1989 ◽  
Vol 257 (5) ◽  
pp. G798-G808 ◽  
Author(s):  
C. C. Chou ◽  
A. Alemayehu ◽  
M. J. Mangino
Keyword(s):  
Blood Flow ◽  
Thromboxane A2 ◽  
Prostaglandin I2 ◽  
O2 Uptake ◽  
Blood Concentrations ◽  
Anesthetized Dogs ◽  
Txa2 Receptor ◽  
Txa2 Receptor Antagonist ◽  
Dose Dependent

The role of prostanoids in regulation of jejunal blood flow (JBF) was studied in anesthetized dogs. Intra-arterial infusions of arachidonate produced biphasic changes and dose-dependent decreases in jejunal vascular resistance (JVR) in untreated and aspirin-pretreated dogs, respectively; mefenamate abolished these responses. The jejunum released prostaglandin I2 (PGI2) greater than PGE2 greater than thromboxane A2 (TXA2) (radioimmunoassay) under resting conditions, and food enhanced the release of PGE2 greater than PGI2 greater than TXA2 greater than PGF2 alpha. Addition of arachidonate to food enhanced TXA2 and PGF2 alpha releases and decreased PGI2 and PGE2 releases, while inhibiting the food-induced increases in JBF and O2 uptake; mefenamate inhibited these arachidonate actions. A TXA2 receptor antagonist (SQ-29548) reversed the arachidonate vascular and metabolic actions. Intra-arterial infusions of PGI2 or PGE2 decreased, whereas TXA2 analogue U-44069 or PGF2 alpha increased JVR. A mixture of these prostanoids infused at blood concentrations similar to the increase observed during food placement did not alter JVR. At concentrations similar to the increases observed when arachidonate was added to luminal food, the infusions increased JVR and abolished the food-induced decrease in JVR. In conclusion, jejunal productions of PGI2, PGE2, TXA2, and PGF2 alpha increase during nutrient absorption. Addition of arachidonate to food attenuates the former two and enhances the latter two releases, which act to attenuate food-induced jejunal hyperemia.

Effects of infusions of various doses of bovine growth hormone-releasing factor on blood hormones and metabolites in lactating Holstein cows

1989 ◽  
Vol 122 (3) ◽  
pp. 671-679 ◽  
Author(s):  
W. J. Enright ◽  
L. T. Chapin ◽  
W. M. Moseley ◽  
S. A. Zinn ◽  
M. B. Kamdar ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Growth Hormone ◽  
Serum Concentration ◽  
Dairy Cattle ◽  
Holstein Cows ◽  
Bovine Growth Hormone ◽  
Blood Concentrations ◽  
Somatomedin C ◽  
Esterified Fatty Acids ◽  
Blood Hormones

ABSTRACT In two experiments, the effects of i.v. infusions of various doses of bovine GH-releasing factor (GRF) on blood hormones and metabolites in lactating Holstein cows were determined. In experiment 1, cows were infused with GRF (0, 3·125, 6·25, 12·5, 25·0 or 50·0 mg/cow per 24 h) for 24 h. Blood was sampled at −1, 5, 11, 15 and 23 h relative to the start of the infusion. The serum concentration of somatomedin C (SM-C) before infusion was 303 ± 8 (s.e.m.) μg/l. Doses of GRF of between 3·125 and 50·0 mg were equipotent in stimulating (P < 0·05) SM-C by 1·5- to 2·5-fold. GRF-induced increases in SM-C occurred by 11 h from the start of the infusion. In experiment 2, primiparous cows were infused with GRF (0, 1 or 3 mg/24 h) for 20 days. Blood was sampled for 12 h on days 1, 10 and 19. The 1 mg dose of GRF increased (P < 0·05) blood concentrations of SM-C (on days 10 and 19) and glucose (on day 19), but did not affect blood concentrations of prolactin, insulin, cortisol, tri-iodothyronine (T3), thyroxine (T4), non-esterified fatty acids (NEFA) or glucose. The 3 mg dose of GRF increased (P < 0·05) blood concentrations of SM-C (on days 10 and 19), T3 (on days 10 and 19), insulin (on day 19), NEFA (on days 1, 10 and 19) and glucose (on day 19), but did not affect blood concentrations of prolactin, cortisol or T4. We conclude that these data are consistent with the hypothesis that the galactopoietic effect of exogenous GRF in dairy cattle is mediated by increased secretion of GH. Journal of Endocrinology (1989) 122, 671–679

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