MedWorm: Physiology

Neuroeffector ca2+ transients for the direct measurement of purine release and indirect measurement of cotransmitters in rodents

Experimental Physiology — Sat, 11 Oct 2008 04:00:00 +0100

Determining whether ATP and noradrenaline are released from the same vesicle at mature autonomic neuroeffector junctions is challenging because of the difficulty of simultaneously detecting the packeted release of these neurotransmitters. Contraction, overflow and electrophysiology experiments all show that both ATP and noradrenaline are released following field stimulation (although the ratio might vary) from autonomic nerves in tissues including the vas deferens, rat tail artery and mesenteric artery. The occurrence of purinergic neuroeffector Ca2+ transients (NCTs) has been used to detect the packeted release of the neurotransmitter ATP acting on postjunctional P2X receptors to cause Ca2+ influx. Neuroeffector Ca2+ transients can also be used to detect the local effects of noradrenaline through its [alpha]2-adrenoceptor-mediated prejunctional autoinhibitory effects on nerve terminal Ca2+ concentration and the probability of exocytosis (measured by counting NCTs). Evidence is presented that exocytosis from sympathetic varicosities does not occur in a manner independent of the history of that varicosity, but rather that the release of a packet of ATP transiently suppresses (or predicts the transient suppression of) subsequent release. This could arise by autoinhibition (by the prejunctional action of noradrenaline or purines) or due to a transient shortage of vesicles readily available for release. In summary, two high-resolution approaches are proposed to measure the intermittent release of packets of neurotransmitter: (1) local transient suppression of nerve terminal Ca2+ transients; and (2) the local and transient inhibition of NCTs to infer local autoinhibition, hence transmitter release. Such approaches may allow the packeted corelease of ATP and noradrenaline to be investigated without the need to measure both neurotransmitters directly. (Source: Experimental Physiology)

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Reactive oxygen species and inflammatory mediators enhance muscle spindles mechanosensitivity in rats.

Pflugers Archiv : European Journal of Physiology — Fri, 10 Oct 2008 04:00:00 +0100

Reactive oxygen species and inflammatory mediators enhance muscle spindles mechanosensitivity in rats.

Pflugers Arch. 2008 Oct 10;

Authors: Delliaux S, Brerro-Saby C, Steinberg JG, Jammes Y

We tested the hypothesis that reactive oxygen species (ROS) and inflammatory mediators affect transduction properties of muscle spindles. In rats, muscle spindles response to high-frequency vibration (HFV) was recorded before and after (1) injection of hydrogen peroxide (H(2)O(2)) in control rats and animals pre-treated with diclofenac (anti-inflammatory substance), (2) injection of bradykinin and (3) fatigue induced by muscle stimulation (MS) in control rats and rats receiving diclofenac, superoxide dismutase (SOD) or H(2)O(2). Muscular oxidative stress and inflammation induced by H(2)O(2) or MS were assessed by measurements of isoprostanes and IL-6 levels. In control rats, H(2)O(2), bradykinin and MS significantly enhanced the HFV response. Pre-treatment with SOD abolished the post-MS-enhanced HFV response whereas diclofenac lowered the peak HFV response to MS and H(2)O(2). H(2)O(2) injection and MS elicited significant and similar increases in isoprostanes and IL-6. We report a direct modulation of muscle spindles mechanosensitivity by ROS and inflammatory mediators.

PMID: 18846383 [PubMed - as supplied by publisher]

(Source: Pflugers Archiv : European Journal of Physiology)

Cardiac and coronary function in the langendorff-perfused mouse heart model

Experimental Physiology — Fri, 10 Oct 2008 04:00:00 +0100

The Langendorff mouse heart model is widely employed in studies of myocardial function and responses to injury (e.g. ischaemia). Nonetheless, marked variability exists in its preparation and functional properties. We examined the impact of early growth (8, 16, 20 and 24 weeks), sex, perfusion fluid [Ca2+] and pacing rate on contractile function and responses to 20 min ischaemia followed by 45 min reperfusion. We also assessed the impact of strain, and tested the utility of the model in studying coronary function. Under normoxic conditions, hearts from 8-week-old male C57BL/6 mice (2 mm free perfusate [Ca2+], 420 beats min[ndash]1) exhibited 145 ± 2 mmHg left ventricular developed pressure (LVDP). Force development declined by [sim]15% (126 ± 5 mmHg) with a reduction in free [Ca2+] to 1.35 mm, and by 25% (108 ± 3 mmHg) with increased pacing to 600 beats min[ndash]1. While elevated heart rate failed to modify ischaemic outcome, the lower [Ca2+] significantly improved contractile recovery (by >30%). We detected minimal sex-dependent differences in normoxic function between 8 and 24 weeks, although age modified contractile function in males (increased LVDP at 24 versus 8 weeks) but not females. Both male and female hearts exhibited age-related reductions in ischaemic tolerance, with a significant decline in recovery evident at 16 weeks in males and later, at 20[ndash]24 weeks, in females (versus recoveries in hearts at 8 weeks). Strain also modified tolerance to ischaemia, with similar responses in hearts from C57BL/6, 129/sv, Quackenbush Swiss and FVBN mice, but substantially greater tolerance in BALB/c hearts. In terms of vascular function, baseline coronary flow (20[ndash]25 ml min[minus]1 g[minus]1) was 50[ndash]60% of maximally dilated flows, and coronary reactive and functional hyperaemic responses were pronounced (up to 4-fold elevations in flow in hearts lacking ventricular balloons). These data indicate that attention to age (and sex) of mice will reduce variability in contractile function and ischaemic responses. Even small differences in perfusion fluid [Ca2+] also significantly modify tolerance to ischaemia (whereas modest shifts in heart rate do not impact). Ischaemic responses are additionally strain dependent, with BALB/c hearts displaying greatest intrinsic tolerance. Finally, the model is applicable to the study of vascular reactivity, providing large responses and excellent reproducibility. (Source: Experimental Physiology)

Assessment of physiological demand in kitesurfing

European Journal of Applied Physiology — Wed, 08 Oct 2008 12:14:04 +0100

Abstract To evaluate the physiological demands of kitesurfing, ten elite subjects performed an incremental running test on a 400-m track and a 30-min on-water crossing trial during a light crosswind (LW, 12–15 knots). Oxygen uptake æè × V \textO 2 öø was estimated from the heart rate (HR) recorded during the crossing trial using the individual HR- × V \textO2 relationship determined during the incremental test. Blood lactate concentration [Lab] was measured at rest and 3 min after the exercise completion. Mean HR and estimated × V \textO2 values represented, respectively 80.6 ± 7.5% of maximal heart rate and 69.8 ± 11.7% of maximal oxygen uptake for board speeds ranging from 15 to 17 knots. Low values for [Lab] were observed at the end of crossing trial (2.1 ± 1.2 mmol l−1. This first analysis of kitesurfing suggests that the energy demand is mainly sustained by aerobic metabolism during a LW condition. Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s00421-008-0879-3Authors F. Vercruyssen, Université de Toulon-Var Laboratoire Handibio, groupe “Mouvement altéré et efficience énergétique”, UFR STAPS 83957 La Garde Cedex FranceN. Blin, Direction départementale et régionale de Paris, Ile de France 6/8 rue Eugène Oudiné 75013 Paris FranceD. L’Huillier, DLS Kiteboarding Company 85 470 Brétignolles sur mer FranceJ. Brisswalter, Université de Toulon-Var Laboratoire Handibio, groupe “Mouvement altéré et efficience énergétique”, UFR STAPS 83957 La Garde Cedex France Journal European Journal of Applied PhysiologyOnline ISSN 1439-6327Print ISSN 1439-6319 (Source: European Journal of Applied Physiology)

Effects of muscular biopsy on the mechanics of running

European Journal of Applied Physiology — Wed, 08 Oct 2008 12:14:04 +0100

Abstract Muscle biopsy is a widely used technique in protocols aiming at studying physical capacities and fiber profiles of athletes, and muscular adaptations to exercise. Side effects of biopsy alone on physiological parameters have recently been pointed out, and we sought to determine whether a single biopsy had effects on the main stride mechanical parameters. Ten male runners performed 4-min runs before and after undergoing a biopsy of their left vastus lateralis muscle. Step frequency and duty factor were significantly higher after biopsy (2.86 ± 0.14 vs. 2.82 ± 0.15 Hz, and 0.77 ± 0.04 vs. 0.75 ± 0.05, respectively), whereas other factors were significantly lower: maximal vertical ground reaction force (1,601 ± 240 vs. 1,643 ± 230 N), loading rate (53.9 ± 12.8 vs. 58.4 ± 13.5 bw s−1), center of mass vertical displacement (0.056 ± 0.008 vs. 0.058 ± 0.008 m) and external mechanical work at each step (1.14 ± 0.10 vs. 1.24 ± 0.10 J kg−1 step−1). These effects were observed on the left (biopsed) leg, but also on the right one for the external mechanical work, the duty factor and the maximal vertical ground reaction force, showing that a single biopsy had both ipsi- and contralateral effects on running mechanics. Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s00421-008-0888-2Authors Jean-Benoit Morin, Universite de Saint-Etienne Unité de Recherche PPEH St Etienne FrancePierre Samozino, Universite de Saint-Etienne Unité de Recherche PPEH St Etienne FranceLéonard Féasson, Universite de Saint-Etienne Unité de Recherche PPEH St Etienne FranceAndré Geyssant, Universite de Saint-Etienne Unité de Recherche PPEH St Etienne FranceGuillaume Millet, Universite de Saint-Etienne Unité de Recherche PPEH St Etienne France Journal European Journal of Applied PhysiologyOnline ISSN 1439-6327Print ISSN 1439-6319 (Source: European Journal of Applied Physiology)

