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Overview of the P2 receptors.

The release of nucleotides in extracellular fluids can result from cell necrosis, exocytosis of secretory granules (such as platelet dense granules), or efflux through membrane channels. In addition, recent evidence suggests that vesicular trafficking is an important pathway of nucleotide release. Once in the extracellular fluids, they are rapidly degraded by ectonucleotidases, such as CD39, that play a key role in neutralizing the platelet aggregatory action of adenosine diphosphate (ADP), and act on two families of receptors: the ionotropic P2X receptors and the G-protein-coupled P2Y receptors. The family of P2X receptors encompasses seven genes. Currently, there are eight genuine P2Y receptors that can be subdivided into two structurally distinct subfamilies. Whereas P2X receptors are receptors of ATP, the different P2Y receptors are activated by distinct nucleotides, diphosphates or triphosphates, or purines or pyrimidines, some of them being conjugated to sugars. The study of knockout mice has demonstrated that P2X receptors play important roles in the neurogenic control of smooth muscle contraction, in pain and visceral perception, and in macrophage functions. The phenotype of P2Y null mice so far is more restricted: inhibition of platelet aggregation to ADP and increased bleeding time in P2Y (1)(-/-) and P2Y (12)(-/-) mice and lack of epithelial responsiveness to nucleotides in airways (P2Y (2)(-/-)) and intestine (P2Y (4)(0/-)).

Adenosine Diphosphate↗

[Molecular dynamics of K+ transport and its crucial involvement in signal transduction].

Potassium ion (K+) is the only cation whose concentration in intracellular solution is more abundant than in extracellular fluid. In higher animals, each of the cells, which is bathed in the extracellular fluid containing approximately 5 mM K+, has approximately 140 mM K+ in its cytoplasm. Physiological experiments have reported that the glial cells such as brain astrocytes and retinal Müller cells highly express K+ conductance on their membrane. The K+ conductance is thought to be responsible for transport of K+ from the extracellular regions of high K+, which is elicited by the excitation of neurons, to those of low K+. This so-called glial K(+)-buffering action is essential for maintenance of neuronal activity. Types and distribution of the K+ channels involved in the buffering action, however, have remained unknown for a long time. Recently, we have identified that an inwardly rectifying K+ channel, Kir4.1, is dominated in glial cells and plays a central role in the K(+)-buffering action. We also found that Kir4.1 is enriched on the processes of astrocytes wrapping synapses and blood vessels. Furthermore, some of the Kir4.1 is assembled with Kir5.1, suggesting that a heteromultimer of Kir4.1 and Kir5.1 plays a distinct role in the glia.

Animals↗

Bed rest immobilization with various oral sodium supply: plasma hormones and body fluids.

OBJECTIVE: To answer the question if plasma hormone concentrations (plasma renin activity--PRA, vasopressin--pAVP, and aldosterone concentration) due to antiorthostatic immobilization (8 days -6 degree head-down tilt bed rest--HDBR) are altered by oral salt load, we provided constant sodium supply during 4 days ambulatory conditions followed by 8 days HDBR in 10 normotensive men. METHODS: A low' (LS: 143 10 mM) and high' (HS: 434+/-17 mM Na+/d excreted) sodium treatment were provided in randomized order, separated > or = 1 mo. Before and at the end of HDBR, hemodynamic variables and thoracic impedance were determined, and blood was taken for aldosterone and PRA, venous hematocrit, and plasma mass density. Extracellular fluid volume and pAVP were determined every second day. Whole body electrical impedance spectroscopy was employed to assess changes in extracellular volume, hormone determinations were done with radioimmunoassay, mass density measurements with the mechanical oscillator technique. RESULTS: Extracellular volume decreased with HDBR (LS: -4.0%, p=0.002; HS: -5.8%, p=0.018) without significant difference between salt treatments. Resting hormone levels were not altered by HDBR, but pAVP was lower (5.5+/-0.1 pg/ml) in HS than in LS (7.2+/-0.3 pg/ml) as was plasma aldosterone (HS: 69+/-7 pg/ml, LS: 180+/-24 pg/ml). On the other hand, HDBR reduced extracellular volume by ?5% irrespective of dietary sodium supply. CONCLUSIONS: Our data support the hypothesis that hormonal activities are more affected by oral salt load than by simulated short-term space flight, and suggest that the reduction of extracellular fluid volume due to head down bed rest is not influenced by moderate changes of dietary sodium supply.

