Importance of Residual Water Permeability on the Excretion of Water during Water Diuresis in Rats

When the concentration of sodium (Na+) in arterial plasma (PNa) declines sufficiently to inhibit the release of vasopressin, water will be excreted promptly when the vast majority of aquaporin 2 water channels (AQP2) have been removed from luminal membranes of late distal nephron segments. In this setting, the volume of filtrate delivered distally sets the upper limit on the magnitude of the water diuresis. Since there is an unknown volume of water reabsorbed in the late distal nephron, our objective was to provide a quantitative assessment of this parameter. Accordingly, rats were given a large oral water load, while minimizing non-osmotic stimuli for the release of vasopressin. The composition of plasma and urine were measured. The renal papilla was excised during the water diuresis to assess the osmotic driving force for water reabsorption in the inner medullary collecting duct. During water diuresis, the concentration of creatinine in the urine was 13-fold higher than in plasma, which implies that ~8% of filtered water was excreted. The papillary interstitial osmolality was 600 mOsm/L > the urine osmolality. Since 17% of filtered water is delivered to the earliest distal convoluted tubule micropuncture site, we conclude that half of the water delivered to the late distal nephron is reabsorbed downstream during water diuresis. The enormous osmotic driving force for the reabsorption of water in the inner medullary collecting duct may play a role in this reabsorption of water. Possible clinical implications are illustrated in the discussion of a case example

Cell Walls of Saccharomyces cerevisiae Differentially Modulated Innate Immunity and Glucose Metabolism during Late Systemic Inflammation

BACKGROUND: Salmonella causes acute systemic inflammation by using its virulence factors to invade the intestinal epithelium. But, prolonged inflammation may provoke severe body catabolism and immunological diseases. Salmonella has become more life-threatening due to emergence of multiple-antibiotic resistant strains. Mannose-rich oligosaccharides (MOS) from cells walls of Saccharomyces cerevisiae have shown to bind mannose-specific lectin of Gram-negative bacteria including Salmonella, and prevent their adherence to intestinal epithelial cells. However, whether MOS may potentially mitigate systemic inflammation is not investigated yet. Moreover, molecular events underlying innate immune responses and metabolic activities during late inflammation, in presence or absence of MOS, are unknown. METHODS AND PRINCIPAL FINDINGS: Using a Salmonella LPS-induced systemic inflammation chicken model and microarray analysis, we investigated the effects of MOS and virginiamycin (VIRG, a sub-therapeutic antibiotic) on innate immunity and glucose metabolism during late inflammation. Here, we demonstrate that MOS and VIRG modulated innate immunity and metabolic genes differently. Innate immune responses were principally mediated by intestinal IL-3, but not TNF-α, IL-1 or IL-6, whereas glucose mobilization occurred through intestinal gluconeogenesis only. MOS inherently induced IL-3 expression in control hosts. Consequent to LPS challenge, IL-3 induction in VIRG hosts but not differentially expressed in MOS hosts revealed that MOS counteracted LPS's detrimental inflammatory effects. Metabolic pathways are built to elucidate the mechanisms by which VIRG host's higher energy requirements were met: including gene up-regulations for intestinal gluconeogenesis (PEPCK) and liver glycolysis (ENO2), and intriguingly liver fatty acid synthesis through ATP citrate synthase (CS) down-regulation and ATP citrate lyase (ACLY) and malic enzyme (ME) up-regulations. However, MOS host's lower energy demands were sufficiently met through TCA citrate-derived energy, as indicated by CS up-regulation. CONCLUSIONS: MOS terminated inflammation earlier than VIRG and reduced glucose mobilization, thus representing a novel biological strategy to alleviate Salmonella-induced systemic inflammation in human and animal hosts

Comparison of glucose and fructose transport into adipocytes of the rat.

The purpose of these studies was to define the properties of the systems that transport hexoses into adipocytes. Glucose appears to enter adipocytes on a single transport system whose maximum velocity is stimulated by insulin and which is competitively inhibited by cytochalasin B, 5-thioglucose, fructose, mannose and 3-O-methylglucose. In contrast, fructose enters adipocytes by at least two separate mechanisms, one an insulin-sensitive transporter (probably the glucose transporter) and the other a mechanism that is insensitive to insulin. The fructose concentration required for half-maximal rates of transport is at least an order of magnitude higher than that for glucose and the maximum velocity of fructose transport is more than double that for glucose

Is accelerated oxidation of lactate required for dichloroacetate to lower the level of lactate in blood?

