bluuebunny/crossref_metadata_2025 huggingface dataset:
Unlike mice, dogs exhibit effective glucoregulation during low-dose portal and peripheral glucose infusion
Authors: Moore Mary Courtney , Cardin Sylvain , Edgerton Dale S. , Farmer Ben , Neal Doss W. , Lautz Margaret , Cherrington Alan D.
Published: January 2004

Portal infusion of glucose in the mouse at a rate equivalent to basal endogenous glucose production causes hypoglycemia, whereas peripheral infusion at the same rate causes significant hyperglycemia. We used tracer and arteriovenous difference techniques in conscious 42-h-fasted dogs to determine their response to the same treatments. The studies consisted of three periods: equilibration (100 min), basal (40 min), and experimental (180 min), during which glucose was infused at 13.7 μmol· kg–1·min–1 into a peripheral vein (PE, n = 5) or the hepatic portal (PO, n = 5) vein. Arterial blood glucose increased ∼0.8 mmol/l in both groups. Arterial and hepatic sinusoidal insulin concentrations were not significantly different between groups. PE exhibited an increase in nonhepatic glucose uptake (non-HGU; Δ8.6 ± 1.2 μmol·kg–1·min–1) within 30 min, whereas PO showed a slight suppression (Δ–3.7 ± 3.1 μmol·kg–1·min–1). PO shifted from net hepatic glucose output (NHGO) to uptake (NHGU; 2.5 ± 2.8 μmol·kg–1·min–1) within 30 min, but PE still exhibited NHGO (6.0 ± 1.9 μmol·kg–1·min–1) at that time and did not initiate NHGU until after 90 min. Glucose rates of appearance and disappearance did not differ between groups. The response to the two infusion routes was markedly different. Peripheral infusion caused a rapid enhancement of non-HGU, whereas portal delivery quickly activated NHGU. As a result, both groups maintained near-euglycemia. The dog glucoregulates more rigorously than the mouse in response to both portal and peripheral glucose delivery.
Identification of a novel mitochondrial protein (“mitoNEET”) cross-linked specifically by a thiazolidinedione photoprobe
Authors: Colca Jerry R. , McDonald William G. , Waldon Daniel J. , Leone Joseph W. , Lull June M. , Bannow Carol A. , Lund Eric T. , Mathews W. Rodney
Published: January 2004

Thiazolidinediones address underlying causes of type 2 diabetes, although their mechanism of action is not clearly understood. The compounds are thought to function as direct activators of the nuclear receptor PPARγ (peroxisome proliferator-activated receptor-γ), although pioglitazone, the weaker agonist of the two thiazolidinediones now in clinical use, seems to have more useful effects on circulating lipids. We have used tritiated pioglitazone and a photoaffinity cross-linker to identify a novel binding site in mitochondria. A saturable binding site for [3H]pioglitazone was solubilized from the membranes with CHAPS and migrated as a large complex by size exclusion chromatography. The binding correlated with a <17-kDa protein (m17), marked by a photoaffinity cross-linker, in both subcellular location and selectivity of competition by analogs. The protein was isolated and identified by mass spectrometry analysis and NH2-terminal sequencing. Three synthetic peptides with potential antigenic properties were synthesized from the predicted nontransmembrane sequence to generate antibodies in rabbits. Western blots show that this protein, which we have termed “mitoNEET,” is located in the mitochondrial fraction of rodent brain, liver, and skeletal muscle, showing the identical subcellular location and migration on SDS-PAGE as the protein cross-linked specifically by the thiazolidinedione photoprobe. The protein exists in low levels in preadipocytes, and expression increases exponentially in differentiated adipocytes. The synthetic protein bound to solid phase associated with a complex of solubilized mitochondrial proteins, including the trifunctional β-oxidation protein. It is possible that thiazolidinedione modification of the function of the mitochondrial target may contribute to lipid lowering and/or antidiabetic actions.
Nonhepatic glucose production in humans
Authors: Battezzati Alberto , Caumo Andrea , Martino Francesca , Sereni Lucia Piceni , Coppa Jorgelina , Romito Raffaele , Ammatuna Mario , Regalia Enrico , Matthews Dwight E. , Mazzaferro Vincenzo , Luzi Livio
Published: January 2004

Extrahepatic glucose release was evaluated during the anhepatic phase of liver transplantation in 14 recipients for localized hepatocarcinoma with mild or absent cirrhosis, who received a bolus of [6,6-2H2]glucose and l-[3-13C]alanine or l-[1,2-13C2]glutamine to measure glucose kinetics and to prove whether gluconeogenesis occurred from alanine and glutamine. Twelve were studied again 7 mo thereafter along with seven healthy subjects. At the beginning of the anhepatic phase, plasma glucose was increased and then declined by 15%/h. The right kidney released glucose, with an arteriovenous gradient of -3.7 mg/dl. Arterial and portal glucose concentrations were similar. The glucose clearance was 25% reduced, but glucose uptake was similar to that of the control groups. Glucose production was 9.5 ± 0.9 μmol·kg-1· min-1, 30% less than in controls. Glucose became enriched with 13C from alanine and especially glutamine, proving the extrahepatic gluconeogenesis. The gluconeogenic precursors alanine, glutamine, lactate, pyruvate, and glycerol, insulin, and the counterregulatory hormones epinephrine, cortisol, growth hormone, and glucagon were increased severalfold. Extrahepatic organs synthesize glucose at a rate similar to that of postabsorptive healthy subjects when hepatic production is absent, and gluconeogenic precursors and counterregulatory hormones are markedly increased. The kidney is the main, but possibly not the unique, source of extrahepatic glucose production.
Reduced β-cell mass and altered glucose sensing impair insulin-secretory function in βIRKO mice
Authors: Otani Kenichi , Kulkarni Rohit N. , Baldwin Aaron C. , Krutzfeldt Jan , Ueki Kohjiro , Stoffel Markus , Kahn C. Ronald , Polonsky Kenneth S.
Published: January 2004

