bluuebunny/crossref_metadata_2025 huggingface dataset:
3D-SHELL ELEMENTS AND THEIR UNDERLYING MATHEMATICAL MODEL
Authors: CHAPELLE D. , FERENT A. , BATHE K. J.
Published: February 2004

We focus on a family of shell elements which are a direct generalization of the shell elements most commonly used in engineering practice. The elements in the family include the effects of the through-the-thickness normal stress and can be employed to couple directly with surrounding media on either surfaces of the shell. We establish the "underlying" mathematical model of the shell discretization scheme, and we show that this mathematical model features the same asymptotic behaviors — when the shell thickness becomes increasingly smaller — as classical shell models. The question of "locking" of the finite element discretization is also briefly addressed and we point out that, for an effective finite element scheme, the MITC approach of interpolation is available.
NEUTRINO CURRENT IN A GRAVITATIONAL PLANE WAVE COLLISION BACKGROUND
Authors: BINI DONATO , CHERUBINI CHRISTIAN , CRUCIANI GIANLUCA , LUNARI ANDREA
Published: February 2004

The behaviour of a massless Dirac field on a general spacetime background representing two colliding gravitational plane waves is discussed in the Newman–Penrose formalism. The geometrical properties of the neutrino current are analysed and explicit results are given for the special Ferrari–Ibañez solution.
GRAVITATIONAL FIELD OF A GLOBAL MONOPOLE IN KALB–RAMOND BACKGROUND
Authors: RAHAMAN F. , RAY T. , FARUK O. , MUKHERJEE R. , MAITY K. , MAL S.
Published: February 2004

The problem of global monopole in Kalb–Ramond background is investigated. A comparison is made with the corresponding results predicted by general relativity.
FINITE-RANGE GRAVITY AND ITS ROLE IN GRAVITATIONAL WAVES, BLACK HOLES AND COSMOLOGY
Authors: BABAK S. V. , GRISHCHUK L. P.
Published: February 2004

Theoretical considerations of fundamental physics, as well as certain cosmological observations, persistently point out to permissibility, and maybe necessity, of macroscopic modifications of the Einstein general relativity. The field theoretical formulation of general relativity helped us to identify the phenomenological seeds of such modifications. They take place in the form of very specific mass terms, which appear in addition to the field theoretical analog of the usual Hilbert–Einstein Lagrangian. We derive and study exact nonlinear equations of the theory, along with its linear approximation. We interpret the added terms as masses of spin-2 and spin-0 gravitons. The arising finite-range gravity is a fully consistent theory, which smoothly approaches general relativity in the massless limit, that is, when both masses tend to zero and the range of gravity tends to infinity. We show that all local weak-field predictions of the theory are in perfect agreement with the available experimental data. However, some other conclusions of the nonlinear massive theory are in a striking contrast with those of general relativity. We show in detail how the arbitrarily small mass terms eliminate the black hole event horizon and replace a permanent power-law expansion of a homogeneous isotropic universe with an oscillatory behaviour. One variant of the theory allows the cosmological scale factor to exhibit an 'accelerated expansion' instead of slowing down to a regular maximum of expansion. We show in detail why the traditional, Fierz–Pauli, massive gravity is in conflict not only with the static-field experiments, but also with the available indirect gravitational-wave observations. At the same time, we demonstrate the incorrectness of the widely held belief that the non-Fierz–Pauli theories possess "negative energies" and "instabilities."
ACTIONS FOR VACUUM EINSTEIN'S EQUATION WITH A KILLING SYMMETRY
Authors: HE HAN , MA YONGGE , YANG XUEJUN
Published: February 2004

In a space–time M with a Killing vector field ξa which is either everywhere timelike or everywhere spacelike, the collection of all trajectories of ξa gives a three-dimensional space S. Besides the symmetry-reduced action from that of Einstein–Hilbert, an alternative action of the fields on S is also proposed which gives the same fields equations as those reduced from the vacuum Einstein equation on M.
SCALAR HYPERBOLIC EQUATION WITH GR-TYPE NONLINEARITY
Authors: KHOKHLOV A. M. , NOVIKOV I. D.
Published: February 2004