Restoration of vital activity of cooled animals without rewarming the body

European Journal of Applied Physiology — Wed, 08 Oct 2008 12:14:04 +0100

Abstract The fatality of deep hypothermia in non-hibernating mammals follows the cessation of respiration and heart beat, and a massive influx of calcium (Ca++) into cells. This review presents evidence relating to restoration of key physiological functions during hypothermia in several animal preparations. For example, in anaesthetized hypothermic rats (body temperature 16–17°C), a pharmacologically induced reduction in intracellular [Ca++] [via intravenous administration of an ethylenediaminetatraacetate (EDTA) solution (0.15–0.16 mmole)] has been shown to restore cold shivering and respiration after several minutes. Also, activity in an isolated rat heart preparation has been shown to be halted when temperature is reduced in the range 14–12°C. However, decreasing the perfusate [potassium] by a factor of 2–3 relative to normal blood levels restored contractile activity. In conclusion, it is possible to restore the activity of key physiological systems involved in the thermoregulatory responses to sustained hypothermia without the need to rewarm the organism. Content Type Journal ArticleCategory Review ArticleDOI 10.1007/s00421-008-0875-7Authors K. P. Ivanov, Russian Academy of Sciences I.P. Pavlov Institute of Physiology Nab. Makarova, 6 199034 St Petersburg Russia Journal European Journal of Applied PhysiologyOnline ISSN 1439-6327Print ISSN 1439-6319 (Source: European Journal of Applied Physiology)

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Physiological research.

Physiological Research — Wed, 08 Oct 2008 10:14:31 +0100

Physiological research.

Physiol Res. 2008;57 Suppl 2:i-iii

Authors: Styk J

PMID: 18837115 [PubMed - in process]

(Source: Physiological Research)

Hypoxia augments apnea-induced increase in hemoglobin concentration and hematocrit

European Journal of Applied Physiology — Wed, 08 Oct 2008 09:50:22 +0100

Abstract Increased hemoglobin concentration (Hb) and hematocrit (Hct), attributable to spleen contraction, raise blood gas storage capacity during apnea, but the mechanisms that trigger this response have not been clarified. We focused on the role of hypoxia in triggering these Hb and Hct elevations. After horizontal rest for 20 min, 10 volunteers performed 3 maximal apneas spaced by 2 min, each preceded by a deep inspiration of air. The series was repeated using the same apneic durations but after 1 min of 100% oxygen (O2) breathing and O2 inspiration prior to each apnea. Mean apneic durations were 150, 171, and 214 s for apneas 1, 2, and 3, respectively. Relative to pre-apnea values, the mean post-apneic arterial O2 saturation nadir was 84.7% after the air trial and 98% after the O2 trial. A more pronounced elevation of both Hb and Hct occurred during the air trial: after apnea 1 with air, mean Hb had increased by 1.5% (P < 0.01), but no clear increase was found after the first apnea with O2. After the third apnea with air Hb had increased by 3.0% (P < 0.01), and with O2 by 2.0% (P < 0.01). After the first apnea with air Hct had increased by 1.9% (P < 0.01) and after 3 apneas by 3.0% (P < 0.01), but Hct did not change significantly in the O2 trial. In both trials, Hb and Hct were at pre-apneic levels 10 min after apneas. Diving bradycardia during apnea was the same in both trials. We conclude that hypoxia contributes to spleen contraction during apnea, likely through chemosensor-related sympathetic output. There are, however other factors involved that trigger spleen contraction even in the absence of hypoxia. Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s00421-008-0873-9Authors Matt X. Richardson, Mid Sweden University Environmental Physiology Group 83125 Östersund SwedenRobert de Bruijn, Mid Sweden University Environmental Physiology Group 83125 Östersund SwedenErika Schagatay, Mid Sweden University Environmental Physiology Group 83125 Östersund Sweden Journal European Journal of Applied PhysiologyOnline ISSN 1439-6327Print ISSN 1439-6319 (Source: European Journal of Applied Physiology)

Nutritional condition and physiology of paternal care in two congeneric species of black bass ( micropterus spp.) relative to stage of offspring development

Wed, 08 Oct 2008 09:50:14 +0100

Abstract Parental care requires a complex integration of physiology and behaviour, yet little is known about the physiological and energetic consequences or correlates of these behaviours. Using two species of male black bass (smallmouth bass, Micropterus dolomieu; largemouth bass, M. salmoides) as a model, the focus of this study was to determine the biochemical and hematological indicators of change in nutritional status and potential for chronic stress. This was accomplished by randomly sampling individuals at four stages across parental care. Additionally, a subset of individuals was repeatedly sampled at three brood development stages to track changes in biochemical factors within the individual. Though there were changes in physiological factors across parental care in randomly sampled fish of both species (declines in plasma glucose in largemouth bass; decreases in hematocrit and plasma chloride in smallmouth bass), repeated sampling of individuals was determined to be a more appropriate sampling technique due to natural variability in biochemical factors among individual fish. Repeated sampling of smallmouth bass did not adversely influence physiological metrics or brood abandonment. However, there were higher incidences of nest abandonment in repeatedly sampled largemouth bass. Amongst the repeatedly sampled smallmouth bass, nutritional indicators such as plasma triglyceride levels decreased indicating individual fasting across the majority of parental care. Increases in plasma calcium and magnesium towards the end of care indicated that feeding most likely resumed when the brood was close to independence after ~3 weeks of care. Lastly, several indicators of chronic stress, such as plasma glucose and chloride levels, increased throughout the parental care period. These sublethal stressors are indicative of decreasing body condition associated with prolonged activity and fasting which may have marked impacts on the ability of an individual to continue parental care for the current brood and impact subsequent individual fitness. Further research into the mechanistic relationships between behaviour, physiology, and energetics during the parental care period will provide a better understanding of the decisions by individuals facing multiple trade-offs that ultimately lead to differences in individual fitness. Content Type Journal ArticleCategory Original PaperDOI 10.1007/s00360-008-0309-1Authors Kyle C. Hanson, Carleton University Fish Ecology and Conservation Physiology Laboratory, Ottawa-Carleton Institute for Biology 1125 Colonel By Drive Ottawa ON K1S 5B6 CanadaSteven J. Cooke, Carleton University Fish Ecology and Conservation Physiology Laboratory, Ottawa-Carleton Institute for Biology 1125 Colonel By Drive Ottawa ON K1S 5B6 Canada Journal Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental PhysiologyOnline ISSN 1432-136XPrint ISSN 0174-1578 (Source: Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology)

Plant ion channels: gene families, physiology, and functional genomics analysis.

Annual Review of Physiology — Wed, 08 Oct 2008 04:00:00 +0100

Plant Ion Channels: Gene Families, Physiology, and Functional Genomics Analysis.

Annu Rev Physiol. 2008 Oct 8;

Authors: Ward JM, Mäser P, Schroeder JI

Distinct potassium, anion, and calcium channels in the plasma membrane and vacuolar membrane of plant cells have been identified and characterized by patch clamping. Primarily owing to advances in Arabidopsis genetics and genomics, and yeast functional complementation, many of the corresponding genes have been identified. Recent advances in our understanding of ion channel genes that mediate signal transduction and ion transport are discussed here. Some plant ion channels, for example, ALMT and SLAC anion channel subunits, are unique. The majority of plant ion channel families exhibit homology to animal genes; such families include both hyperpolarizationand depolarization-activated Shaker-type potassium channels, CLC chloride transporters/channels, cyclic nucleotide-gated channels, and ionotropic glutamate receptor homologs. These plant ion channels offer unique opportunities to analyze the structural mechanisms and functions of ion channels. Here we review gene families of selected plant ion channel classes and discuss unique structure-function aspects and their physiological roles in plant cell signaling and transport. Expected final online publication date for the Annual Review of Physiology Volume 71 is February 4, 2009. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

PMID: 18842100 [PubMed - as supplied by publisher]

(Source: Annual Review of Physiology)

Transfer of the cyp4a region of chromosome 5 from lewis to dahl s rats attenuates renal injury.

American Journal of Physiology. Renal Physiology — Wed, 08 Oct 2008 04:00:00 +0100

Transfer of the CYP4A region of chromosome 5 from Lewis to Dahl S rats attenuates renal injury.