Administration, Oral↗

Retinal lesions affect extracellular glutamate levels in sensory-deprived and remote non-deprived regions of cat area 17 as revealed by in vivo microdialysis.

This study aimed at gaining insight into the role of the excitatory neurotransmitter glutamate in topographic map reorganization in the sensory systems of adult mammals after restricted deafferentations. Hereto, in vivo microdialysis was used to sample extracellular glutamate from sensory-deprived and non-deprived visual cortex of adult awake cats 18 to 53 days after the induction of restricted binocular retinal lesions, and in topographically corresponding cortical regions of control animals. A microbore HPLC-ED method was applied for the analysis of the microdialysates. In normal subjects, the visual cortex subserving central and peripheral vision showed similar extracellular fluid glutamate concentrations. In contrast, in animals with homonymous central retinal lesions, the extracellular glutamate concentration was significantly lower in central, sensory-deprived cortex compared to peripheral, non-deprived cortex. Compared to control regions in normal subjects, glutamate decreased in the extracellular fluid of deprived cortex but increased significantly in remote non-deprived visual cortex. These results not only suggest an activity-dependent regulation of the glutamate levels in visual cortex but also imply a role for perilesional cortical regions in topographic map reorganization following sensory deafferentation.

Animals↗

Factors affecting the extension of peritumoural brain oedema. A CT-study.

In human brain tumours the extension of peritumoural brain oedema may vary considerably. 37 brain tumours of various pathology and 2 abscesses were examined to identify the factors and mechanisms responsible for the oedema spreading. Peritumoural oedema profiles were determined towards the white matter and ventricle by measuring the CT-numbers of consecutive tissue blocks of 3.0-3.6 mm from the tumour to the normal white matter or the ventricle. It was found that neither the size of the tumour nor the histology has a close relationship to the amount of peritumoural oedema. The distance of oedema spreading rather is determined by the amount of fluid accumulation in the white matter immediately bordering the tumour. This relationship corresponds to a semilogarithmic function and represents the relation between the tumour-adjacent accumulation of extracellular fluid volume and the distance of extracellular fluid movement. The analysis of this relation leads to the suggestion that pressure gradients and bulk flow are involved in the development of human peritumoural oedema.

Brain Edema↗

Effect of extracellular space on kallikrein excretion in the rat.

Urinary kallikrein excretion was positively correlated with urine flow and negatively with urinary osmolality, it was also positively correlated with inulin space and its both components, plasma volume and interstitial space. We postulate that increased extracellular fluid increases kallikrein excretion and kallikrein avoids water reabsorption leading to a decrease in the extracellular fluid.

Animals↗

Patterns of cerebrospinal fluid catechols support increased central noradrenergic responsiveness in aging and Alzheimer's disease.

BACKGROUND: High cerebrospinal fluid (CSF) norepinephrine (NE) concentrations in aging and Alzheimer's disease (AD) could reflect decreased NE clearance from central nervous system (CNS) extracellular fluid or increased release of NE into CNS extracellular fluid. Measuring CSF concentrations of the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), an estimate of NE clearance, and the NE precursor dihydroxyphenylacetic acid (DOPA), an estimate of NE biosynthesis, can help differentiate these mechanisms. METHODS: NE, DHPG, and DOPA were determined by HPLC in CSF and plasma obtained following yohimbine, clonidine, and placebo. Ten AD, 10 older, and 11 young subjects were studied. RESULTS: CSF DOPA following yohimbine was higher in older and AD than in young subjects. CSF DHPG did not differ among groups. Plasma DOPA following yohimbine was higher in AD than in young subjects. CONCLUSIONS: During alpha-2 adrenoreceptor blockade in both aging and AD, there are increased responses of CNS NE biosynthesis and release with unchanged CNS NE clearance. This pattern is consistent with partial loss of CNS noradrenergic neurons with compensatory activation of remaining CNS noradrenergic neurons. Given the marked loss of locus coeruleus (LC) noradrenergic neurons in AD, achievement of high CSF NE suggests particularly prominent compensatory activation of remaining LC neurons in this disorder.

Adrenergic alpha-Agonists↗

MultiHance: help or hype?