We study a scalar hyperbolic partial differential equation, [Formula: see text], with nonlinear terms similar to those of the equations of general relativity. The equation has a number of non-trivial analytical solutions whose existence rely on a delicate balance between linear and nonlinear terms. We formulate two classes of second-order accurate central-difference schemes, CFLN and MOL, for numerical integration of this equation. Solutions produced by the schemes converge to exact solutions at any fixed time t when numerical resolution is increased. However, in certain cases integration becomes asymptotically unstable when t is increased and resolution is kept fixed. This behavior is caused by subtle changes in the balance between linear and nonlinear terms when the equation is discretized. Changes in the balance occur without violating second-order accuracy of discretization. We thus demonstrate that a second-order accuracy, althoug necessary for convergence at finite t, does not guarantee a correct asymptotic behavior and long-term numerical stability. Accuracy and stability of integration are greatly improved by an exponential transformation of the unknown variable.
ENTANGLEMENT OF IDENTICAL PARTICLES AND REFERENCE PHASE UNCERTAINTY
Authors: VACCARO JOHN A. , ANSELMI FABIO , WISEMAN HOWARD M.
Published: February 2004

We have recently introduced a measure of the bipartite entanglement of identical particles, E P , based on the principle that entanglement should be accessible for use as a resource in quantum information processing. We show here that particle entanglement is limited by the lack of a reference phase shared by the two parties, and that the entanglement is constrained to reference-phase invariant subspaces. The super-additivity of E P results from the fact that this constraint is weaker for combined systems. A shared reference phase can only be established by transferring particles between the parties, that is, with additional nonlocal resources. We show how this nonlocal operation can increase the particle entanglement.
QUANTUM COMMUNICATION COMPLEXITY PROTOCOLS BASED ON HIGHER-DIMENSIONAL ENTANGLED SYSTEMS
Authors: BRUKNER ČASLAV , PATEREK TOMASZ , ŻUKOWSKI MAREK
Published: February 2004

We introduce new communication complexity problems whose quantum solution exploits entanglement between higher-dimensional systems. We show that the quantum solution is more efficient than the broad class of classical ones. The difference between the efficiencies for the quantum and classical protocols grows with the dimensionality of the entangled systems.
REALIZATION OF UNITARY MAPS VIA PROBABILISTIC PROGRAMMABLE QUANTUM PROCESSORS
Authors: ZIMAN MÁRIO , BUŽEK VLADIMÍR
Published: February 2004

We analyze probabilistic realizations of programmable quantum processors that allow us to realize unitary operations on qubits as well as on qudits. Programmable processors are composed of two inputs — the data register and the program register. In the input state of the program register information about the operation that is supposed to be performed on the data is encoded. At the output of the probabilistic processor a measurement over the program register is performed. An intrinsic property of probabilistic processors is that they sometimes fail, but we know when this happens. We present a complete analysis of two processors: (1) The so-called [Formula: see text] processor that is based on a simple controlled-NOT gate. (2) The so-called [Formula: see text] processor that utilizes the quantum-information-distributor circuit.
5-HT induces duodenal mucosal bicarbonate secretion via cAMP- and Ca2+-dependent signaling pathways and 5-HT4 receptors in mice
Authors: Tuo Bi-Guang , Sellers Zachary , Paulus Petra , Barrett Kim E. , Isenberg Jon I.
Published: February 2004