Pancreatic β-cell-restricted knockout of the insulin receptor results in hyperglycemia due to impaired insulin secretion, suggesting that this cell is an important target of insulin action. The present studies were undertaken in β-cell insulin receptor knockout (βIRKO) mice to define the mechanisms underlying the defect in insulin secretion. On the basis of responses to intraperitoneal glucose, ∼7-mo-old βIRKO mice were either diabetic (25%) or normally glucose tolerant (75%). Total insulin content was profoundly reduced in pancreata of mutant mice compared with controls. Both groups also exhibited reduced β-cell mass and islet number. However, insulin mRNA and protein were similar in islets of diabetic and normoglycemic βIRKO mice compared with controls. Insulin secretion in response to insulin secretagogues from the isolated perfused pancreas was markedly reduced in the diabetic βIRKOs and to a lesser degree in the nondiabetic βIRKO group. Pancreatic islets of nondiabetic βIRKO animals also exhibited defects in glyceraldehyde- and KCl-stimulated insulin release that were milder than in the diabetic animals. Gene expression analysis of islets revealed a modest reduction of GLUT2 and glucokinase gene expression in both the nondiabetic and diabetic mutants. Taken together, these data indicate that loss of functional receptors for insulin in β-cells leads primarily to profound defects in postnatal β-cell growth. In addition, altered glucose sensing may also contribute to defective insulin secretion in mutant animals that develop diabetes.
Ammonium effects on colonic Cl- secretion: anomalous mole fraction behavior
Authors: Worrell Roger T. , Oghene Jennifer , Matthews Jeffrey B.
Published: January 2004

A significant amount of ammonium ([Formula: see text]) is absorbed by the colon. The nature of [Formula: see text] effects on transport and [Formula: see text] transport itself in colonic epithelium is poorly understood. The goal of this study was to elucidate the effects of [Formula: see text] on cAMP-stimulated Cl- secretion in the colonic cell line T84. In HEPES-buffered solutions, application of basolateral [Formula: see text] resulted in a reduced level of Cl- secretory current. The effect of [Formula: see text] appears to occur by at least three mechanisms: 1) basolateral membrane depolarization, 2) a competitive effect with K+, and 3) a long-term (>20 min) increase in transepithelial resistance (TER). The competitive effect with K+ exhibits anomalous mole fraction behavior. Transepithelial current relative to that in 10 mM basolateral K+ was inhibited 15% by 10 mM [Formula: see text] alone and by 30% with a mixture of 2 mM K+ and 8 mM [Formula: see text]. A mole fraction mix of 2 mM K+:8 mM [Formula: see text] produced a greater inhibition of basolateral membrane K+ current than pure K+ or [Formula: see text] alone. Similar anomalous behavior was also observed for inhibition of bumetanide-sensitive 36Cl- uptake, e.g., Na+-K+-2Cl--cotransporter (NKCC-1). No anomalous effect was observed on Na+-K+-ATPase current. Both NKCC-1 and Na+-K+-ATPase activity were elevated in 10 mM [Formula: see text] with respect to 10 mM K+. The effect on TER did not exhibit anomalous mole fraction behavior. The overall effect of basolateral [Formula: see text] on cAMP-stimulated transport is dependent on the [Formula: see text] ratio at the basolateral membrane, where o is outside of the cell.
Aspirin, but not NO-releasing aspirin (NCX-4016), interacts with selective COX-2 inhibitors to aggravate gastric damage and inflammation
Authors: Wallace John L. , Zamuner Stella R. , McKnight Webb , Dicay Michael , Mencarelli Andrea , del Soldato Piero , Fiorucci Stefano
Published: January 2004

Aceylation of cyclooxygenase (COX)-2 by aspirin can trigger the formation of 15(R)-epilipoxin A4, or aspirin-triggered lipoxin (ATL). ATL exerts protective effects in the stomach. Selective COX-2 inhibitors block ATL synthesis and exacerbate aspirin-induced gastric damage. Nitric oxide-releasing aspirins, including NCX-4016, have antiplatelet effects similar to aspirin but do not cause gastric damage. In the present study, we examined whether or not NCX-4016 triggers ATL synthesis and/or upregulates gastric COX-2 expression and the effects of coadministration of NCX-4016 with a selective COX-2 inhibitor on gastric mucosal injury and inflammation. Rats were given aspirin or NCX-4016 orally and either vehicle or a selective COX-2 inhibitor (celecoxib) intraperitoneally. Gastric damage was blindly scored, and granulocyte infiltration into gastric tissue was monitored through measurement of myeloperoxidase activity. Gastric PG and ATL synthesis was measured as was COX-2 expression. Whereas celecoxib inhibited gastric ATL synthesis and increased the severity of aspirin-induced gastric damage and inflammation, coadministration of celecoxib and NCX-4016 did not result in damage or inflammation. NCX-4016 did not upregulate gastric COX-2 expression nor did it trigger ATL synthesis (in contrast to aspirin). Daily administration of aspirin for 5 days resulted in significantly less gastric damage than that seen with a single dose, as well as augmented ATL synthesis. Celecoxib reversed this effect. In contrast, repeated administration of NCX-4016 failed to cause gastric damage, whether given alone or with celecoxib. These studies support the notion that NCX-4016 may be an attractive alternative to aspirin for indications such as cardioprotection, including in individuals also taking selective COX-2 inhibitors.
Activation of intestinal smooth muscle cells by interstitial cells of Cajal in simulation studies
Authors: Sperelakis Nicholas , Daniel Edwin E.
Published: January 2004