Am J Physiol Renal Physiol. 2008 Oct 8;

Authors: Williams JM, Sarkis A, Hoagland KM, Fredrich K, Ryan RP, Moreno C, Lopez B, Lazar J, Fenoy FJ, Sharma M, Garrett MR, Jacob HJ, Roman RJ

This study examined the effect of transfer of overlapping regions of chromosome 5 that includes (4A(+)) or excludes (4A(-)) the CYP4A genes from the Lewis rat on the renal production of 20-HETE and the development of hypertension-induced renal disease in congenic strains of Dahl S rats. The production of 20-HETE was higher in the outer medulla of 4A(+) than in Dahl S or 4A(-) rats. MAP rose to 190+/-7 and 185+/-3 mmHg in Dahl S and 4A(-) rats fed a high salt (HS) diet for 21 days, but only to 150+/-5 mmHg in the 4A(+) strain. Protein excretion increased to 423+/-40 and 481+/-37 mg/day in Dahl S and 4A(-) rats versus 125+/-15 mg/day in the 4A(+) strain. Baseline glomerular capillary pressure (Pgc) was lower in 4A(+) rats (38+/-1 mmHg) than in Dahl S rats (42+/-1 mmHg). Pgc increased to 50+/-1 mmHg in Dahl S rats fed a HS diet, while it remained unaltered in 4A(+) rats (39+/-1 mmHg). Baseline glomerular permeability to albumin (Palb) was lower in 4A(+) rats (0.19+/-0.05) than in Dahl S or 4A(-) rats (0.39+/-0.02). Palb rose to approximately 0.61+/-0.03 in 4A(-) and Dahl S rats fed a HS diet for 7 days but it remained unaltered in the 4A(+) rats. The expression of TGF-beta2 was higher in glomeruli of Dahl S rats than in 4A(+) rats fed either a low salt (LS) or HS diet. Chronic administration of a 20-HETE synthesis inhibitor (HET0016, 10 mg/kg/day, s.c.) reversed the fall in MAP and renoprotection seen in 4A(+) rats. These results indicate that the introgression of the CYP4A genes from Lewis rats into the Dahl S rats increases the renal formation of 20-HETE and attenuates the development of hypertension and renal disease. Key words: Hypertension, Glomerulosclerosis, 20-HETE, Dahl salt-sensitive rats.

PMID: 18842817 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Renal Physiology)

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Ablation of developing podocytes disrupts cellular interactions and nephrogenesis both inside and outside the glomerulus.

American Journal of Physiology. Renal Physiology — Wed, 08 Oct 2008 04:00:00 +0100

Ablation of developing podocytes disrupts cellular interactions and nephrogenesis both inside and outside the glomerulus.

Am J Physiol Renal Physiol. 2008 Oct 8;

Authors: Jia Q, McDill BW, Sankarapandian B, Wu S, Liapis H, Holzman LB, Capecchi MR, Miner JH, Chen F

Podocyte loss in adults leads to glomerulosclerosis. However, the impact of podocyte loss on glomerulogenesis and the development of the kidney as a whole has not been directly studied. Here, we used a podocyte-specific Cre transgene to direct the production of diphtheria toxin (DTA) inside podocytes during nephrogenesis. Affected podocytes underwent translational arrest and apoptosis, leading to oliguria, proteinuria, hematuria, interstitial hemorrhage, and perinatal death. Glomerular cell-cell interactions were disrupted, even before overt podocyte apoptosis. VEGF production by podocytes was greatly decreased, and this was associated with reduced endothelial fenestration and altered glomerular vascular architecture. In addition to these glomerular anomalies, embryonic podocyte ablation also led to structural changes and increased apoptosis in proximal tubules. The collecting ducts, however, only showed molecular changes that are likely an indirect effect of the greatly reduced urine flow. Although podocyte loss significantly impacted the development and maintenance of the vasculature both inside and outside the glomerulus, our results suggest that there is a lack of long range signaling from deep seated, mature glomeruli to the differentiating cells in the outer nephrogenic zone. This study illustrates the tight integration of various cell types in the developing kidney and shows that the impact of podocyte loss during development is much greater than that in adults. This study also shows the specificity and effectiveness of a genetically controlled podocyte ablation system in mice where the additional readily available tools can further expand its applications. Key words: Kidney development, glomerulogenesis, Diphtheria toxin.

PMID: 18842818 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Renal Physiology)

Glomerular epithelial cells in the urine: what has to be done to make them worthwhile ?

American Journal of Physiology. Renal Physiology — Wed, 08 Oct 2008 04:00:00 +0100

GLOMERULAR EPITHELIAL CELLS IN THE URINE: WHAT HAS TO BE DONE TO MAKE THEM WORTHWHILE ?

Am J Physiol Renal Physiol. 2008 Oct 8;

Authors: Skoberne A, Konieczny A, Schiffer M

The significance of the native urine sediment in the differential of glomerular diseases needs no further comments. However the question arises whether it could be useful to develop a more specific diagnostic approach to identify the origin of renal epithelial cells that can be detected in the urine sediments as well. Especially the detection of podocytes in the urine could be a valuable non-invasive method to get information about the disease activity or disease type and could be used as a follow up after a biopsy in an outpatient setting. So far there are only a few studies that analyzed the clinical relevance of renal epithelial cells in the urine systematically or prospective. The reason for this could be the nature of the material since it will remain unclear whether detachment and changes in the urine milieu have a direct effect on the expression of marker proteins on the detected cells. Dedifferentiation or transdifferentiation of cells that goes along with changed marker expression is certainly also part of the underlying disease process. This review summarizes the available information on marker proteins that have been successfully used in the diagnostic of "podocytes" in the urine. Furthermore it gives an overview of marker expression on podocytes in situ in development and disease and examines the role of glomerular epithelial shedding in the urine at the interface of basic science and clinical medicine. Key words: Podocytes, Parietal Cells, Urine Diagnostics, Podocyturia.

PMID: 18842819 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Renal Physiology)

The role of p75ntr in female rat urinary bladder with cyclophosphamide (cyp)-induced cystitis.

American Journal of Physiology. Renal Physiology — Wed, 08 Oct 2008 04:00:00 +0100

The Role of p75NTR in Female Rat Urinary Bladder with Cyclophosphamide (CYP)-Induced Cystitis.

Am J Physiol Renal Physiol. 2008 Oct 8;

Authors: Klinger MB, Vizzard MA

Previous studies demonstrated changes in urinary bladder neurotrophin content and upregulation of neurotrophin receptors, TrkA and the p75 neurotrophin receptor (p75(NTR)), in micturition reflex pathways after cyclophosphamide (CYP)-induced cystitis. p75(NTR) can bind NGF and modulate NGF-TrkA binding and signaling. We examined p75(NTR) expression and the role of p75(NTR) in the micturition reflex in control and CYP-treated rats. p75(NTR)-immunoreactivity (IR) was present throughout the urinary bladder. CYP-induced cystitis (4 hour (h), 48 h, chronic) increased (p </= 0.05) p75(NTR) expression in whole urinary bladder as shown by western blotting. The role of p75(NTR) in bladder function in control and CYP-treated rats was determined using conscious cystometry and immunoneutralization or PD90780, a compound known to specifically block NGF binding to p75(NTR). An anti-p75(NTR) monoclonal antibody or PD90780 was infused intravesically and cystometric parameters were evaluated. Both methods of p75(NTR) blockade significantly (p </= 0.05) decreased the intercontraction interval and void volume in control and CYP-treated rats. Intravesical infusion of PD90780 also significantly (p </= 0.001) increased intravesical pressure and increased the number of number of non-voiding contractions during the filling phase. Control intravesical infusions of isotype matched IgG and vehicle were without effect. Intravesical instillation of PD90780 significantly (p </= 0.01) reduced the volume threshold to elicit a micturition contraction in control rats (no inflammation) and CYP-treated in a closed urinary bladder system. These studies demonstrate: (1) ubiquitous p75(NTR) expression in urinary bladder and increased expression with CYP-induced cystitis; (2) p75(NTR) blockade at the level of the urinary bladder produces bladder hyperreflexia in control and CYP-treated rats. The overall activity of the urinary bladder reflects the balance of NGF-p75(NTR) and NGF-TrkA signaling. Key words: PD90780, conscious cystometry, western blotting, bladder hyperreflexia.

PMID: 18842820 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Renal Physiology)

Loop of henle interaction with interstitial nodal spaces in the renal inner medulla.

American Journal of Physiology. Renal Physiology — Wed, 08 Oct 2008 04:00:00 +0100

Loop of Henle Interaction with Interstitial Nodal Spaces in the Renal Inner Medulla.

Am J Physiol Renal Physiol. 2008 Oct 8;

Authors: Pannabecker TL

Understanding dynamics of NaCl reabsorption from loops of Henle, and cellular and physiological consequences, requires a clear understanding of structural relationships of loops with other functional elements of the inner medulla (IM). Pathways taken by ascending thin limbs (ATLs) and prebend segments along the corticopapillary axis were evaluated for the outer zone of the IM of Munich-Wistar rat. Connectivity between these segments and microdomains of interstitium adjacent to CDs and abutting ascending vasa recta (interstitial nodal spaces) was assessed by evaluating their physical contacts. For each secondary CD cluster, the number of contacts made between the total population of ATLs and interstitial nodal spaces declines as a function of depth below the OM-IM boundary at near the same exponential rate that loop number declines. The proportion of each loop that makes contact with nodal spaces is inversely related to loop length. Prebend and postbend equivalent length ATL segments lie in contact with an interstitial nodal space along nearly their entire lengths. The number of contacts made by the total population of prebend or postbend segments exhibits a marked, periodic increase and decrease as a function of depth below the OM-IM boundary; this number of contacts correlates with equivalent periodic changes in prebend number. Simulations of loop distribution indicate that small discontinuities in loop distribution contribute to periodic changes in prebend number. Convergence of IM loop bends within CD clusters likely plays an essential role in NaCl compartmentalization by promoting NaCl reabsorption near interstitial regions lying adjacent to CDs and AVR. Key words: concentrating mechanism, countercurrent system, computer-assisted reconstruction, NaCl transport, urea transport.