In previous studies, we have found that 5-hydroxytryptamine (5-HT) is a potent stimulant of duodenal mucosal bicarbonate secretion (DMBS) in mice. The aim of the present study was to determine the intracellular signaling pathways and 5-HT receptor subtypes involved in 5-HT-induced DMBS. Bicarbonate secretion by murine duodenal mucosa was examined in vitro in Ussing chambers. 5-HT receptor involvement in DMBS was inferred from pharmacological studies by using selective 5-HT receptor antagonists and agonists. The expression of 5-HT4 receptor mRNA in duodenal mucosa and epithelial cells was analyzed by RT-PCR. cAMP-dependent signaling pathway inhibitors MDL-12330A, Rp-cAMP, and H-89 and Ca2+-dependent signaling pathway inhibitors verapamil and W-13 markedly reduced 5-HT-stimulated duodenal bicarbonate secretion and short-circuit current ( Isc), whereas cGMP-dependent signaling pathway inhibitors NS-2028 and KT-5823 failed to alter these responses. Both SB-204070 and high-dose ICS-205930 (selective 5-HT4 receptor antagonists) markedly inhibited 5-HT-stimulated bicarbonate secretion and Isc, whereas methiothepine (5-HT1 receptor antagonist), ketanserin (5-HT2 receptor antagonist), and a low concentration of ICS-205930 (5-HT3 receptor antagonist) had no effect. RS-67506 (partial 5-HT4 receptor agonist) concentration-dependently increased bicarbonate secretion and Isc, whereas 5-carboxamidotryptamine (5-HT1 receptor agonist), α-methyl-5-HT (5-HT2 receptor agonist), and phenylbiguanide (5-HT3 receptor agonist) did not significantly increase bicarbonate secretion or Isc. RT-PCR analysis confirmed the expression of 5-HT4 receptor mRNA in murine duodenal mucosa and epithelial cells. These results demonstrate that 5-HT regulates DMBS via both cAMP- and Ca2+-dependent signaling pathways and 5-HT4 receptors located in the duodenal mucosa and/or epithelial cells.
Demonstration of functional role of TECK/CCL25 in T lymphocyte-endothelium interaction in inflamed and uninflamed intestinal mucosa
Authors: Hosoe Naoki , Miura Soichiro , Watanabe Chikako , Tsuzuki Yoshikazu , Hokari Ryota , Oyama Tokushige , Fujiyama Yoichi , Nagata Hiroshi , Ishii Hiromasa
Published: February 2004

It has recently been suggested that C-C chemokines may play a role in the organ-specific homing of lymphocytes, but there is not enough in vivo evidence in intestinal mucosa. The aim of this study was to examine whether thymus-expressed chemokine (TECK)/CCL25 and its ligand CCR9 are involved in T-lymphocyte interaction with microvessels of murine intestinal mucosa. T lymphocytes from the small intestine were fluorescence labeled, and their adhesion to mucosal microvessels was observed by intravital microscopy. Lamina proprial lymphocytes (LPL) and intraepithelial lymphocytes (IEL) adhered to both the small intestine and colon, and desensitization of CCR9 with TECK/CCL25 or anti-TECK/CCL25 antibody significantly inhibited these adhesions only in small intestine. At both sites, TNF-α significantly increased LPL adhesion but not IEL adhesion. Desensitization of CCR9 or anti-TECK/CCL25 antibody also attenuated the TNF-α-induced LPL adhesion in the small intestine. Increased expression of TECK/CCL25 by TNF-α was observed in the lamina propria of small intestine. TECK/CCL25 may thus play an important role in the adherence of mucosal lymphocytes to the microvessels of the small intestine but not the colon under uninflamed as well as inflamed conditions.
TNF-α-induced increase in intestinal epithelial tight junction permeability requires NF-κB activation
Authors: Ma Thomas Y. , Iwamoto Gary K. , Hoa Neil T. , Akotia Vimesh , Pedram Ali , Boivin Michel A. , Said Hamid M.
Published: February 2004

Crohn's disease (CD) patients have an abnormal increase in intestinal epithelial permeability. The defect in intestinal tight junction (TJ) barrier has been proposed as an important etiologic factor of CD. TNF-α increases intestinal TJ permeability. Because TNF-α levels are markedly increased in CD, TNF-α increase in intestinal TJ permeability could be a contributing factor of intestinal permeability defect in CD. Our purpose was to determine some of the intracellular mechanisms involved in TNF-α modulation of intestinal epithelial TJ permeability by using an in vitro intestinal epithelial system consisting of filter-grown Caco-2 monolayers. TNF-α produced a concentration- and time-dependent increase in Caco-2 TJ permeability. TNF-α-induced increase in Caco-2 TJ permeability correlated with Caco-2 NF-κB activation. Inhibition of TNF-α-induced NF-κB activation by selected NF-κB inhibitors, curcumin and triptolide, prevented the increase in Caco-2 TJ permeability, indicating that NF-κB activation was required for the TNF-α-induced increase in Caco-2 TJ permeability. This increase in Caco-2 TJ permeability was accompanied by down-regulation of zonula occludens (ZO)-1 proteins and alteration in junctional localization of ZO-1 proteins. TNF-α modulation of ZO-1 protein expression and junctional localization were also prevented by NF-κB inhibitors. TNF-α did not induce apoptosis in Caco-2 cells, suggesting that apoptosis was not the mechanism involved in TNF-α-induced increase in Caco-2 TJ permeability. These results demonstrate for the first time that TNF-α-induced increase in Caco-2 TJ permeability was mediated by NF-κB activation. The increase in permeability was associated with NF-κB-dependent downregulation of ZO-1 protein expression and alteration in junctional localization.
Transforming growth factor-α directly augments histidine decarboxylase and vesicular monoamine transporter 2 production in rat enterochromaffin-like cells
Authors: Kazumori Hideaki , Ishihara Shunji , Rumi Mohammad A. K. , Ortega-Cava Cesar F. , Kadowaki Yasunori , Kinoshita Yoshikazu
Published: February 2004