Activation of a two-dimensional sheet network (5 parallel chains of 5 cells each) of simulated intestinal smooth muscle cells (SMCs) by one interstitial cell of Cajal (ICC) was modeled by PSpice simulation. The network of 25 cells was not interconnected by gap-junction channels; instead, excitation was transmitted by the electric field that develops in the junctional clefts (JC) when the prejunctional membrane fires an action potential (AP). Transverse propagation between the parallel chains occurs similarly. The ICC cell was connected to cell E5 of the network [5th cell of the 5th (E) chain] via a high-resistance junction. The stimulating current, applied to the ICC cell interior, was made to resemble the endogenous undershooting slow wave ( ISW). An ISW of 2.4 nA (over a rise time of 4 ms) took the ICC cell from a resting potential (RP) of -80 mV to a membrane potential of -41 mV. The slow wave produced a large negative cleft potential in the JC ( VJC; ICC-E5). The Vjc brought the postjunctional membrane of E5 to threshold, causing this cell to fire an AP. This, in turn, propagated throughout the SMC network. If the ICC cell was given an RP of -55 mV (like SMC) and a slow wave of 40 mV amplitude ( ISW of 1.8 nA), it still activated the SMC network. This was also true when the ICC cell was made excitable (developing an overshooting, fast-rising AP). In summary, one ICC cell displaying a slow wave was capable of activating a network of SMC in the absence of gap junctions.
Involvement of calcitonin gene-related peptide in control of human fetoplacental vascular tone
Authors: Dong Yuan-Lin , Vegiraju Sujatha , Chauhan Madhu , Gangula Pandu R. R. , Hankins Gary D. V. , Goodrum Linda , Yallampalli Chandra
Published: January 2004

Calcitonin gene-related peptide (CGRP), one of the most potent endogenous vasodilators known, has been implicated in vascular adaptations and placental functions during pregnancy. The present study was designed to examine the existence of CGRP-A receptor components, the calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 1 (RAMP1), in the human placenta and the vasoactivity of CGRP in the fetoplacental circulation. Immunofluorescent staining of the human placenta in term labor using polyclonal anti-CRLR and RAMP1 antibodies revealed that labeling specifically concentrated in the vascular endothelium and the underlying smooth muscle cells in the umbilical artery/vein, chorionic artery/vein, and stem villous vessels as well as in the trophoblast layer of the placental villi. In vitro isometric force measurement showed that CGRP dose dependently relaxes the umbilical artery/vein, chorionic artery/vein, and stem villous vessels. Furthermore, CGRP-induced relaxation of placental vessels are inhibited by a CGRP receptor antagonist (CGRP8–37), ATP-sensitive potassium (KATP) channel blocker (glybenclamide), and cAMP-dependent protein kinase A inhibitor (Rp-cAMPS) and partially inhibited by a nitric oxide inhibitor ( Nω-nitro-l-arginine methyl ester). We propose that CGRP may play a role in the control of human fetoplacental vascular tone, and the vascular dilations in response to CGRP may involve activation of KATP channels, cAMP, and a nitric oxide pathway.
Intracellular Ca2+ regulates responsiveness of cardiac L-type Ca2+ current to protein kinase A: role of calmodulin
Authors: Walsh Kenneth B. , Cheng Qi
Published: January 2004

The goal of this study was to determine whether the protein kinase A (PKA) responsiveness of the cardiac L-type Ca2+ current ( ICa) is affected during transient increases in intracellular Ca2+ concentration. Ventricular myocytes were isolated from 3- to 4-day-old neonatal rats and cultured on aligned collagen thin gels. When measured in 1 or 2 mM Ca2+ external solution, the aligned myocytes displayed a large ICa that was weakly regulated (20% increase) during stimulation of PKA by 2 μM forskolin. In contrast, application of forskolin caused a 100% increase in ICa when the external Ca2+ concentration was reduced to 0.5 mM or replaced with Ba2+. This Ca2+-dependent inhibition was also observed when the cells were treated with 1 μM isoproterenol, 100 μM 3-isobutyl-1-methylxanthine, or 500 μM 8-bromo-cAMP. The responsiveness of ICa to PKA was restored during intracellular dialysis with a calmodulin (CaM) inhibitory peptide but not during treatment with inhibitors of protein kinase C, Ca2+/CaM-dependent protein kinase, or calcineurin. Adenoviral-mediated expression of a CaM molecule with mutations in all four Ca2+-binding sites also increased the PKA sensitivity of ICa. Finally, adult mouse ventricular myocytes displayed a greater response to forskolin and cAMP in external Ba2+. Thus Ca2+ entering the myocyte through the voltage-gated Ca2+ channel regulates the PKA responsiveness of ICa.
PPARγ activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes
Authors: Bagi Zsolt , Koller Akos , Kaley Gabor
Published: January 2004