PMID: 18842821 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Renal Physiology)

Conditional fast expression and function of multimeric trpv5 channels using shield-1.

American Journal of Physiology. Renal Physiology — Wed, 08 Oct 2008 04:00:00 +0100

Conditional fast expression and function of multimeric TRPV5 channels using Shield-1.

Am J Physiol Renal Physiol. 2008 Oct 8;

Authors: Schoeber JP, van de Graaf SF, Lee KP, Wittgen HG, Hoenderop JG, Bindels RJ

A recently described novel controllable method to regulate protein expression is based on a mutated FK506-binding protein-12 (mtFKBP) that is unstable and rapidly degraded in mammalian cells. This instability can be conferred to other proteins directly fused to mtFKBP. Binding of a synthetic cell-permeant ligand (Shield-1) to mtFKBP reverses the instability, allowing conditional expression of mtFKBP-fused proteins. We adapted this strategy to study multimeric plasma membrane proteins using the ion channel TRPV5 as model protein. mtFKBP-TRPV5 forms functional ion channels and its expression can be controlled in a time- and dose-dependent fashion using Shield-1. Moreover, in the presence of Shield-1, mtFKBP-TRPV5 formed heteromultimeric channels with untagged TRPV5, which were co-degraded upon washout of Shield-1 - providing a strategy to study multimeric plasma membrane protein complexes without the need to destabilize all individual subunits. Key words: Conditional protein expression, inducible system, ion channels, heteromultimerization.

PMID: 18842822 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Renal Physiology)

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Sodium, potassium, chloride, and bicarbonate-related effects on blood pressure and electrolyte homeostasis in deoxycorticosterone acetate-treated rats.

American Journal of Physiology. Renal Physiology — Wed, 08 Oct 2008 04:00:00 +0100

Sodium, potassium, chloride, and bicarbonate-related effects on blood pressure and electrolyte homeostasis in deoxycorticosterone acetate-treated rats.

Am J Physiol Renal Physiol. 2008 Oct 8;

Authors: Ziomber A, Machnik A, Dahlmann A, Dietsch P, Beck FX, Wagner H, Hilgers KF, Luft FC, Eckardt KU, Titze J

Na(+) loading without Cl(-) fails to increase blood pressure in the DOCA model. We compared the changes in the total body (TB) effective Na(+), K(+), Cl(-), and water (TBW) content, as well as in intracellular (ICV) or extracellular (ECV) volume in rats receiving DOCA-NaCl, DOCA-NaHCO3, or DOCA-KHCO3. We divided 42 male rats into 5 groups. Group 1 was untreated, Group 2 received 1% NaCl, Groups 3, 4, and 5 were DOCA-treated and received 1% NaCl, 1.44% NaHCO3, or 1.7% KHCO3 to drink. We measured mean arterial blood pressure (MAP) after 3 weeks directly. Tissue electrolyte and water content was measured by chemical analysis. Compared to controls, DOCA-NaCl increased MAP, while DOCA-NaHCO3 and DOCA-KHCO3 did not. DOCA-NaCl increased TBNa(+) 26% but only moderately increased TBW. DOCA-NaHCO3 led to similar TBNa(+) excess, while TBW and ICV, but not ECV, were increased more than in DOCA-NaCl rats. DOCA-KHCO3 did not affect TBNa(+) or volume. At a given TB(Na(+)+K(+)) and TBW, MAP in DOCA-NaCl rats was higher than in control, DOCA-NaHCO3, and DOCA-KHCO3 rats, indicating that hypertension in DOCA-NaCl rats was not dependent on total body (Na(+)+K(+)) and water mass balance. Skin volume retention was hypertonic compared to serum and paralleled hypertension in DOCA-NaCl rats. These rats had higher TB(Na(+)+K(+))/TBW ratio in accumulated fluid than DOCA-NaHCO3 rats. DOCA-NaCl rats also had increased intracellular Cl(-) concentrations in skeletal muscle. We conclude that excessive cellular electrolyte redistribution and/or intracellular Na(+) or Cl(-) accumulation may play an important role in the pathogenesis of salt-sensitive hypertension. Key words: hypertension, Na storage, hypertonicity, iso-osmolality, intracellular chloride.

PMID: 18842823 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Renal Physiology)

Mammalian hibernation as a model of disuse osteoporosis: the effects of physical inactivity on bone metabolism, structure, and strength.

Wed, 08 Oct 2008 04:00:00 +0100

Mammalian hibernation as a model of disuse osteoporosis: the effects of physical inactivity on bone metabolism, structure, and strength.

Am J Physiol Regul Integr Comp Physiol. 2008 Oct 8;

Authors: McGee-Lawrence ME, Carey HV, Donahue SW

Reduced skeletal loading typically leads to bone loss because bone formation and bone resorption become unbalanced. Hibernation is a natural model of musculoskeletal disuse because hibernating animals greatly reduce weight bearing activity, and therefore they would be expected to lose bone. Some evidence suggests that small mammals like ground squirrels, bats, and hamsters do lose bone during hibernation, but the mechanism of bone loss is unclear. In contrast, hibernating bears maintain balanced bone remodeling and preserve bone structure and strength. Differences in the skeletal responses of bears and smaller mammals to hibernation may be due to differences in their hibernation patterns; smaller mammals may excrete calcium liberated from bone during periodic arousals throughout hibernation, leading to progressive bone loss over time, whereas bears may have evolved more sophisticated physiological processes to recycle calcium, prevent hypercalcaemia, and maintain bone integrity. Investigating the roles of neural and hormonal control of bear bone metabolism could give valuable insight into translating the mechanisms which prevent disuse induced bone loss in bears into novel therapies for treating osteoporosis. Key words: hibernation, bone, calcium, disuse osteoporosis.

PMID: 18843088 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology)

Differential [ca2+]i signaling of vasoconstriction in mesenteric microvessels of normal and reduced uterine perfusion pregnant rats.

Wed, 08 Oct 2008 04:00:00 +0100

Differential [Ca2+]i Signaling of Vasoconstriction in Mesenteric Microvessels of Normal and Reduced Uterine Perfusion Pregnant Rats.

Am J Physiol Regul Integr Comp Physiol. 2008 Oct 8;

Authors: Chen W, Khalil RA

Vascular resistance and blood pressure (BP) are reduced during late normal pregnancy (Norm-Preg). In contrast, studies in human preeclampsia and in animal models of hypertension in pregnancy (HTN-Preg) have suggested that localized reduction in uterine perfusion pressure (RUPP) in late pregnancy is associated with increased systemic vascular resistance and BP; however, the vascular mechanisms involved are unclear. Because Ca(2+) is a major determinant of vascular contraction, we hypothesized that the [Ca(2+)]i signaling of vasoconstriction is differentially regulated in systemic microvessels during normal and RUPP in late pregnancy. Pressurized mesenteric microvessels from Norm-Preg and RUPP rats were loaded with fura-2 in preparation for simultaneous measurement of diameter and [Ca(2+)]i (presented as fura-2 340/380 ratio). Basal [Ca(2+)]i was lower in RUPP (0.73+/-0.03) compared to Norm-Preg rats (0.82+/-0.03). Membrane depolarization by 96 mM KCl, phenylephrine (Phe, 10(-5) M), angiotensin II (AngII, 10(-7) M), or endothelin-1 (ET-1, 10(-7) M) caused an initial peak followed by maintained vasoconstriction and [Ca(2+)]i. KCl caused similar peak vasoconstriction and [Ca(2+)]i in Norm-Preg and RUPP rats. Maximum vasoconstriction to Phe, AngII, and ET-1 was not significantly different between Norm-Preg and RUPP rats. In contrast, the initial Phe, AngII, and ET-1 induced 340/380 ratio ([Ca(2+)]i) was reduced in RUPP compared to Norm-Preg rats. Also, the [Ca(2+)]i-vasoconstriction relationship was similar in KCl-treated, but shifted to the left in Phe, AngII and ET-1 treated microvessels of RUPP compared to Norm-Preg rats. The lower agonist-induced [Ca(2+)]i signal of vasoconstriction and the leftward shift in the [Ca(2+)]i-vasoconstriction relationship in microvessels of RUPP compared to Norm-Preg rats suggest activation of [Ca(2+)]i sensitization pathway(s). The similarity in vasoconstriction in RUPP and Norm-Preg rats suggests that such [Ca(2+)]i sensitization pathway(s) may also provide a feedback effect on Ca(2+) mobilization/homeostatic mechanisms to protect against excessive vasoconstriction in systemic microvessels during RUPP in late pregnancy. Key words: resistance vessels, vascular smooth muscle, calcium, pregnancy.