MultiHance (Gd-BOPTA) couples specific, long lasting enhancement of magnetic resonance signal intensity in the liver parenchyma with the plasma kinetics of agents targeted to the extracellular fluid space. Therefore, this new contrast agent may be used both as an extracellular fluid agent, such as Magnevist (Gd-DTPA) or ProHance (gadoteridol) or as a liver-specific agent, such as Teslascan (mangafodipir) or iron oxides (e.g., Endorem). The clinical studies conducted so far have shown that MultiHance improves liver cancer detection by magnetic resonance imaging, the characterization of liver lesions, when used in combination with bolus dynamic magnetic resonance imaging, and the diagnostic performance of magnetic resonance imaging in extra-hepatic organ areas, such as brain and spine and the cardiovascular system. This brief article attempts to define the potential utility of this novel agent in the daily clinical setting, taking into account what is already available in radiology departments. It summarizes briefly the clinical need for a magnetic resonance contrast agent which improves the impact of magnetic resonance imaging for both the detection and characterization of focal liver lesions and concludes with the affirmation that MultiHance would be a definite help to radiologists working on all aspects of magnetic resonance imaging.

Carcinoma, Hepatocellular↗

Protein exudation induced by manipulation of the intestines and mesentery during laparotomy in rat. A study of the mechanism of 'third space' loss.

BACKGROUND-MATERIALS: Much extracellular fluid administration is required during major surgery because of the functional loss of extracellular fluid. In the present study we investigated the effect of manipulation of the intestines and mesentery in a rat laparotomy model. METHODS-RESULTS-CONCLUSIONS: The results showed that manipulation significantly increased the amount of protein exudated into the peritoneal space and induced a marked histopathological inflammatory response including polymorphonuclear leukocyte infiltration and mast cell degradation. These findings suggest that the inflammatory response induced by manipulation may, at least in part, explain the underlying mechanism of 'third space' loss during abdominal intestinal surgery.

Animals↗

Adaptive responses to sustained volume expansion in hyponatraemic rats.

Studies were carried out to evaluate adaptive responses to water retention in an experimental model of the syndrome of inappropriate antidiuresis (SIAD). Hyponatraemia was induced by continuous s.c. infusions of the antidiuretic vasopressin analogue 1-deamino-[8-D-arginine]-vasopressin in rats ingesting a 5% (w/v) dextrose solution. After 48 h of sustained decreases in the plasma concentration of Na+ to 23-25% of normal levels, all body fluid compartments were significantly expanded: plasma volume estimated by changes in plasma protein concentration was increased by 26%, extracellular fluid volume estimated by 22Na volume of distribution was increased by 24%, and total body water estimated by 3H2O volume of distribution was increased by 16%. Despite marked increases in all body fluid compartment volumes, mean arterial blood pressure was only modestly increased to 110 +/- 2 mmHg in conscious hyponatraemic rats. Consistent with the sustained volume expansion, both basal and stimulated plasma renin activities were significantly suppressed in the hyponatraemic rats. Plasma vasopressin levels were similarly suppressed, and the hyponatraemic rats showed a striking absence of endogenous vasopressin secretion in response to marked intravascular volume depletion (15-45%) produced by s.c. administration of polyethylene glycol. Plasma concentrations of atrial natriuretic peptide were initially stimulated four- to fivefold above basal levels in response to the water-induced volume expansion, but by 48 h fell to ranges not significantly different from basal unstimulated levels, despite continued plasma and extracellular fluid volume expansion at that time. These results illustrate that multiple haemodynamic and hormonal adaptive responses occur with sustained dilutional hyponatraemia in rats, and suggests that these can be of sufficient magnitude to allow continued water retention without necessarily provoking either escape from antidiuresis or continued natriuresis. In contrast with previous studies in experimental animals in which hyponatraemia was maintained by continuous forced administration of hypotonic fluid, rats in this model reached a steady state with characteristics resembling many of those observed clinically in patients with SIAD.

Animals↗

A new model examining intracellular and extracellular activity of amoxicillin, azithromycin, and clarithromycin in infected cells.