We tested the hypothesis that short-term treatment of mice with Type 2 diabetes mellitus (DM) with rosiglitazone (ROSI), an agonist of peroxisome proliferator-activated receptor-γ, ameliorates the impaired coronary arteriolar dilation by reducing oxidative stress via a mechanism unrelated to its effect on hyperglycemia and hyperinsulinemia. Control and Type 2 DM ( db/db) mice were treated with ROSI (3 mg·kg–1·day–1) for 7 days, which did not significantly affect their serum concentration of glucose and insulin. Compared with controls, in db/db mice serum levels of 8-isoprostane and dihydroethydine-detectable superoxide production in carotid arteries were significantly elevated and were reduced by ROSI treatment. In coronary arterioles (diameter, ∼80 μm) isolated from db/db mice, the reduced dilations to ACh, the nitric oxide (NO) donor NONOate, and increases in flow were significantly augmented either by in vitro administration of apocynin, an inhibitor of NAD(P)H-oxidase, or by in vivo ROSI treatment, responses that were then significantly reduced by the NO synthase inhibitor Nω-nitro-l-arginine methyl ester. In aortas of db/db mice, activity of SOD and catalase was reduced, whereas NAD(P)H oxidase activity was enhanced. ROSI treatment enhanced catalase and reduced NAD(P)H oxidase activity but did not affect the activity of SOD. These findings suggest that ROSI treatment enhances NO mediation of coronary arteriolar dilations due to the reduction of vascular NAD(P)H oxidase-derived superoxide production and enhancement of catalase activity. Thus, in addition to the previously revealed beneficial metabolic effects, the antioxidant action of rosiglitazone may protect coronary arteriolar function in Type 2 DM.
Ca2+ entry is essential for cell strain-induced lamellar body fusion in isolated rat type II pneumocytes
Authors: Frick Manfred , Bertocchi Cristina , Jennings Paul , Haller Thomas , Mair Norbert , Singer Wolfgang , Pfaller Walter , Ritsch-Marte Monika , Dietl Paul
Published: January 2004

Using a new equibiaxial strain device, we investigated strain-induced Ca2+ signals and their relation to lamellar body (LB) exocytosis in single rat alveolar type II (AT II) cells. The strain device allows observation of single cells while inducing strain to the entire substratum. AT II cells tolerated high strain amplitudes up to 45% increase in cell surface area (ΔCSA) without release of lactate dehydrogenase or ATP. Strain exceeding a threshold of ∼8% ΔCSA resulted in a transient rise of the cytoplasmic Ca2+ concentration in some cells. Higher strain levels increased the fraction of Ca2+-responding cells. The occurrence of strain-induced Ca2+ signals depended on cell-cell contacts, because lone cells (i.e., cells without cell-cell contacts) did not exhibit Ca2+ signals. Above threshold, the amplitude of the Ca2+ signal as well as the number of stimulated LB fusions correlated well with the amplitude of strain. Furthermore, stimulated LB fusions occurred only in cells exhibiting a Ca2+ signal; 50 μM Gd3+ in the bath affected neither Ca2+ signals nor fusions. Intracellular Ca2+ release was triggered at higher strain amplitudes and inhibited by thapsigargin. Removal of bath Ca2+ completely inhibited Ca2+ signals and fusions. We conclude that strain of AT II cells stimulates a Ca2+ entry pathway that is highly sensitive to strain and a prerequisite for subsequent Ca2+ release. Both mechanisms result in a graded response of fusions to strain. Our data also allow us to introduce the term “effective strain” as the physiologically relevant portion of the strain amplitude.
Pulmonary surfactant secretion in briefly cultured mouse type II cells
Authors: Gobran Laurice I. , Rooney Seamus A.
Published: January 2004

There is little information on the regulation of surfactant secretion in mouse type II cells. We isolated type II cells from C57BL/6 and FVB mice, cultured them overnight, and then examined their response to known surfactant secretagogues. Secretion of phosphatidylcholine, surfactant protein (SP)-B and SP-C was stimulated by terbutaline, 5′- N-ethylcarboxyamidoadenosine (NECA), ATP, UTP, TPA, and ionomycin. Phosphatidylcholine secretion was increased approximately twofold by all agonists in both strains of mice. The response to terbutaline and NECA is the same as in rat type II cells, whereas the response to ATP, UTP, TPA, and ionomycin is considerably less. Secretion of SP-B and SP-C was increased sevenfold by terbutaline and threefold by ATP, effects similar to those in rat type II cells. The response to terbutaline was significantly decreased in type II cells from β2-adrenergic receptor null mice. These data establish that briefly cultured type II cells provide a suitable model for investigation of surfactant secretion in normal and genetically altered mice.
NO, but not CO, attenuates anaphylaxis-induced postsinusoidal contraction and congestion in guinea pig liver
Authors: Ruan Zonghai , Shibamoto Toshishige , Shimo Tomohiro , Tsuchida Hideaki , Koizumi Tomonobu , Nishio Matomo
Published: January 2004

The pathophysiology of the hepatic vascular response to anaphylaxis in guinea pig is not known. We studied effects of anaphylaxis on hepatic vascular resistances and liver weight in isolated perfused livers derived from guinea pigs sensitized with ovalbumin. We also determined whether nitric oxide (NO) or carbon monoxide (CO) modulates the hepatic anaphylaxis. The livers were perfused portally and recirculatingly at constant flow with diluted blood. With the use of the double-occlusion technique to estimate the hepatic sinusoidal pressure (Pdo), portal venous resistance (Rpv) and hepatic venous resistance (Rhv) were calculated. An antigen injection caused venoconstriction characterized by an increase in Rpv greater than Rhv and was accompanied by a large liver weight gain. Pretreatment with the NO synthase inhibitor NG-nitro-l-arginine methyl ester, but not the heme oxygenase inhibitor zinc protoporphyrin IX, potentiated the antigen-induced venoconstriction by increasing both Rpv and Rhv (2.2- and 1.2-fold increase, respectively). In conclusion, anaphylaxis causes both pre- and postsinusoidal constriction in isolated guinea pig livers. However, the increases in postsinusoidal resistance and Pdo cause hepatic congestion. Endogenously produced NO, but not CO, modulates these responses.
Attenuated thermoregulatory sweating and cutaneous vasodilation after 14-day bed rest in humans
Authors: Michikami Daisaku , Kamiya Atsunori , Fu Qi , Iwase Satoshi , Mano Tadaaki , Sunagawa Kenji
Published: January 2004

