Naloxone inhibits the plasma epinephrine response to ACTH but not to 2-deoxy-D-glucose in rats

Intravenous injection of (1-24) ACTH and 2-deoxy-d-glucose (2DG) stimulated the plasma epinephrine and norepinephrine levels in pentobarbital-anesthetized male rats. Naloxone, a specific opiate antagonist, inhibited the plasma epinephrine response to ACTH but not to 2DG. Norepinephrine release induced by ACTH or 2DG was not affected by naloxone. These results suggest that the opioid peptidergic synapse might be involved in the ACTH- but not in the 2DG-induced epinephrine release.     

Chronic changes in plasma triglyceride levels do modify platelet membrane microviscosity in rats

Lipid metabolism disorders were proposed to mediate numerous cell membrane alterations in various forms of hypertension. Elevated plasma triglycerides were found to be associated with changes in membrane structure and function related to altered microviscosity in particular domains of the cell membrane. The aim of our study was to determine if an abnormal triglyceride metabolism might play a causal role in these alterations of membrane dynamics. Using genetically hypertensive rats of the Prague hereditary hypertriglyceridemic (HTG) strain we investigated whether the elevation of circulating triglycerides induced by high fructose intake and/or their lowering by chronic gemfibrozil treatment (for 10 weeks starting at the age of 6 weeks) are followed by reciprocal changes in membrane microviscosity. Two different fluorescent probes exploring either the outer membrane leaflet (TMA-DPH anisotropy) or the membrane lipid core (DPH anisotropy) were used in platelets of HTG rats. DPH (diphenylhexatriene) fluorescence anisotropy was decreased in platelets of fructose-treated HTG animals with highly elevated plasma triglyceride levels, whereas it was increased in gemfibrozil-treated HTG rats in which triglyceride levels were almost normalized. On the contrary, TMA-DPH (trimethylamino-diphenylhexatriene) anisotropy was not substantially altered in platelets from HTG rats by the above modifications of circulating triglycerides. No changes of plasma cholesterol or blood pressure were associated with the triglyceride-dependent modifications of membrane core microviscosity. Our interventional study demonstrates a major causal role of circulating triglycerides in the control of the microviscosity of membrane lipid core.     

Experimental dissociation of food intake and plasma beta-endorphin following 2-deoxy-D-glucose in rats

The present studies were undertaken to further assess the role of plasma beta-endorphin (beta-EP) in the hyperphagia induced by the glucose antimetabolite, 2-deoxy-D-glucose (2-DG). Plasma concentrations of immunoreactive beta-EP (ir-beta-EP) were measured at the end of the first hour of feeding in all animals treated with 400 mg/kg 2-DG. Previous studies had shown a consistent, positive association between 2-DG hyperphagia and plasma ir-beta-EP concentrations, but the present data revealed dissociations between hyperphagia and plasma ir-beta-EP. Dexamethasone administration blocked the 2-DG-induced rise in plasma ir-beta-EP, but had no effect on the 2-DG hyperphagia measured at 1 hour. Forced drinking of a 2% NaCl solution decreased 2-DG hyperphagia, but not the 2-DG induced rise in plasma ir-beta-EP. Thus, elevations in plasma ir-beta-EP are not necessary for the full expression of 2-DG-induced hyperphagia in dexamethasone-treated rats. Furthermore, decreased feeding responses to 2-DG could coexist with increased levels of plasma ir-beta-EP in NaCl-treated normal rats. Elevations in plasma ir-beta-EP do not appear to be the critical opiate link in 2-DG induced hyperphagia.     

Effects of arginine vasotocin on levels of plasma gonadotropins and prolactin in ovariectomized conscious rats

Arginine vasotocin was injected into the third ventricle or intravenously in conscious, ovariectomized rats and its effect on gonadotropin and prolactin release evaluated. The peptide lowered plasma levels of both LH and prolactin in doses of 40 or 100 ng given intraventricularly. The higher dose was slightly more effective than the lower dose. Intravenous injection of a 1-microgram dose of vasotocin failed to alter plasma LH in the ovariectomized animals; however, a 5-micrograms dose induced a slight depression apparent at only 60 min following injection. Intravenous injection of 1 microgram produced a significant lowering of plasma prolactin, whereas a dramatic lowering followed the injection of the higher dose. Plasma FSH was unaffected in these experiments. Incubation of dispersed anterior pituitary cells from ovariectomized rats with various doses of vasotocin revealed no effect of the peptide on the release of FSH, LH, or prolactin. It also did not alter the response to LHRH, but it partially blocked the action of dopamine to inhibit prolactin release. The data indicate that quite low doses of arginine vasotocin act within the brain to inhibit LH and prolactin secretion in ovariectomized, conscious animals.     