PMID: 18843089 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology)

Chewing and taste increase blood velocity in the celiac but not the superior mesenteric arteries.

Wed, 08 Oct 2008 04:00:00 +0100

Chewing and taste increase blood velocity in the celiac but not the superior mesenteric arteries.

Am J Physiol Regul Integr Comp Physiol. 2008 Oct 8;

Authors: Someya N, Hayashi N

To investigate the role of chewing and taste in the meal-induced rapid increase in splanchnic blood flow, we compared the blood flow responses in the celiac artery (CA) and superior mesenteric artery (SMA) to chewing solid food with a chocolate taste (FOOD) and paraffin wax without taste (WAX). After 5 min of baseline measurement, 15 healthy subjects repeated chewing and expectorating the FOOD or WAX every 20 s for 4 min followed by 10 min of recovery measurement. We measured the mean blood velocity (MBV) in the CA and SMA. The baseline MBVs in the CA and SMA did not differ between the FOOD and WAX trials. The MBV in the CA was lower than baseline at the 1st min of chewing in both trials. It was higher than baseline at the 3rd min of FOOD chewing, whereas it did not increase during and after WAX chewing. The MBV in the CA was higher in the FOOD trial than in the WAX trial at the 3rd min of chewing and thereafter. In contrast, the MBV in the SMA did not change throughout the protocols. These results suggest that the taste of food plays a role in meal-induced hyperemia in the CA but not the SMA. Key words: visceral artery, cephalic phase, gustation, mastication.

PMID: 18843090 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology)

Tetradecylthioacetic acid down-regulates cyclooxygenase 2 in the renal cortex of two-kidney, one-clip hypertensive rats.

Wed, 08 Oct 2008 04:00:00 +0100

Tetradecylthioacetic acid down-regulates cyclooxygenase 2 in the renal cortex of two-kidney, one-clip hypertensive rats.

Am J Physiol Regul Integr Comp Physiol. 2008 Oct 8;

Authors: Bivol LM, Hultstrom M, Gudbrandsen OA, Berge RK, Iversen BM

The effect of tetradecylthioacetic acid (TTA) on the cyclooxygenase (COX) system was investigated in 2K1C hypertensive rats. The systolic blood pressure (BP) was increased 6 weeks after clipping to 183 +/- 4 mmHg vs.127 +/- 3 mmHg in TTA treated 2K1C rats. The COX1 protein expression was not affected either by the 2K1C procedure or by TTA treatment. COX2 expression was up-regulated in both kidneys, but to a greater extent in the clipped kidney. COX2 activity was 16+/-3% in control and 38 +/-2% (p<0.001) in the clipped kidney, and COX2 protein expression was 1.3 +/-0.04 in control and 1.6 +/- 0.12 in the clipped kidney (p=0.006). TTA reduced COX2 activity to control levels. Subcutaneously infusion of a COX2 inhibitor did not reduce BP. Peroxisome proliferator-activated receptors (PPARs) were detected in both kidneys and PPAR delta was up-regulated in the non-clipped kidney after TTA treatment. Prostaglandin E2 (PGE2) in renal cortex was increased in 2K1C (31 +/-0.3 in the clipped and 28 +/-0.2 pg.ml(-1) non-clipped kidney, p<0.001 compared to control). TTA lowered the PGE2 to control level. Renal blood flow (RBF) response to exogenous angiotensin II (ANG II) injected into the control and non-clipped kidney was exaggerated after indomethacin treatment, but unchanged in the non-clipped kidney of 2K1C TTA group. Overall, these results indicate that after 6 weeks of treatment, TTA down-regulated COX2 activity, which have potentially important effects on the regulation of renal hemodynamics but does not explain TTAs ability to lower blood pressure Key words: Cyclooxygenase , RBF, ANG II, PGE2.

PMID: 18843091 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology)

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Adverse effects of chronic circadian desynchronization in animals in a "challenging" environment.

Wed, 08 Oct 2008 04:00:00 +0100

Adverse effects of chronic circadian desynchronization in animals in a "challenging" environment.

Am J Physiol Regul Integr Comp Physiol. 2008 Oct 8;

Authors: Preuss F, Tang Y, Laposky AD, Arble D, Keshavarzian A, Turek FW

Continuous disruption of circadian rhythms, as seen in human shift workers, has been associated with the development of a number of adverse mental and physiological conditions. However, scientific evidence linking circadian disruption to overall health, particularly in animal models, is not well documented. In this study, we demonstrate that exposing C57BL/6J mice to 12hr phase shifts every 5 days for 3 months had no effect on body weight or intestinal physiology. However, when animals were further challenged with Dextran Sodium Sulfate to induce colitis, chronic shifting of the LD cycle led to a dramatic increase in the progression of the colitis as indicated by reduced body weight, abnormal intestinal histopathology and an exacerbated inflammatory response. These data indicate that circadian disruption is an important pre-disposing factor that may provoke the onset or worsening of various disease states such as inflammatory disorders. This study provides further evidence for continued investigations using animal models of circadian disruption to examine the consequences of circadian disruption on health when organisms are faced with a challenging environment. Key words: circadian rhythms, shift work, challenging environment, circadian disorganization.

PMID: 18843092 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology)

Effect of food availability and leptin on the physiology and hypothalamic gene expression of the golden spiny mouse: a desert rodent that does not hoard food.

Wed, 08 Oct 2008 04:00:00 +0100

Effect of food availability and leptin on the physiology and hypothalamic gene expression of the golden spiny mouse: a desert rodent that does not hoard food.

Am J Physiol Regul Integr Comp Physiol. 2008 Oct 8;

Authors: Gutman R, Hacmon-Keren R, Choshniak I, Kronfeld-Schor N

Food availability and quality in desert habitats is spatially and temporally unpredictable, and animals face periods of food shortage. The golden spiny mouse (Acomys russatus) is an omnivorous desert rodent that does not hoard food, necessitating its withstanding such periods by physiological means alone. In response to food restriction, plasma leptin concentrations, core body temperature and energy expenditure of the spiny mouse decrease significantly after 24 hours, and most spiny mouse are able to maintain their body mass on ca 85% of ad libitum for a prolonged period of time. Both one day food deprivation and long-term food restriction had a significant effect on body mass and plasma leptin concentrations (which decreased significantly with a high correlation) as well as on the orexigenic Agrp (which increased significantly as a result of the 24 h food deprivation); and on NPY (in which the increase was more pronounced under long-term food restriction); but had no effect on the anorexigenic POMC and CART. Leptin administration to food-restricted spiny mice did not affect food intake or the rate of decrease in body mass, indicating that it can not overcome the drive to eat when food is scarce. However it did result in a significant decrease in NPY levels, and the spiny mice spent less time at low body temperatures compared to PBS-treated golden spiny mice. These results show that in food- restricted golden spiny mice leptin affects thermogenesis but not food consumption, and suggest that the thermoregulatory effects of leptin are mediated by NPY. Key words: torpor, thermogenesis, Acomys russatus, hypothalamic neuropeptides.

PMID: 18843093 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology)

Behavioral and electrophysiological taste responses change following brief or prolonged dietary sodium deprivation.

Wed, 08 Oct 2008 04:00:00 +0100

Behavioral and electrophysiological taste responses change following brief or prolonged dietary sodium deprivation.

Am J Physiol Regul Integr Comp Physiol. 2008 Oct 8;

Authors: Garcia JM, Curtis KS, Contreras RJ

Dietary Na(+) deprivation elicits a hormonal response to promote sodium conservation and a behavioral response to increase sodium ingestion. It has generally been accepted that the former occurs within 24-h after sodium deprivation, while the latter is delayed and may not appear until as much as 10 d later. Na(+) deprivation of similar duration also decreases the sensitivity of the chorda tympani nerve (CT) to NaCl, suggesting that changes in CT responses are necessary for increased NaCl intake. However, previous work from our laboratory showed that licking responses to NaCl solutions increase following only two days of Na(+) deprivation, suggesting rapidly occurring changes in response to NaCl taste. The current experiments examined the effects of two days of dietary Na(+) deprivation on CT responses to NaCl and patterns of NaCl consumption and found that Na(+)-deficient rats licked significantly more during the first NaCl intake bout compared to control rats. CT responses to NaCl were reduced at all concentrations after brief Na(+) deprivation compared to Na(+)-replete controls and did not decrease further with prolonged (10 d) dietary Na(+) deficiency. Moreover, amiloride, which suppressed CT responses to NaCl by approximately 30% in controls, had virtually no effect on CT responses in Na(+)-deprived rats. Thus, two days of Na(+) deprivation are sufficient to alter patterns of ingestion of concentrated NaCl and to reduce gustatory responses to NaCl. Thus, changes in gustatory responses to NaCl during dietary Na(+) deprivation may involve the amiloride-sensitive component of the CT. Key words: salt appetite, gustatory processing, chorda tympani nerve.

PMID: 18843094 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology)

Sleep-wake regulation is altered in leptin resistant (db/db) genetically obese and diabetic mice.