We investigated the effect of head-down bed rest (HDBR) for 14 days on thermoregulatory sweating and cutaneous vasodilation in humans. Fluid intake was ad libitum during HDBR. We induced whole body heating by increasing skin temperature for 1 h with a water-perfused blanket through which hot water (42°C) was circulated. The experimental room was air-conditioned (27°C, 30–40% relative humidity). We measured skin blood flow (chest and forearm), skin temperatures (chest, upper arm, forearm, thigh, and calf), and tympanic temperature. We also measured sweat rate by the ventilated capsule method in which the skin area for measurement was drained by dry air conditioned at 27°C under similar skin temperatures in both trials. We calculated cutaneous vascular conductance (CVC) from the ratio of skin blood flow to mean blood pressure. From tympanic temperature-sweat rate and -CVC relationships, we assessed the threshold temperature and sensitivity as the slope response of variables to a given change in tympanic temperature. HDBR increased the threshold temperature for sweating by 0.31°C at the chest and 0.32°C at the forearm, whereas it reduced sensitivity by 40% at the chest and 31% at the forearm. HDBR increased the threshold temperature for cutaneous vasodilation, whereas it decreased sensitivity. HDBR reduced plasma volume by 11%, whereas it did not change plasma osmolarity. The increase in the threshold temperature for sweating correlated with that for cutaneous vasodilation. In conclusion, HDBR attenuated thermoregulatory sweating and cutaneous vasodilation by increasing the threshold temperature and decreasing sensitivity. HDBR increased the threshold temperature for sweating and cutaneous vasodilation by similar magnitudes, whereas it decreased their sensitivity by different magnitudes.
Heritability of maximal isometric muscle strength in older female twins
Authors: Tiainen Kristina , Sipilä Sarianna , Alen Markku , Heikkinen Eino , Kaprio Jaakko , Koskenvuo Markku , Tolvanen Asko , Pajala Satu , Rantanen Taina
Published: January 2004

The purpose of the present study was to examine genetic and environmental effects on maximal isometric handgrip, knee extension, and ankle plantar flexion strength. In addition, we wanted to investigate whether the strength of these three muscle groups shares a genetic component or whether the genetic effect is specific for each muscle group. Muscle strength was measured as part of the Finnish Twin Study on Aging in 97 monozygotic (MZ) and 102 dizygotic (DZ) female twin pairs, aged 63-76 yr. The MZ and DZ individuals did not differ from each other in age, body height, weight, or self-related health. The age-adjusted pairwise (intraclass) correlations of the MZ and DZ twins were, respectively, 0.462 and 0.242 in knee extension, 0.435 and 0.345 in handgrip, and 0.512 and 0.435 in ankle plantar flexion strength. The multivariate genetic analysis showed that handgrip and knee extension strength shared a genetic component, which accounted for 14% (95% confidence interval: 4-28%) of the variance in handgrip strength and 31% (95% confidence interval: 18-45%) in knee extension strength. The influence of genetic effects on ankle plantar flexion strength was minor and not significant. Furthermore, these three muscle groups had a nongenetic familial effect in common and nonshared environmental effects in common. The results suggested that muscle strength is under a genetic regulation, but also environmental effects have a significant role in explaining the variability in the muscle strength.
Discriminating age and disability effects in locomotion: neuromuscular adaptations in musculoskeletal pathology
Authors: McGibbon Chris A. , Krebs David E.
Published: January 2004

We identified biomechanical variables indicative of lower extremity dysfunction, distinct from age-related gait adaptations, and examined interrelationships among these variables to better understand the neuromuscular adaptations in gait. Sagittal plane ankle, knee, and hip peak angles, moments, and powers and spatiotemporal parameters were acquired during preferred-speed gait in 120 subjects: 45 healthy young, 37 healthy elders, and 38 elders with functional limitations due to lower extremity musculoskeletal pathology, primarily arthritis. Multiple analysis of covariance with discriminate analysis, adjusted for gait speed, was used to identify the variables discriminating groups. Correlation analysis was used to explore interrelationships among these variables within each group. Healthy elders were discriminated (sensitivity 76%, specificity 82%) from young adults via decreased late-stance ankle plantar flexion angle, increased late-stance knee power absorption, and early-stance hip extensor power generation. Disabled elders were discriminated (sensitivity 74%, specificity 73%) from healthy elders via decreased late-stance ankle plantar flexor moment and power generation, increased early-stance ankle dorsiflexor moment, and late-stance hip flexor moment and power absorption. Relationships among variables showed a higher degree of coupling for the disabled elders compared with the healthy groups, suggesting a reduced ability to alter motor strategies. Our data suggest that, beyond age-related changes, elders with lower extremity dysfunction rely excessively on passive action of hip flexors to provide propulsion in late stance and contralateral ankle dorsiflexors to enhance stability. These findings support a growing body of evidence that gait changes with age and disablement have a neuromuscular basis, which may be informative in a motor control framework for physical therapy interventions.
Effects of carbohydrate availability on sustained shivering I. Oxidation of plasma glucose, muscle glycogen, and proteins
Authors: Haman François , Péronnet François , Kenny Glen P. , Doucet Éric , Massicotte Denis , Lavoie Carole , Weber Jean-Michel
Published: January 2004