For the production and vesicle storage of histamine, Enterochromaffin-like (ECL) cells express histidine decarboxylase (HDC) and vesicular monoamine transporter 2 (VMAT2). Although HDC and VMAT2 show dynamic changes during gastric ulcer healing, the control system of their expression has not been fully investigated. In the present study, we investigated the effect of transforming growth factor-α (TGF-α) and proinflammatory cytokines on HDC and VMAT2 expression in rat ECL cells. Time course changes in the expression of TGF-α during the healing of acetic acid-induced ulcers were studied. EGF receptor (EGFR) expression was also examined in ECL cells, whereas the direct effects of TGF-α and proinflammatory cytokines on HDC and VMAT2 expression in ECL cells were investigated using in vivo and in vitro models. During the process of ulcer healing, expression of TGF-α mRNA was markedly augmented. Furthermore, EGFR was identified in isolated ECL cells. TGF-α stimulated HDC and VMAT2 mRNA expression and protein production and also increased histamine release from ECL cells. Selective EGFR tyrosine kinase inhibitor tyrphostin AG1478 almost completely inhibited HDC and VMAT2 gene expression induced by TGF-α in vivo and in vitro. During gastric mucosal injury, TGF-α was found to stimulate ECL cell functions by increasing HDC and VMAT2 expression.
Inflammation and Cancer I. Rodent models of infectious gastrointestinal and liver cancer
Authors: Rogers Arlin B. , Fox James G.
Published: February 2004

Chronic gastrointestinal and liver infections account for a significant percentage of human cancer deaths. Rodent models help elucidate how infection can lead to malignancy. Helicobacter pylori, the leading cause of human gastric tumors, produces similar disease in Mongolian gerbils. H. pylori, H. felis, and H. hepaticus induce stomach, lower bowel, or liver tumors in susceptible wild-type and genetically engineered mice. Immune dysregulated mice recapitulate features of inflammatory bowel disease including colon carcinoma. Hepatitis B and C virus transgenic mice provide insights into viral hepatitis and hepatocellular carcinoma. Rodent models enhance our understanding of infectious cancer pathogenesis and suggest novel targets for intervention.
Role of myoglobin as a scavenger of cellular NO in myocardium
Authors: Kreutzer Ulrike , Jue Thomas
Published: February 2004

Recent studies have detected a 1H nuclear magnetic resonance (NMR) reporter signal of metmyoglobin (metMb) during bradykinin stimulation of an isolated mouse heart. The observation has led to the hypothesis that Mb reacts with cellular nitric oxide (NO). However, the hypothesis depends on an unequivocal detection of metMb signals in vivo. In solution, nitrite oxidization of Mb produces a characteristic set of paramagnetically shifted 1H NMR signals. In the upfield spectral region, MbO2 and MbCO exhibit the γCH3 Val E11 signals at –2.8 and –2.4 ppm, respectively. In the same spectral region, nitrite oxidation of Mb produces a set of signals at –3.7 and –4.7 ppm at 35°C. Previous studies have confirmed the visibility of metMb signals in perfused rat myocardium. With bradykinin infusion, perfusion pressure and rate-pressure product decrease, consistent with endogenous NO formation. However, neither myocardial O2 consumption nor high-energy phosphate levels, as reflected in the 31P NMR signals, show any significant change. Bradykinin still triggers a similar physiological response even in the presence of CO that is sufficient to inhibit 86% Mb. In all cases, the 1H NMR spectra from perfused rat myocardium reveal no metMb signals. The results suggest that bradykinin-induced NO does not interact significantly with cellular Mb to produce an NMR-detectable quantity of metMb in the perfused rat myocardium. As a consequence, the experiments cannot confirm the intriguing proposal that Mb acts as a cellular NO scavenger.
Adult rat cardiomyocytes exhibit capacitative calcium entry
Authors: Hunton Dacia L. , Zou LuYun , Pang Yi , Marchase Richard B.
Published: February 2004