Increased plasma apoM levels impair triglyceride turnover in mice

ObjectiveApolipoprotein M (apoM) is an essential transporter of plasma Sphingosine-1-Phosphate (S1P), typically attached to all lipoprotein classes, but with a majority bound to high density lipoproteins (HDL). ApoM-deficient mice display an increased activity in brown adipose tissue and a concomitant fast turnover of triglycerides. In what manner apoM/S1P affect the triglyceride metabolism is however still unknown and explored in the present study.MethodsTriglyceride turnover and potentially associated metabolic pathways were studied in the female human apoM transgenic mouse model (apoM-Tg) with increased plasma apoM and S1P levels. The model was compared with wild type (WT) mice.ResultsApoM-Tg mice had a reduced plasma triglyceride turnover rate and a lower free fatty acid uptake in subcutaneous adipocytes compared to WT mice. Screening for potential molecular mechanisms furthermore revealed a reduction in plasma lipase activity in apoM-Tg animals. Overexpression of apoM also reduced the plasma levels of fibroblast growth factor 21 (FGF21).ConclusionsThe study features the significant role of the apoM/S1P axis in maintaining a balanced triglyceride metabolism. Further, it also highlights the risk of inducing dyslipidaemia in patients receiving S1P-analouges and additionlly emphasizes the apoM/S1P axis as a potential therapeutic target in treatment of hypertriglyceridemia.     

Genetic determinants of plasma triglyceride levels in (OLETF x BN) x OLETF backcross rats

Altered lipid metabolism is closely associated with diabetes in humans, although predisposing genetic factors that affect hyperlipidemia have not yet been clarified. Our previously established OLETF strain is an obese rat model of type II diabetes, exhibiting hypertriglycemia as well as hyperinsulinemia, hyperglycemia, insulin resistance, and abundant abdominal fat. To identify genetic factors responsible for dyslipidemic phenotypes in OLETF rats, we performed a whole-genome scan using 293 male (OLETF x BN) x OLETF backcross rats. Our analysis identified two significant quantitative trait loci (QTLs), on rat chromosomes 1 and 8, that are related to fasting triglyceride levels. The chromosome 1 QTL colocalized with Dmo1 (diabetes mellitus, OLETF type 1), a locus previously shown to associate strongly with both fat levels and body weight. The other significant QTL localizes to the chromosome 8 marker D8Mit2, in a region where several apo-lipoprotein genes are clustered.     

Acute pulmonary alveolar hypoxia increases lung and plasma endothelin-1 levels in conscious rats.

To investigate the effect of pulmonary alveolar hypoxia on the synthesis and release of endothelin (ET)-1, ET-1-like immunoreactivity (-LI) levels of the lung and plasma were measured in conscious unrestrained rats under hypoxic conditions. Sixty-min exposure to alveolar hypoxia (10% O2 or 5% O2) increased the ET-1-LI level in the lung. The plasma ET-1-LI level in hypoxic rats also increased significantly. The increase of plasma and lung ET-1-LI levels were parallel to the severity of hypoxia. These results demonstrates that acute pulmonary alveolar hypoxia increases lung and plasma ET-1-LI levels in conscious unrestrained rats, suggesting a possible physiological or pathophysiological significance of ET in alveolar hypoxia.     

Effect of 2-deoxy-D-glucose on hypothalamic-pituitary-thyroid axis in rats

The intraperitoneal administration to rats of 500 mg/kg body weight of 2-deoxy-D-glucose, an analog of glucose which produces intracellular glucopenia with rise in extracellular fluid glucose concentration, is followed by a significant though transient reduction of hypothalamic TRH content, observed at 15 and 25 minutes after drug administration. A subsequent increase in serum thyrotropin followed by that of triiodothyronine concentration was also observed. These findings indicate that the neuroglucopenia induced by 2-deoxy-D-glucose may play a role in the regulating the hypothalamic-pituitary-thyroid axis.     