Wed, 08 Oct 2008 04:00:00 +0100

Sleep-wake regulation is altered in leptin resistant (db/db) genetically obese and diabetic mice.

Am J Physiol Regul Integr Comp Physiol. 2008 Oct 8;

Authors: Laposky AD, Bradley MA, Williams DL, Bass J, Turek FW

Recent epidemiological and clinical studies indicate that the control of sleep-wake states may be an important factor in the regulation of energy metabolism. Leptin is a peripherally synthesized hormone that has critical signaling properties in the brain for the control of long-term energy homeostasis. In this study, we examined the hypothesis that leptin signaling exerts a role in sleep-wake regulation and that leptin may represent an important mechanistic link in the coordination of sleep-wake states and metabolism. Sleep-wake patterns were recorded in a genetic mouse model of obesity and diabetes, the db/db mouse, which harbors a mutation in a particular isoform of the leptin receptor (long form, LRb). We found that db/db mice exhibit a variety of alterations in sleep regulation, including an increase in overall sleep time, a dramatic increase in sleep fragmentation, attenuated diurnal rhythmicity in REM sleep and NREM EEG delta power (a measure of sleep homeostatic drive), and a decrease in the compensatory response to acute (i.e. 6 hours) sleep deprivation. The db/db mice also generated low amounts of locomotor activity and a reduction in the diurnal rhythm of activity. These results indicate that impaired leptin signaling has deleterious effects on the regulation of sleep amount, sleep architecture and temporal consolidation of these arousals states. In summary, leptin may represent an important molecular component in the integration of sleep, circadian rhythms and energy metabolism. Key words: sleep fragmentation, metabolic syndrome, energy metabolism, sleep homeostasis, sleep deprivation.

PMID: 18843095 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology)

Imidazoline-induced amplification of glucose- and carbachol-stimulated insulin release includes a marked suppression of islet nitric oxide generation in the mouse

Acta Physiologica — Wed, 08 Oct 2008 04:00:00 +0100

Aim: The role of islet nitric oxide (NO) production in insulin-releasing mechanisms is unclear. We examined whether the beneficial effects of the imidazoline derivative RX 871024 (RX) on [beta]-cell function might be related to perturbations of islet NO production.Methods: Experiments were performed with isolated islets or intact mice challenged with glucose or carbachol with or without RX treatment. Insulin was determined with radioimmunoassay, NO generation with high-performance liquid chromatography and expression of inducible NO synthase (iNOS) with confocal microscopy.Results: RX treatment, in doses lacking effects on basal insulin, greatly amplified insulin release stimulated by the NO-generating secretagogues glucose and carbachol both in vitro and in vivo. RX also improved the glucose tolerance curve. Islets incubated at high glucose levels (20 mmol L[minus]1) displayed increased NO production derived from both neuronal constitutive NO synthase (ncNOS) and iNOS. RX abrogated this glucose-induced NO production concomitant with amplification of insulin release. Confocal microscopy revealed abundant iNOS expression in [beta] cells after incubation of islets at high but not low glucose levels. This was abolished after RX treatment. Similarly, islets cultured for 24 h at high glucose levels showed intense iNOS expression in [beta] cells. This was abrogated with RX and followed by an amplified glucose-induced insulin release.Conclusion: RX effectively counteracts the negative impact of [beta]-cell NO generation on insulin release stimulated by glucose and carbachol suggesting imidazoline compounds by virtue of NOS inhibitory properties being of potential therapeutic value for treatment of [beta]-cell dysfunction in hyperglycaemia and type 2 diabetes. (Source: Acta Physiologica)

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Bis deficiency results in early lethality with metabolic deterioration and involution of the spleen and thymus.

American Journal of Physiology. Endocrinology and Metabolism — Tue, 07 Oct 2008 04:00:00 +0100

Bis deficiency results in early lethality with metabolic deterioration and involution of the spleen and thymus.

Am J Physiol Endocrinol Metab. 2008 Oct 7;

Authors: Youn DY, Lee DH, Lim MH, Yoon JS, Lim JH, Jung SE, Yeum CE, Park CW, Youn HJ, Lee JS, Lee SB, Ikawa M, Okabe M, Tsujimoto Y, Lee JH

Bis (Bcl-2 interacting cell death suppressor), also known as Bag3 or CAIR-1, is involved in anti-stress and anti-apoptotic pathways. In addition to Bcl-2, Bis binds to several proteins, suggesting it has diverse functions in normal and pathological conditions. To better define the physiological function of Bis in vivo, we developed bis-deficient mice using a cre-loxP system. Targeted disruption of exon 4 of the bis gene was demonstrated by Southern blotting and PCR, and Western blotting showed that no intact or truncated Bis protein was synthesized in bis(-/-) mice. While heterozygotes were fertile and appeared normal, Bis-deficient mice showed growth retardation and died by 3 weeks after birth. The relative weight of the thymus and spleen was reduced and the total number of white blood cells, splenocytes and thymocytes were significantly reduced compared to wild-type littermates. Serum profiles indicated that significant hypoglycemia as well as decrease in triglyceride and cholesterol levels. Expression profiles of metabolic genes indicated that gluconeogenesis and beta-oxidation are activated in the liver of bis(-/-) mice. This activation, as well as a decrease in peripheral fat and an induction of fatty liver, appears to be an adaptive response to hypoglycemia. Our study reveals that absence of Bis has considerable influences on postnatal growth and survival, possibly due to a nutritional impairment. Key words: bis, knock out, hypoglycemia, thymus.

PMID: 18840758 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Endocrinology and Metabolism)

Palmitate and lipopolysaccharide-activated macrophages evoke contrasting insulin responses in muscle cells.

American Journal of Physiology. Endocrinology and Metabolism — Tue, 07 Oct 2008 04:00:00 +0100

Palmitate and lipopolysaccharide-activated macrophages evoke contrasting insulin responses in muscle cells.

Am J Physiol Endocrinol Metab. 2008 Oct 7;

Authors: Samokhvalov V, Bilan PJ, Schertzer JD, Antonescu CN, Klip A

Factors secreted by macrophages contribute to whole-body insulin resistance, acting in part on adipose tissue. Muscle is the major tissue for glucose disposal, but how macrophage-derived factors impact skeletal muscle glucose uptake is unknown, or whether the macrophage environment influences this response. We hypothesized that conditioned medium from macrophages pretreated with palmitate or lipopolysaccharide (LPS) would directly affect insulin action and glucose uptake in muscle cells. L6-GLUT4myc myoblasts were exposed to conditioned medium from RAW264.7 macrophages pretreated with palmitate or LPS. Conditioned medium from palmitate-treated RAW264.7 macrophages inhibited myoblast insulin-stimulated glucose uptake, GLUT4 translocation and Akt phosphorylation, while activating JNK, p38 MAPK, decreasing IB- and elevating inflammation markers. Surprisingly, and opposite to its effects on adipose cells, conditioned medium from LPS-treated macrophages stimulated myoblast insulin-stimulated glucose uptake, GLUT4 translocation and Akt phosphorylation, without affecting stress kinases or inflammation indices. This medium had markedly elevated IL-10 levels, and IL-10, alone, potentiated insulin action in myoblasts and partly reversed the insulin resistance imparted by medium from palmitate-treated macrophages. IL-10 neutralizing antibodies blunted the positive influence of LPS-macrophage conditioned medium. We conclude that myoblasts and adipocytes respond differentially to cytokines. Further, depending on their environment, macrophages negatively or positively influence muscle cells. Macrophages exposed to palmitate produce a mixture of proinflammatory cytokines that reduce insulin action in muscle cells; conversely, LPS-activated macrophages increase insulin action, likely via IL-10. Macrophages may be an integral element in glucose homeostasis in vivo, relaying effects of circulating factors to skeletal muscle. Key words: macrophages, skeletal muscle cells, inflammation, insulin resistance, interleukin-10.

PMID: 18840759 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Endocrinology and Metabolism)

Fasting-induced suppression of lh secretion does not require activation of atp-sensitive potassium (katp) channels.

American Journal of Physiology. Endocrinology and Metabolism — Tue, 07 Oct 2008 04:00:00 +0100

Fasting-Induced Suppression of LH Secretion Does Not Require Activation of ATP-Sensitive Potassium (KATP) Channels.

Am J Physiol Endocrinol Metab. 2008 Oct 7;

Authors: Huang W, Acosta-Martinez M, Horton TH, Levine J

Reproductive hormone secretions are inhibited by fasting and restored by feeding. Metabolic signals mediating these effects include fluctuations in serum glucose, insulin, and leptin. Because KATP channels mediate glucose-sensing and many actions of insulin and leptin in hypothalamic neurons, we assessed their role in suppressing LH secretion during food restriction. Vehicle or a KATP channel blocker, tolbutamide, were infused into the lateral cerebroventricle in ovariectomized mice that were either fed or fasted for 48 hours. Tolbutamide infusion resulted in a two-fold increase in LH concentrations in both fed and fasted mice compared to both fed and fasted vehicle-treated mice. However, tolbutamide did not reverse the suppression of LH in the majority of fasted animals. In SUR1 null mutant mice (SUR1(-/-)), which are deficient in hypothalamic KATP channels, and their wild type (WT) littermates, a 48hr fast was found to reduce serum LH concentrations in both WT and SUR(-/-)mice. The present study demonstrates that (1) blockade of KATP channels elevates LH secretion regardless of energy balance, and (2) acute fasting suppresses LH secretion in both SUR1(-/-) and WT mice. These findings support the hypothesis that KATP channels are linked to the regulation of GnRH release, but are not obligatory for mediating the effects of fasting on GnRH/LH secretion. Thus, it is unlikely that the modulation of KATP channels either as part of the classical glucose-sensing mechanism, or as a component of insulin or leptin signaling, plays a major role in the suppression of GnRH and LH secretion during food restriction. Key words: sulfonylurea, SUR1, GnRH, metabolic signals.