We examined mechanisms by which dichloroacetate (DCA), an activator of pyruvate dehydrogenase (PDH), led to a decrease in the concentration of lactate in blood in a unique "metabolic setting," where the concentration of lactate in blood was 5.4 ± 0.5 mmol/L. Elevated levels of lactate were induced in anaesthetized rabbits by the administration of a large dose of insulin. The rate of consumption of oxygen was 1.2 ± 0.1 mmol/min, the respiratory quotient was close to unity, and close to half of the PDH was in its active form; therefore, virtually all ATP synthesis should require flux through PDH. Hence, we predicted that DCA should not cause a significant decrease in the concentration of lactate in blood in this model. In contrast, if DCA was effective, new insights could be obtained into its mechanisms of action, at least in this setting. During steady-state hyperlactatemia, DCA was given as its sodium salt, 2 mmol/kg (n = 10); a control group (n = 5) received equimolar NaCl. Forty minutes later, the level of lactate in blood in the DCA group was 1.3 ± 0.2 mmol/L, significantly lower than in the NaCl group (4.2 ± 0.6 mmol/L). To determine the organ(s) responsible for removing lactate, arteriovenous differences were measured in organs drained by the jugular, femoral, and hepatic veins. There was no net uptake of lactate in these drainage beds after DCA was administered. From a quantitative analysis of the rate of removal of lactate and the rate of consumption of oxygen, it seems unlikely that the majority of the decrease in lactate could be directly attributed to an increase in its oxidation.Key words: lactic acidosis, dichloroacetate, pyruvate dehydrogenase, metabolism. </jats:p

An Acute Infusion of Lactic Acid Lowers the Concentration of Potassium in Arterial Plasma by Inducing a Shift of Potassium into Cells of the Liver in Fed Rats

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Potassium (K&lt;sup&gt;+&lt;/sup&gt;) input occurs after meals or during ischemic exercise and is accompanied by a high concentration of &lt;i&gt;L&lt;/i&gt;-lactate in plasma (P&lt;sub&gt;L-lactate&lt;/sub&gt;). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We examined whether infusing 100 µmol &lt;i&gt;L&lt;/i&gt;-lactic acid/min for 15 min would lead to a fall in the arterial plasma K&lt;sup&gt;+&lt;/sup&gt; concentration (P&lt;sub&gt;K&lt;/sub&gt;). We also aimed to evaluate the mechanisms involved in normal rats compared with rats with acute hyperkalemia caused by a shift of K&lt;sup&gt;+&lt;/sup&gt; from cells or a positive K&lt;sup&gt;+&lt;/sup&gt; balance. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; There was a significant fall in P&lt;sub&gt;K&lt;/sub&gt; in normal rats (0.25 m&lt;i&gt;M&lt;/i&gt;) and a larger fall in P&lt;sub&gt;K&lt;/sub&gt; in both models of acute hyperkalemia (0.6 m&lt;i&gt;M&lt;/i&gt;) when the P&lt;sub&gt;L-lactate&lt;/sub&gt; rose. The arterial P&lt;sub&gt;K&lt;/sub&gt; increased by 0.8 m&lt;i&gt;M&lt;/i&gt; (p &lt; 0.05) 7 min after stopping this infusion despite a 2-fold rise in the concentration of insulin in arterial plasma (P&lt;sub&gt;Insulin&lt;/sub&gt;). There was a significant uptake of K&lt;sup&gt;+&lt;/sup&gt; by the liver, but not by skeletal muscle. In rats pretreated with somatostatin, P&lt;sub&gt;Insulin&lt;/sub&gt; was low and infusing &lt;i&gt;L&lt;/i&gt;-lactic acid failed to lower the P&lt;sub&gt;K&lt;/sub&gt;. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; A rise in the P&lt;sub&gt;L-lactate&lt;/sub&gt; in portal venous blood led to a fall in the P&lt;sub&gt;K&lt;/sub&gt; and insulin was permissive. Absorption of glucose by the Na&lt;sup&gt;+&lt;/sup&gt;-linked glucose transporter permits enterocytes to produce enough ADP to augment aerobic glycolysis, raising the P&lt;sub&gt;L-lactate&lt;/sub&gt; in the portal vein to prevent postprandial hyperkalemia.</jats:p