Effect of hemorrhage on plasma atriopeptin levels in conscious dogs

An increase in atrial pressure has been shown to cause an increase in the concentration of atrial peptides (atriopeptin) in plasma. We therefore hypothesized that a reduction in atrial pressure would decrease the concentration of atriopeptin in plasma. In formulating this hypothesis we assumed that changes in the concentration of other circulating hormones or changes in cardiac nerve activity during hemorrhage would not affect the secretion of atriopeptin. To test the hypothesis, we bled sham-operated conscious dogs at a rate of 0.8 ml.kg-1.min-1 to decrease right and left atrial pressures. Hemorrhage was continued until a total of 30 ml of blood per kilogram body weight had been removed. Identical experiments were performed on conscious cardiac-denervated dogs. The concentration of plasma atriopeptin was decreased in each group of dogs after 10 ml of blood per kilogram of body weight had been removed, but the decrease achieved statistical significance only in the cardiac-denervated dogs. Further hemorrhage, however, produced no further decreases in circulating atriopeptin in either group even though atrial pressures continued to decline as more blood was removed. A comparison of the atriopeptin response to hemorrhage revealed no significant difference between the sham-operated and cardiac-denervated dogs, thus providing no evidence for a specific effect of cardiac nerves on atriopeptin secretion during hemorrhage. Our results demonstrate that the relationship between atrial pressure and plasma atriopeptin that has been observed repeatedly during atrial stretch is not evident during relatively slow, prolonged hemorrhage. There is, however, a small decline in circulating atriopeptin during the initial stage of hemorrhage that could be of biological significance.     

Effects of interleukins on plasma arginine vasopressin and oxytocin levels in conscious, freely moving rats.

To elucidate whether interleukins are involved in vasopressin or oxytocin release during cytokine-related stressful conditions, we examined the effects of human interleukin-1 beta and interleukin-6 on plasma vasopressin and oxytocin levels in rats. Interleukin-1 beta administrated intravenously stimulated both the vasopressin and oxytocin secretion in dose-dependent manners. Neither hormone release was observed following interleukin-6 administration. Pretreatment with aspirin significantly attenuated the effects of interleukin-1 beta on both the vasopressin and oxytocin levels. SC-19220, a prostaglandin E2 receptor antagonist, did not affect the interleukin-1 beta-induced increase of plasma oxytocin levels, but almost completely abolished its effect on plasma vasopressin levels. These results suggest that under certain stressful conditions which accompany the stimulation of cytokine production, interleukin-1 is involved in the increase of plasma vasopressin and oxytocin levels and, moreover, different kinds of prostaglandins are suggested to participate in these interleukin-1-induced hormone release.     

Elevation of rhesus monkey plasma luteinizing hormone levels in response to E series prostaglandins

Experiments were carried out to assess the influence of prostaglandins (viz. PGE₁, PGE₂ and PGF_2α) on plasma concentrations of FSH and LH in the female rhesus monkey. Monkeys were ovariectomized and treated with estradiol benzoate to suppress endogenous gonadotropin levels prior to these experiments. Femoral venous blood was taken at intervals following a single carotid arterial injection of the PG in anesthetized monkeys. FSH and LH concentrations, determined by radioimmunoassay, were not significantly altered in 4 control animals receiving saline (2) or ethanol-saline (2), the vehicles for PGF_2α and for the E series PGs, respectively. PGE₁ (5mg) effected dramatic elevations of LH within 5 min in 3 animals and the high plasma concentrations were maintained at least for 60 min. Similarly, 5.0 mg of PGE₂ effected rapid elevation of LH concentrations, from 2- to 7-fold pre-injection levels in 3 animals. In contrast, FSH levels were not so markedly altered by PGE₁ and PGE₂, but in general, appeared to be somewhat decreased by these treatments. PGF_2α had no effect on plasma FSH and LH concentrations. These data demonstrate the ability of PGs of the E series to elevate plasma LH concentrations in the rhesus monkey and support studies in other species suggesting a modulating role for PGs on gonadotropin secretion or release.     