PMID: 18840760 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Endocrinology and Metabolism)

Pharmacological activation of lxr in utero directly influences abc transporter expression and function in mice but does not affect adult cholesterol metabolism.

American Journal of Physiology. Endocrinology and Metabolism — Tue, 07 Oct 2008 04:00:00 +0100

Pharmacological activation of LXR in utero directly influences ABC transporter expression and function in mice but does not affect adult cholesterol metabolism.

Am J Physiol Endocrinol Metab. 2008 Oct 7;

Authors: van Straten EM, Huijkman NC, Baller JF, Kuipers F, Plosch T

Cholesterol is critical for several cellular functions and essential for normal fetal development. Therefore, its metabolism is tightly controlled during all life stages. The Liver X Receptors alpha (LXRalpha; NR1H3) and beta (LXRbeta; NR1H2) are nuclear receptors that are of key relevance in coordinating cholesterol and fatty acid metabolism. The aim of this study was to elucidate whether fetal cholesterol metabolism can be influenced in utero via pharmacological activation of LXR and whether this would have long-term effects on cholesterol homeostasis. Administration of the LXR agonist T0901317 to pregnant mice via their diet (0.015% wt/wt) led to induced fetal hepatic expression levels of the cholesterol transporter genes Abcg5/g8 and Abca1, higher plasma cholesterol levels and lower hepatic cholesterol levels compared to controls. These profound changes during fetal development did not affect cholesterol metabolism in adulthood, nor influence coping with a high fat/ high cholesterol (HFHC) diet. This study shows that the LXR system is functional in fetal mice and susceptible to pharmacological activation. Despite massive changes in fetal cholesterol metabolism, regulatory mechanisms involved in cholesterol metabolism return to a 'normal' state in offspring and allow coping with a high fat/high cholesterol diet. Key words: nuclear receptors, ATP binding cassette transporter, fetal development, Liver X receptor.

PMID: 18840761 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Endocrinology and Metabolism)

Mechanism of attenuation of muscle protein degradation induced by tumour necrosis factor alpha and angiotensin ii by {beta}-hydroxy-{beta}-methylbutyrate.

American Journal of Physiology. Endocrinology and Metabolism — Tue, 07 Oct 2008 04:00:00 +0100

MECHANISM OF ATTENUATION OF MUSCLE PROTEIN DEGRADATION INDUCED BY TUMOUR NECROSIS FACTOR ALPHA AND ANGIOTENSIN II BY {beta}-HYDROXY-{beta}-METHYLBUTYRATE.

Am J Physiol Endocrinol Metab. 2008 Oct 7;

Authors: Eley HL, Russell ST, Tisdale MJ

Both tumor necrosis factor-alpha (TNF-alpha)/interferon-gamma (IFN-gamma) and angiotensin II (Ang II) induced an increase in total protein degradation in murine myotubes, which was completed attenuated by treatment with beta-hydroxy-beta-methylbutyrate (HMB; 50microM). There was an increase in formation of reactive oxygen species (ROS) within 30min, as well as an increase in the activity of both caspase-3 and -8, and both effects were attenuated by HMB. Moreover, inhibitors of caspase-3 and -8 completely attenuated both ROS formation and total protein degradation induced by TNF-alpha/IFN-gamma and Ang II. There was an increased autophosphorylation of dsRNA-dependent protein kinase (PKR), which was attenuated by the specific caspase-3 and -8 inhibitors. Neither ROS formation or protein degradation occurred in myotubes expressing a catalytically inactive PKR variant, PKRDelta6, in response to TNF-alpha/IFN-gamma, in comparison with myotubes expressing wild-type PKR, although there was still activation of caspases-3 and -8. HMB also attenuated activation of PKR, suggesting that it was important in protein degradation. Formation of ROS was attenuated by rotenone, an inhibitor of the mitochondrial electron transport chain, L-nitro arginine methyl ester, an inhibitor of nitric oxide synthase and SB203580, a specific inhibitor of p38 mitogen activated protein kinase (p38 MAPK), which also attenuated total protein degradation. Activation of p38MAPK by PKR provides the link to ROS formation. These results suggest that TNF-alpha/IFN-gamma and Ang II induce muscle protein degradation by a common signaling pathway, which is attenuated by HMB, and that this involves the initial activation of caspase-3 and -8, followed by autophosphorylation and activation of PKR, which then leads to increased ROS formation via activation of p38MAPK. Increased ROS formation is known to induce protein degradation through the ubiquitin-proteasome pathway. Key words: tumor necrosis factor alpha, protein degradation, ROS, PKR.

PMID: 18840762 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Endocrinology and Metabolism)

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Berson award lecture 2008 four grams of glucose.

American Journal of Physiology. Endocrinology and Metabolism — Tue, 07 Oct 2008 04:00:00 +0100

Berson Award Lecture 2008 Four Grams of Glucose.

Am J Physiol Endocrinol Metab. 2008 Oct 7;

Authors: Wasserman DH

Four grams of glucose circulate in the blood of a person weighing 70 kilograms. This glucose is critical for normal function in many cell types. In accordance with the importance of these four grams of glucose, a sophisticated control system is in place to maintain blood glucose constant. Our focus has been on the mechanisms by which the flux of glucose from liver to blood and from blood to skeletal muscle is regulated. The body has a remarkable capacity to satisfy the nutritional need for glucose, while still maintaining blood glucose homeostasis. The essential role of glucagon and insulin and the importance of distributed control of glucose fluxes are highlighted in this review. With regard to the latter, studies are presented that show how regulation of muscle glucose uptake is regulated by glucose delivery to muscle, glucose transport into muscle, and glucose phosphorylation within muscle. Key words: insulin, glycogen, glucose transport, hexokinase, catecholamines.

PMID: 18840763 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Endocrinology and Metabolism)

Cellular retinol-binding protein, type iii (crbp-iii) is a ppar-{gamma} target gene and plays a role in lipid metabolism.

American Journal of Physiology. Endocrinology and Metabolism — Tue, 07 Oct 2008 04:00:00 +0100

Cellular retinol-binding protein, type III (CRBP-III) is a PPAR-{gamma} target gene and plays a role in lipid metabolism.

Am J Physiol Endocrinol Metab. 2008 Oct 7;

Authors: Zizola CF, Schwartz GJ, Vogel S

Cellular retinol-binding protein, type III (CRBP-III) belongs to the family of intracellular lipid-binding proteins, which includes the adipocyte binding protein aP2. In the cytosol CRBP-III binds retinol, the precursor of retinyl ester and the active metabolite retinoic acid. The goal of the present work is to understand the regulation of CRBP-III expression and its role in lipid metabolism. Using electromobility shift assays, luciferase reporter assays, and chromatin immunoprecipitation assays we found that CRBP-III is a direct target of PPARgamma. Moreover, CRBP-III expression was induced in adipose tissue of mice following treatment with the PPARgamma agonist rosiglitazone. To examine a potential role of CRBP-III in regulating lipid metabolism in vivo, mice deficient of CRBP-III (C-III-KO) were maintained on a high fat diet (HFD). C-III-KO mice fed a HFD have decreased hepatic steatosis compared to wild-type mice fed a HFD. These differences were partly explained by decreased serum free fatty acid levels and decreased free fatty acid efflux from the adipose tissue of C-III-KO mice. In addition the lack of CRBP-III was associated with reduced food intake, an increased respiratory energy ratio and an altered body composition with decreased adiposity and increased lean body mass. Furthermore, C-III-KO mice had increased expression of genes involved in mitochondrial fatty acid oxidation in brown adipose tissue and were more cold tolerant compared to wild-type mice fed a HFD. In summary, we demonstrate that CRBP-III is a PPARgamma target gene and plays a role in lipid metabolism and whole-body energy metabolism. Key words: Adipose tissue, retinoids, lipolysis, brown adipose tissue.

PMID: 18840764 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Endocrinology and Metabolism)

Mouse breast cancer model-dependent changes in metabolic syndrome-associated phenotypes caused by maternal dioxin exposure and dietary fat.

American Journal of Physiology. Endocrinology and Metabolism — Tue, 07 Oct 2008 04:00:00 +0100

Mouse breast cancer model-dependent changes in metabolic syndrome-associated phenotypes caused by maternal dioxin exposure and dietary fat.