Carbohydrates (CHO) can play an important thermogenic role during shivering, but the effect of their availability on the use of other oxidative fuels is unclear. Using indirect calorimetry and tracer methods ([U-13C]glucose ingestion), we have determined the specific contributions of plasma glucose, muscle glycogen, proteins, and lipids to total heat production (Ḣprod) in men exposed to cold for 2-h (liquid-conditioned suit perfused with 10°C water). Measurements were made after low-CHO diet and exercise (Lo) and high-CHO diet without exercise (Hi). The size of CHO reserves had no effect on Ḣprod but a major impact on fuel selection before and during shivering. In the cold, a complete shift from lipid oxidation for Lo (53, 28, and 19% Ḣprod for lipids, CHO, and proteins, respectively) to CHO-based metabolism for Hi (23, 65, and 12% Ḣprod for lipids, CHO, and proteins, respectively) was observed. Plasma glucose oxidation remains a minor fuel under all conditions (<13% Ḣprod), falling to 7% Ḣprod for Lo. Therefore, adjusting plasma glucose oxidation to compensate for changes in muscle glycogen oxidation is not a strategy used for maintaining heat production. Instead, proteins and lipids share responsibility for this compensation. We conclude that humans can show remarkable flexibility in oxidative fuel selection to ensure that heat production is not compromised during sustained cold exposure.
Effects of modulators of sarcoplasmic Ca2+ release on the development of skeletal muscle fatigue
Authors: Germinario E. , Esposito A. , Megighian A. , Midrio M. , Betto R. , Danieli-Betto D.
Published: January 2004

The reduced release of Ca2+ from sarcoplasmic reticulum (SR) is considered a major determinant of muscle fatigue. In the present study, we investigated whether the presence of dantrolene, an established inhibitor of SR Ca2+ release, or caffeine, a drug facilitating SR Ca2+ release, modifies muscle fatigue development. Accordingly, the effects of Ca2+ release modulators were analyzed in vitro in mouse fast-twitch [extensor digitorum longus (EDL)] and slow-twitch (soleus) muscles, fatigued by repeated short tetani (40 Hz for 300 ms, 0.5 s-1 in soleus and 60 Hz for 300 ms, 0.3 s-1 in EDL, for 6 min). Caffeine produced a substantial increase of tetanic tension of both EDL and soleus muscles, whereas dantrolene decreased tetanic tension only in EDL muscle. In both EDL and soleus muscles, 5 μM dantrolene did not affect fatigue development, whereas 20 μM dantrolene produced a positive staircase during the first 3 min of stimulation in EDL muscle and a slowing of fatigue development in soleus muscle. The development of the positive staircase was abolished by the addition of 15 μM ML-7, a selective inhibitor of myosin light chain kinase. On the other hand, caffeine caused a larger and faster loss of tension in both EDL and soleus muscles. The results seem to indicate that the changes in fatigue profile induced by caffeine or dantrolene are mainly due to the changes in the initial tetanic tension caused by the drugs, with the resulting changes in the level of contraction-dependent factors of fatigue, rather than to changes in the SR Ca2+ release during fatigue development.
Renal responses to hemorrhage are age dependent in conscious sheep
Authors: Smith Francine G. , Sener Alp , Basati Raghmeet , Abu-Amarah Isam
Published: January 2004

Experiments were carried out in conscious, chronically instrumented lambs ( n = 8) and young adult sheep ( n = 11) to investigate age-dependent renal responses to hemorrhage. Various parameters of renal function were measured for 1 h before and 1 h after either 10% hemorrhage ( experiment 1) or 20% hemorrhage ( experiment 2). The two experiments were carried out in random order at intervals of 2-5 days. There were no effects of 10-20% hemorrhage on renal plasma flow in either age group. Blood pressure decreased after 20% but not 10% hemorrhage in both age groups. Glomerular filtration rate and filtration fraction decreased after 20% hemorrhage in both age groups, the decrease being greater in lambs than young adult sheep. In response to 20% hemorrhage, urinary flow rate and urinary Na+ excretion rate decreased by 40 min after hemorrhage in young adult sheep but not lambs and remained decreased for 60 min; urinary chloride excretion rate showed a similar response. In lambs but not young adult sheep, free water clearance increased by 20 min after 20% hemorrhage and remained above control at 60 min. Urinary osmolality decreased at 20 min after 20% hemorrhage in young adult sheep but not lambs, returning to control levels by 40 min. These data provide new information that renal responses to hypotensive hemorrhage appear to be developmentally regulated.
Central and peripheral contributions to fatigue in relation to level of activation during repeated maximal voluntary isometric plantar flexions
Authors: Nordlund Maria M. , Thorstensson Alf , Cresswell Andrew G.
Published: January 2004

This study aimed to investigate central and peripheral contributions to fatigue during repeated maximal voluntary isometric plantar flexions (MVCs). Changes in joint torque, level of activation (LOA), resting twitch amplitude (RT), electromyographic signals (EMG), and presynaptic inhibition of Ia afferents were investigated during 9 bouts of 10 MVCs. MVCs lasted for 2 s and were separated by 1 s. The interval between bouts was 10 s. Electrical stimulation was applied to the tibial nerve; at rest to evoke RTs, M waves, and two (1.5-s interval) H reflexes; with the soleus EMG at 30% of that during MVC to evoke M waves and two H reflexes; and during MVCs to measure LOA. Over the nine bouts, LOA decreased by 12.6% and RT by 16.2%. EMG root mean square during MVCs remained unchanged for the soleus and tibialis anterior muscles, but it decreased for medial gastrocnemius. Peripheral fatigue (decrease in RT) was positively correlated to LOA, whereas central fatigue (decrease in LOA) was not. Depression of both H reflexes suggests that presynaptic inhibition after the first bout was partly induced by homosynaptic postactivation depression of the Ia terminal. The H-reflex-to-M-wave ratio increased with fatigue in both passive and active states, with no change in the ratio of the second H reflex to the first, thereby indicating a decrease of presynaptic inhibition during fatigue. The results indicate that both central and peripheral mechanisms contributed to the fatigue observed during repeated MVCs and that the development of peripheral fatigue was influenced by the level of voluntary activation and initial plantar flexor torque.
Cobalt injections into the pedunculopontine nuclei attenuate the reflex diaphragmatic responses to muscle contraction in rats
Authors: Plowey Edward D. , Waldrop Tony G.
Published: January 2004