An in vitro infection model was created using a suspension of macrophages, polymorphonuclear leukocytes, lymphocytes, fibroblasts, and human serum to which pathogen and antibiotic were added. Separate intracellular and extracellular antibiotic concentrations and activity against Staphylococcus aureus and Legionella pneumophila were assessed for three antimicrobial agents: amoxicillin, azithromycin and clarithromycin. Amoxicillin was found almost exclusively in extracellular fluid, where it was active; intracellularly, it was ineffective. Azithromycin, in contrast, was primarily concentrated and active intracellularly, with little activity in extracellular fluid. Clarithromycin was present in both compartments and possessed significant activity both intracellularly and extracellularly.

Amoxicillin↗

Inhibition of carcinoma cell-derived VEGF reduces inflammatory characteristics in xenograft carcinoma.

The stroma of carcinomas shares several characteristics with inflamed tissues including a distorted vasculature, active angiogenesis and macrophage infiltration. In addition, the tumor interstitial fluid pressure (P(IF)) of the stroma is pathologically elevated. We show here that bevacizumab [rhuMab vascular endothelial growth factor (VEGF), Avastin], a monoclonal antibody to VEGF, at a dose of 5 mg/kg modulated inflammation in KAT-4 xenograft human anaplastic thyroid carcinoma tissue. At this dose, bevacizumab reduced the density of macrophages, MHC class II antigen expression by macrophages and IL-1beta mRNA expression. Furthermore, bevacizumab lowered tumor extracellular fluid volume, plasma protein leakage from tumor vessels, the number of CD31-positive structures and tumor P(IF). The tumor plasma volume and the number of alpha-smooth muscle actin-positive vessels, however, remained unchanged. Our data suggest that carcinoma cell-derived VEGF either directly or indirectly participates in maintaining an inflammatory microenvironment in experimental KAT-4 carcinoma. Furthermore, our data indicate that the reduction of inflammation resulting in reduced vascular permeability and decrease in the tumor extracellular fluid volume by bevacizumab contributes to reduced tumor P(IF).

Animals↗

Renin is not synthesized by cardiac and extrarenal vascular tissues. A review of experimental evidence.

A comprehensive review of physiological and molecular biological evidence refutes claims for synthesis of renin by cardiac and vascular tissues. Cardiovascular tissue renin completely disappears after binephrectomy. Residual putative reninlike activity, where investigated, has had the characteristics of lysosomal acid proteases. Occasional reports of renin or renin mRNA in vascular and cardiac tissues can be ascribed to failure to remove the kidneys 24 hours beforehand, overloading of detection systems, problems with stringency in identification, and illegitimate transcripts after more than 25 cycles of polymerase chain reaction. Others, using more stringent criteria, have failed to detect cardiac and vascular renin mRNA. Accordingly, a growing number of investigators have concluded that the kidneys are the only source of cardiovascular tissue renin. Although prorenin is secreted from extrarenal tissues as well as from the kidneys, there is no evidence that it is ever converted to renin in the circulation. The kidney is the only tissue with known capacity to convert prorenin to renin and to secrete active renin into the circulation. Accordingly, renin of renal origin determines plasma and hence, extracellular fluid renin levels. In these loci, angiotensin (Ang) I, formed by renin cleavage of circulating and interstitial fluid angiotensinogen, is in turn cleaved by angiotensin converting enzyme, located in plasma and extracellular fluids and on the luminal surface of pulmonary and systemic vascular endothelial cells, to Ang II, which perfuses and bathes the heart and vasculature. Consistent with this model, plasma renin and angiotensin and the antihypertensive action of renin inhibitors, converting enzyme inhibitor, or Ang II antagonists all disappear after binephrectomy. Thus, the plasma renin level, via Ang II formation, determines renin system vasoconstrictor activity, the antihypertensive potential of anti-renin system drugs, and the risk of heart attack in hypertensive patients. This analysis redirects renin research to renal mechanisms that create the plasma renin level, to renal prorenin biosynthesis and its processing to renin, and to their regulated secretion, extracellular distribution, and possible binding to by target tissues. In this context, it is still possible that changes in circulating and interstitial renin substrate or available converting enzyme might exert subtle modulating influences on Ang II formation. However, this analysis redefines the importance of plasma renin measurements to assess clinical situations, because plasma renin is the only known initiator driving the cardiovascular renin-angiotensin system, and its strength can be measured.

Angiotensin I↗

The connective tissue coverings of leech peripheral nerves: anatomical evidence for the absence of cerebrospinal fluid in the leech.