Am J Physiol Endocrinol Metab. 2008 Oct 7;

Authors: La Merrill M, Baston D, Denison M, Birnbaum L, Pomp D, Threadgill DW

Diets high in fat are associated with increased susceptibility to obesity and metabolic syndrome. Increased adipose tissue that is caused by high fat diets (HFD) results in altered storage of lipophilic toxicants like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which may further increase susceptibility to metabolic syndrome. Since both TCDD and HFD are associated with increased breast cancer risk, we examined their effects on metabolic syndrome-associated phenotypes in three mouse models of breast cancer: 7,12-dimethylbenz[a]anthracene (DMBA), Tg(MMTV-Neu)202Mul/J (HER2) and TgN(MMTV-PyMT)634Mul/J (PyMT), all on an FVB/N genetic background. Pregnant mice dosed with 1 microg/kg of TCDD or vehicle on gestational day 12.5 were placed on HFD or low fat diet (LFD) at parturition. Body weights, percent body fat, and fasting blood glucose were measured longitudinally, and triglycerides were measured at study termination. On HFD, all cancer models reached the pubertal growth spurt ahead of FVB controls. Among mice fed HFD, the HER2 model had a greater increase in body weight and adipose tissue from puberty through adulthood compared to the PyMT and DMBA models. However, the DMBA model consistently had higher fasting blood glucose levels than the PyMT and HER2 models. TCDD only impacted serum triglycerides in the PyMT model maintained on HFD. Since the estrogenic activity of the HFD was three times lower than that of the LFD, differential dietary estrogenic activities did not drive the observed phenotypic differences. Rather, the HFD-dependent changes were cancer-model dependent. These results show that cancer models can have differential effects on metabolic-syndrome associated phenotypes even before cancers arise. Key words: obesity, metabolic syndrome, 2,3,7,8-tetrachlorodibenzo-p-dioxin, PyMT, dimethylbenz[a]anthracene.

PMID: 18840765 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Endocrinology and Metabolism)

Bax signaling mediates palmitate-induced apoptosis in c2c12 myotubes.

American Journal of Physiology. Endocrinology and Metabolism — Tue, 07 Oct 2008 04:00:00 +0100

Bax signaling mediates palmitate-induced apoptosis in C2C12 myotubes.

Am J Physiol Endocrinol Metab. 2008 Oct 7;

Authors: Peterson JM, Wang Y, Bryner R, Williamson DL, Alway SE

Accumulation of free fatty acids in skeletal muscle may at least in part, contribute to insulin resistance and mitochondrial dysfunction leading to apoptosis. Palmitate treatment of several cell lines in vitro results in apoptosis and inhibits Akt/Protein kinase B (Akt) activity in response to insulin. However, the mechanisms regulating palmitate-induced apoptosis in muscle have not been well studied. The purposes of this study were (i) to determine if palmitate-induced apoptosis in C2C12 myotubes, is dependent on Bax to Bcl-2 binding, and (ii) to determine if the changes in Bax to Bcl-2 binding corresponded to decreases in Akt signaling in palmitate treated myotubes. To determine if temporal Akt activity coincided with Bax to Bcl-2 binding, an immunoprecipitation (IP) assay was performed in myotubes after 2-hours of serum starvation followed by 10 minutes of serum reintroduction. The contribution of Bax to palmitate-induced apoptosis was determined by treating myotubes with Bax siRNA. Palmitate treatment increased apoptosis in C2C12 myotubes as shown by a 2-fold increase in DNA fragmentation, a ~5-fold increase in caspase-3 activity, and a 2.5-fold increase in caspase-9 activity. Palmitate treatment significantly reduced Akt protein expression and Akt activity. Furthermore, there was a 4-fold reduction in Bax to Bcl-2 binding after palmitate treatment, which mirrored the reduction in pAkt (Ser473) phosphorylation. Additionally, treatment of the C2C12 myotubes with Bax siRNA attenuated the apoptotic effects of palmitate treatment. These data show that palmitate induces Bax mediated apoptosis in C2C12 myotubes and that this effect corresponds to reductions in Akt (Ser473) phosphorylation. Key words: apoptosis, Bcl2, fatty acids, mitochondria.

PMID: 18840766 [PubMed - as supplied by publisher]

(Source: American Journal of Physiology. Endocrinology and Metabolism)

Cftr and defective endocytosis: new insights in the renal phenotype of cystic fibrosis.

Pflugers Archiv : European Journal of Physiology — Tue, 07 Oct 2008 04:00:00 +0100

CFTR and defective endocytosis: new insights in the renal phenotype of cystic fibrosis.

Pflugers Arch. 2008 Oct 7;

Authors: Jouret F, Devuyst O

Inactivation of the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) causes cystic fibrosis (CF). Although CFTR is expressed in the kidney, no overwhelming renal phenotype is associated with CF. Recent studies have shown that the level of CFTR mRNA in mouse kidney approaches that found in lung. CFTR is particularly abundant in the apical area of proximal tubule cells, where it co-distributes with the Cl(-)/H(+) exchanger ClC-5 and Rab5a in endosomes. The biological relevance of CFTR in proximal tubule endocytosis has been tested in CF mouse models and CF patients. Mice lacking CFTR show a defective receptor-mediated endocytosis, as evidenced by impaired uptake of (125)I-beta(2)-microglobulin, a decreased expression of the cubilin receptor in the kidney, and a significant excretion of cubilin and its low-molecular-weight ligands into the urine. Low-molecular-weight proteinuria (and particularly transferrinuria) is similarly detected in CF patients in comparison with normal controls or patients with chronic lung inflammation. These studies suggest that the functional loss of CFTR impairs the handling of low-molecular-weight proteins by the kidney, supporting a role of CFTR in receptor-mediated endocytosis in proximal tubule cells. The selective proteinuria should be integrated in the pathophysiology of multi-systemic complications increasingly observed in CF patients.

PMID: 18839205 [PubMed - as supplied by publisher]

(Source: Pflugers Archiv : European Journal of Physiology)

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Regulation of potassium (k) handling in the renal collecting duct.

Pflugers Archiv : European Journal of Physiology — Tue, 07 Oct 2008 04:00:00 +0100

Regulation of potassium (K) handling in the renal collecting duct.

Pflugers Arch. 2008 Oct 7;

Authors: Wang WH, Giebisch G

This review provides an overview of the molecular mechanisms of K transport in the mammalian connecting tubule (CNT) and cortical collecting duct (CCD), both nephron segments responsible for the regulation of renal K secretion. Aldosterone and dietary K intake are two of the most important factors regulating K secretion in the CNT and CCD. Recently, angiotensin II (AngII) has also been shown to play a role in the regulation of K secretion. In addition, genetic and molecular biological approaches have further identified new mechanisms by which aldosterone and dietary K intake regulate K transport. Thus, the interaction between serum-glucocorticoid-induced kinase 1 (SGK1) and with-no-lysine kinase 4 (WNK4) plays a significant role in mediating the effect of aldosterone on ROMK (Kir1.1), an important apical K channel modulating K secretion. Recent evidence suggests that WNK1, mitogen-activated protein kinases such as P38, ERK, and Src family protein tyrosine kinase are involved in mediating the effect of low K intake on apical K secretory channels.

PMID: 18839206 [PubMed - as supplied by publisher]

(Source: Pflugers Archiv : European Journal of Physiology)

Impaired glycocalyx barrier properties contribute to enhanced intimal low-density lipoprotein accumulation at the carotid artery bifurcation in mice.

Pflugers Archiv : European Journal of Physiology — Tue, 07 Oct 2008 04:00:00 +0100

Impaired glycocalyx barrier properties contribute to enhanced intimal low-density lipoprotein accumulation at the carotid artery bifurcation in mice.

Pflugers Arch. 2008 Oct 7;

Authors: van den Berg BM, Spaan JA, Vink H

The glycocalyx contributes to the barrier properties of vascular endothelium, and recently, we reported using electron microscopy that glycocalyx is diminished at lesion prone sites in arterial bifurcations in mice. In the present study, we examined using confocal microscopy the dimension and composition of the endothelial glycocalyx at low- and high-risk atherogenic regions within the common carotid (common) and internal carotid branch (sinus) of C57BL/6J mice and compared dimensional variations with its ability to limit transendothelial leakage of low-density lipoprotein (LDL). Confocal laser scanning microscopy of arterial surfaces stained for heparan sulfate and hyaluronan revealed thinner glycocalyces at the sinus region (2.2 +/- 0.7 and 2.3 +/- 0.7 mum, respectively; P < 0.05) than the glycocalyx thickness at the common region (4.3 +/- 1.6 and 4.3 +/- 1.6 mum, respectively). This thinner glycocalyx was associated with impaired LDL retention by the glycocalyx resulting in a two to three times increase in intimal accumulation of LDL 15 min after i.v. bolus administration: 10.8 +/- 5.6 vs. 4.0 +/- 1.9 x 10,000 a.u. (sinus vs. common, P < 0.05). These results indicate that impaired glycocalyx barrier properties may contribute to transendothelial leakage of atherogenic LDL at lesion prone arterial sites.

PMID: 18839207 [PubMed - as supplied by publisher]

(Source: Pflugers Archiv : European Journal of Physiology)

Corrigendum