Previous studies have suggested that neurons in the pedunculopontine nucleus (PPN) are activated during static muscle contraction. Furthermore, activation of the PPN, via electrical stimulation or chemical disinhibition, is associated with increases in respiratory activity observed via diaphragmatic electromyogram recordings. The present experiments address the potential for PPN involvement in the regulation of the reflex diaphragmatic responses to muscle contraction in chloralose-urethane anesthetized rats. Diaphragmatic responses to unilateral static hindlimb muscle contraction, evoked via electrical stimulation of the tibial nerve, were recorded before and subsequent to bilateral microinjections of a synaptic blockade agent (CoCl2) into the PPN. The peak reflex increases in respiratory frequency (9.0 ± 1.0 breaths/min) and minute integrated diaphragmatic electromyogram activity (14.6 ± 3.3 units/min) were attenuated after microinjection of CoCl2 into the PPN (2.6 ± 0.9 breaths/min and 4.6 ± 2.1 units/min, respectively). Consistent diaphragmatic responses were observed in the subset of animals that were barodenervated. Control experiments suggest no effects of PPN synaptic blockade on the cardiovascular responses to muscle contraction. The results are discussed in terms of a potential role for the PPN in modulation of the reflex respiratory adjustments that accompany muscular activity.
Contribution of genetic and environmental effects to postural balance in older female twins
Authors: Pajala Satu , Era Pertti , Koskenvuo Markku , Kaprio Jaakko , Tolvanen Asko , Heikkinen Eino , Tiainen Kristina , Rantanen Taina
Published: January 2004

The aim of the present study was to determine the relative roles of genetic and environmental influences on postural balance in older women. The participants were 97 monozygotic (MZ) and 102 dizygotic (DZ) female twins, aged 64–76 yr. Postural sway was measured during side-by-side stance with eyes open and eyes closed, and during semitandem stance with eyes open on a force platform. Sway data were condensed into four first-order and one second-order latent factors. The second-order factor, named balance, incorporates sway data from multiple tests and thus best describes the phenotype of postural balance. The contribution of genetic and environmental influences on the variability of the latent factors was assessed by using structural equation modeling. Additive genetic influences accounted for 35% and shared environmental influences accounted for 24% of the total variance in the balance factor. In the present study, postural balance in older women had a moderate genetic component. Genetic influences on postural balance may be mediated through gene variation in the systems that control posture. The finding that individual environmental influences accounted for almost one-half of the variance in postural balance points to the potential of targeted interventions to maintain and improve balance control in older persons.
Chronic O2 exposure in the newborn rat results in decreased pulmonary arterial nitric oxide release and altered smooth muscle response to isoprostane
Authors: Belik J. , Jankov R. P. , Pan J. , Yi M. , Chaudhry I. , Tanswell A. K.
Published: January 2004

Chronic oxygen exposure in the newborn rat results in lung isoprostane formation, which may contribute to the pulmonary hypertension evident in this animal model. The purpose of this study was to investigate the pulmonary arterial smooth muscle responses to 8-iso-prostaglandin F2α (8-iso-PGF2a) in newborn rats exposed to 60% O2 for 14 days. Because, in the adult rat, 8-iso-PGF2α may have a relaxant effect, mediated by nitric oxide (NO), we also sought to evaluate the pulmonary arterial NO synthase (NOS) protein content and NO release in the newborn exposed to chronic hyperoxia. Compared with air-exposed control animals, 8-iso-PGF2a induced a significantly greater force ( P < 0.01) and reduced ( P < 0.01) relaxation of precontracted pulmonary arteries in the 60% O2-treated animals. These changes were reproduced in control pulmonary arteries by NOS blockade by using NG-nitro-l-arginine methyl ester. Pulmonary arterial endothelial NOS was unaltered, but the inducible NOS protein content was significantly decreased ( P < 0.01) in the experimental group. Pulmonary ( P < 0.05) and aortic ( P < 0.01) tissue ex vivo NO accumulation was significantly reduced in the 60% O2-treated animals. We speculate that impaired pulmonary vascular tissue NO metabolism after chronic O2 exposure potentiates 8-iso-PGF2α-induced vasoconstriction in the newborn rat, thus contributing to pulmonary hypertension.
Taurine Activates Strychnine-Sensitive Glycine Receptors in Neurons Freshly Isolated From Nucleus Accumbens of Young Rats
Authors: Jiang Zhenglin , Krnjević Kresimir , Wang Fushun , Ye Jiang Hong
Published: January 2004