Chronic ANG II infusion increases plasma triglyceride level by stimulating hepatic triglyceride production in rats

We recently observed that ANG II receptor blocker therapy improved the overproduction of triglyceride (TG) in fructose-fed rats and Zucker fatty rats with insulin resistance, which in turn suggests that ANG II may stimulate TG production. Accordingly, we investigated the effects of ANG II on TG production and the association with insulin resistance in normal rats. Male Wistar rats were continuously infused with ANG II (100 ng.min(-1).kg body wt(-1)) via an osmotic minipump for 14 days. ANG II infusion markedly elevated both the systolic and diastolic blood pressure. The plasma TG level increased twofold, but cholesterol was unchanged. ANG II infusion stimulated the TG secretion rate (TGSR) by twofold and increased the hepatic TG content by 31%. Lipogenesis determined by [2-(3)H]glycerol incorporation into hepatic TG was also significantly increased in ANG II-infused rats. The stimulatory effect of ANG II on TGSR was dose dependent and was not observed until 2 wk after the start of infusion. ANG II infusion significantly reduced insulin sensitivity index (SI) without affecting glucose effectiveness determined by Bergman's minimal model. The plasma TG level was positively correlated with TGSR (r = 0.88, P < 0.001) and inversely with SI (r = -0.80, P < 0.005). These results suggest that chronic ANG II infusion stimulates hepatic TG production, which is partly associated with simultaneous development of insulin resistance. Our results may suggest a new mechanism for the intimate association between hypertension and dyslipidemia.     

In vivo effect of 2-deoxy-D-glucose on adenine nucleotide levels in the liver and skeletal muscle of rats

The present report indicates that 2-deoxy-D-glucose (2-DG) at a single dose causing reduction of Tre has no influence on liver and skeletal muscle content of ATP, ADP and AMP, the ATP/ADP ratio, energy charge potential (ECP) and total adenine nucleotides (TAN). After administration of 2-DG for 3) successive days, the level of ATP, ATP/ADP ratio, the values of ECP and TAN are decreased both in the liver and skeletal muscle. However, 72 hours after the last injection of 2-DG adenine nucleotide contents returned to the values observed in control group, indicating that the in vivo effect of this glucose analogue is fully reversible.     

Apolipoprotein A-V: a potential modulator of plasma triglyceride levels in Turks

The apolipoprotein A-V gene (APOA5) plays an important role in determining plasma triglyceride levels. We studied the effects of APOA5 polymorphisms on plasma triglyceride levels in Turks, a population with low levels of HDL cholesterol and a high prevalence of coronary artery disease. We found 15 polymorphisms, three of which were novel. Seven haplotype-tagging single nucleotide polymorphisms (SNPs) were chosen and genotyped in approximately 3,000 subjects. The rare alleles of the -1464T>C, -1131T>C, S19W, and 1259T>C SNPs were significantly associated with increased triglyceride levels (19-86 mg/dl; P < 0.05) and had clear gene-dose effects. Haplotype analysis of the nine common APOA5 haplotypes revealed significant effects on triglyceride levels (P < 0.001). Detailed analysis of haplotypes clearly showed that the -1464T>C polymorphism had no effect by itself but was a marker for the -1131T>C, S19W, and 1259T>C polymorphisms. The -1131T>C and 1259T>C polymorphisms were in a strong but incomplete linkage disequilibrium and appeared to have independent effects. Thus, the APOA5 -1131T>C, S19W, and 1259T>C rare alleles were associated with significant increases in plasma triglyceride levels. At least one of these alleles was present in approximately 40% of the Turks. Similar associations were observed for -1131T>C and S19W in white Americans living in San Francisco, California.     

Oral NG-nitro-L-arginine in conscious dogs: 24 hour hypertensive response in relation to plasma levels

Summary Haemodynamic changes after oral administration of 30 mg/kg N^G-nitro-L-arginine (L-NNA) were studied in conscious chronically instrumented mongrel dogs throughout a 24 h observation period in order to evaluate the long-term efficacy of L-NNA-induced inhibition of endothelium-dependent relaxation and its relation to plasma L-NNA level. Diastolic blood pressure remained elevated for the entire 24 h observation period, but systolic blood pressure was raised only up to the 6 h value. The hypertensive response was accompanied by bradycardia. The increase in blood pressure and the plasma L-NNA level both reached their maxima at 3 h. The plasma L-NNA level at the end of the observation period was diminished by only 21.7% with respect to the maximum increase, whilst the maximum increase in mean arterial blood pressure was attenuated by 72.2% at 24 h. These data show a dissociation between plasma L-NNA level and the respective blood pressure.