The central nervous system of Hirudo medicinalis is contained within a blood vessel, the ventral longitudinal sinus, but the nervous system is separated from the blood by the visceral endothelium. The visceral endothelium possesses many pinocytotic vesicles and basal infoldings and thus appears active whereas the parietal endothelium appears inactive. The junction between the visceral and parietal endothelia is abrupt. Peripheral nerves in this animal, as in vertebrates, are covered by endoneurium, perineurium, and epineurium. The endoneurium is continous with the fibrous tissue of the segmental ganglia. The perineurium, consisting of a single layer of flattened cells that surrounds the peripheral nerve like a sleeve, is not continuous with the endothelium of the ventral sinus, but is separated from it by 5-10 microns. Therefore, at the point where the peripheral nerve joins the segmental ganglion, the extracellular spaces of the central nervous system, the peripheral nervous system, and the body wall are all confluent. Thus, there are only two compartments of the extracellular space in the leech: the blood, which is enclosed by the endothelia of the coelomic sinuses, and the extracellular fluid of the body, which includes the extracellular fluid of the nervous system. There seems to be no equivalent of cerebrospinal fluid in the gnathobdellid leech.

Animals↗

[Serum uric acid level and fractional excretion of urate in fluid and electrolyte disturbances].

Changes in renal urate clearance may reflect altered glomerular dynamics more precisely than other commonly used indices. Extracellular fluid volume expansion is known to be correlated with uricosuria, while volume depletion is associated with decreased urate excretion. The diagnostic usefulness of measuring serum urate levels and fractional excretions of urate in SIADH, incipient diabetic nephropathy, and prerenal azotemia have been reviewed. In SIADH, profound hypouricemia and markedly increased fractional excretion of urate (FEUA) accompany the extracellular fluid volume expansion. In prerenal azotemia, decreased FEUA may represent a reliable indicator of prerenal azotemia in the differential diagnosis of acute renal failure. In incipient diabetic nephropathy, glomerular hyperfiltration may increase renal urate clearance and lower the serum uric acid level. Hypouricemia may also predict the future progression of incipient nephropathy in type II diabetes.

Biomarkers↗

Influence of aortic constriction on proximal chloride reabsorption during volume expansion.

Extracellular fluid volume expansion is associated with a decrease in the transepithelial chloride gradient in the proximal convoluted tubule. We have previously shown that this effect occurs in the presence of hypo- or hyperchloremia and is not dependent on a change in filtered chloride or bicarbonate load. To determine the influence of filtered fluid load on this effect of volume expansion, micropuncture studies were carried out during acute extracellular fluid volume expansion in rats with (group AC) and without (group CON) a reduction in renal perfusion pressure. Delayed aortic constriction prevented the increase in fluid load (49.7 +/- 2.4 and 49.0 +/- 3.9 nl/min for hydropenia and volume expansion, respectively), but reduced tubule fluid to plasma inulin ratios (2.25 +/- 0.13 and 1.84 +/- 0.8) were maintained. Tubule fluid to plasma chloride ratios did not change in group AC (1.27 +/- 0.03 and 1.25 +/- 0.01) as compared to group CON (1.25 +/- 0.02 and 1.18 +/- 0.02; p less than 0.05). Fractional chloride reabsorption fell in both groups. Absolute chloride reabsorption was highly correlated (p less than 0.001) with absolute fluid reabsorption. These results suggest that filtered fluid load or some related variable is an important determinant of the generation of the chloride gradient in the proximal tubule.

Animals↗

Disorders of water and sodium balance.

The serum sodium concentration reflects a patient's relative water balance and thus determines if the patient needs more or less water than normal maintenance needs would dictate. The serum sodium concentration has no bearing on whether a patient requires sodium restriction or saline administration. Rather, the sodium/saline balance is determined by clinical assessment of the patient's extracellular fluid volume. Physicians must clearly understand the principles involved when assessing a patient's water and sodium needs. After maintenance water needs and any foreseeable ongoing losses have been factored in, an intelligent plan of fluid management can be initiated. Frequent reassessments, with serial weight measurements, clinical evaluations of extracellular fluid volume status, and determinations of serum sodium concentration, are essential to determine if the desired therapeutic goals are being reached.

Body Fluids↗