Although functional glycine receptors (GlyRs) are present in the mature nucleus accumbens (NAcc), an important area of the mesolimbic dopamine system involved in drug addiction, their role has been unclear because the NAcc contains little glycine. However, taurine, an agonist of GlyRs, is abundant throughout the brain, especially during early development. In the present study on freshly dissociated NAcc neurons from young Sprague-Dawley rats (12- to 21-day old), we found that both glycine and taurine can strongly depolarize NAcc neurons and modulate their excitability. In voltage-clamped NAcc neurons, glycine and taurine elicited chloride currents ( IGly and ITau) with an EC50 of 0.12 and 1.25 mM, respectively. The reversal potential of IGly or ITau was 0 mV in conventional whole cell mode and –30 mV in gramicidin-perforated mode. At concentrations <1 mM, both glycine and taurine were very effectively antagonized by strychnine and by picrotoxin (with an IC50 of 60 nM and 36.5 μM for IGly, and 40 nM and 42.2 μM for ITau) but were insensitive to 10 μM bicuculline. The currents elicited by taurine (≤1 mM) showed complete cross-desensitization with IGly, but none with γ-aminobutyric acid (GABA)-induced currents ( IGABA). However, ITau elicited by very concentrated taurine (10 mM) showed partial cross-desensitization with IGABA, and it was substantially antagonized by 10 μM bicuculline. These results indicate that taurine binds mainly to GlyRs in NAcc, but it could be a partial agonist of GABAA receptors. By activating GlyRs, taurine may play an important physiological role in the control of NAcc function, especially during development.
Binaural Interaction Revisited in the Cat Primary Auditory Cortex
Authors: Zhang Jiping , Nakamoto Kyle T. , Kitzes Leonard M.
Published: January 2004

The binaural interactions of neurons were studied in the primary auditory cortex (AI) of barbiturate-anesthetized cats with a matrix of binaural tonal stimuli varying in both interaural level differences (ILD) and average binaural level (ABL). The purpose of this study was to determine: 1) the distribution of preferred binaural combinations (PBCs) of a large population of neurons and its relationships with binaural interactions and binaural monotonicity; 2) whether monaural responses are predictive of binaural responses; and 3) whether there is a restricted set of representative binaural stimulus configurations that could effectively classify the binaural interactions. Binaural interactions were often diverse in the matrix and dependent on both ABL and ILD. Compared with previous studies, a higher proportion of mixed binaural interaction type and a lower proportion of EO/I type were found. No monaural neurons were found. Binaural responses often differed from monaural responses in the number of spikes and/or the form of the response functions. The PBCs of the majority of EO and PB neurons were in the contralateral field and midline, respectively. However, the PBCs of EE units were evenly distributed across the contralateral and ipsilateral fields. The majority of the nonmonotonic neurons responded most strongly to lower ABLs, whereas the majority of monotonic neurons responded most strongly to higher ABLs. This study demonstrated that in AI a restricted set of binaural stimulus configurations is not sufficient to reveal the binaural responses properties. Also, monaural responses are not predictive of binaural responses.
CNS Activation by Noxious Heat to the Hand or Foot: Site-Dependent Delay in Sensory But Not Emotion Circuitry
Authors: Becerra L. , Iadarola M. , Borsook D.
Published: January 2004

Recently, functional magnetic resonance imaging has been used as a novel method of evaluating the CNS response to noxious stimuli. In a previous study, a prolonged noxious thermal stimulus applied to the dorsum of the hand produced more than one hemodynamic response that was temporally segregated. The two major responses displayed activation in primary sensory regions (classic pain circuitry) and regions involved in emotion (reward/aversion circuitry), respectively. In the current study, we applied the same thermal stimulus separately to the dorsum of the left foot and the dorsum of the left hand in the same subjects and compared the hemodynamic responses to evaluate the effects of conduction distance on CNS activation within these two segregated systems. After stimulus delivery to the foot, the hemodynamic response in primary sensory networks occurs after a delay of 3.6 ± 1.3 s as compared with the response after hand stimulation. The relative delay of the hemodynamic response in reward/aversion regions is not significantly different between hand and foot stimulation (0.6 ± 2.1 s). These results within the primary sensory system are consistent with the greater conduction distance of the peripheral nerves from the hand versus the foot. The observation that the response within the reward/aversion pathways occurs with the same rapid temporal characteristics after either hand or foot stimulation supports the notion that the circuitry involved in the evaluation of aversive stimuli is rapid in onset and probably represents a major protective mechanism for survival.
Accumbal Neural Responses During the Initiation and Maintenance of Intravenous Cocaine Self-Administration
Authors: Peoples Laura L. , Lynch Kevin G. , Lesnock Jamie , Gangadhar Nidhi
Published: January 2004

During a chronic extracellular recording session, animals with a history of cocaine self-administration were allowed to initiate drug seeking under drug-free conditions. Later, in the same recording session, animals engaged in intravenous cocaine self-administration. During the drug-free period, 31% of 70 accumbal neurons showed a significant increase in average firing rate in association with either or both the exposure to cues that signaled the onset of cocaine availability and the subsequent onset of drug-seeking behavior. The neurons that showed an average excitatory response during the drug-free period were the only group of neurons that showed an average excitatory phasic response to cocaine-reinforced lever presses during the drug self-administration session. A majority of the neurons that were activated during the drug-free period, like the majority of other neurons, showed decreases in average firing in response to self-administered cocaine. However, the neurons that were activated during the drug-free period maintained a higher rate of firing throughout the self-administration session than did other accumbal neurons. The data of the present study are consistent with the conclusion that accumbal neurons contribute to, or otherwise process, initiation of drug seeking under drug-free conditions and that they do so via primarily excitatory responses. Furthermore, there is continuity between the drug-free and -exposed conditions in neural responses associated with drug seeking. Finally, the data have potential implications for understanding mechanisms that transduce accumbal-mediated drug effects that contribute to drug addiction.