Capacitative Ca2+entry (CCE) refers to the influx of Ca2+through plasma membrane channels activated on depletion of endoplasmic-sarcoplasmic reticulum Ca2+stores. We utilized two Ca2+-sensitive dyes (one monitoring cytoplasmic free Ca2+and the other free Ca2+within the sarcoplasmic reticulum) to determine whether adult rat ventricular myocytes exhibit CCE. Treatments with inhibitors of the sarcoplasmic endoplasmic reticulum Ca2+-ATPases were not efficient in releasing Ca2+from stores. However, when these inhibitors were coupled with either Ca2+ionophores or angiotensin II (an agonist generating inositol 1,4,5 trisphosphate), depletion of stores was observed. This depletion was accompanied by a significant influx of extracellular Ca2+characteristic of CCE. CCE was also observed when stores were depleted with caffeine. This influx of Ca2+was sensitive to four inhibitors of CCE (glucosamine, lanthanum, gadolinium, and SKF-96365) but not to inhibitors of L-type channels or the Na+/Ca2+exchanger. In the whole cell configuration, an inward current of ∼0.7 pA/pF at –90 mV was activated when a Ca2+chelator or inositol (1,4,5)-trisphosphate was included in the pipette or when Ca2+stores were depleted with a Ca2+-ATPase inhibitor and ionophore. The current was maximal at hyperpolarizing voltages and inwardly rectified. The channel was relatively permeant to Ca2+and Ba2+but only poorly to Mg2+or Mn2+. Taken together, these data support the existence of CCE in adult cardiomyocytes, a finding with likely implications to physiological responses to phospholipase C-generating agonists.
A model of graded calcium release and L-type Ca2+ channel inactivation in cardiac muscle
Authors: Bondarenko Vladimir E. , Bett Glenna C. L. , Rasmusson Randall L.
Published: February 2004

We have developed a model of Ca2+ handling in ferret ventricular myocytes. This model includes a novel L-type Ca2+ channel, detailed intracellular Ca2+ movements, and graded Ca2+-induced Ca2+ release (CICR). The model successfully reproduces data from voltage-clamp experiments, including voltage- and time-dependent changes in intracellular Ca2+ concentration ([Ca2+]i), L-type Ca2+ channel current ( ICaL) inactivation and recovery kinetics, and Ca2+ sparks. The development of graded CICR is critically dependent on spatial heterogeneity and the physical arrangement of calcium channels in opposition to ryanodine-sensitive release channels. The model contains spatially distinct subsystems representing the subsarcolemmal regions where the junctional sarcoplasmic reticulum (SR) abuts the T-tubular membrane and where the L-type Ca2+ channels and SR ryanodine receptors (RyRs) are localized. There are eight different types of subsystems in our model, with between one and eight L-type Ca2+ channels distributed binomially. This model exhibits graded CICR and provides a quantitative description of Ca2+ dynamics not requiring Monte-Carlo simulations. Activation of RyRs and release of Ca2+ from the SR depend critically on Ca2+ entry through L-type Ca2+ channels. In turn, Ca2+ channel inactivation is critically dependent on the release of stored intracellular Ca2+. Inactivation of ICaL depends on both transmembrane voltage and local [Ca2+]i near the channel, which results in distinctive inactivation properties. The molecular mechanisms underlying many ICaL gating properties are unclear, but [Ca2+]i dynamics clearly play a fundamental role.
Increased endothelin-1 production in patients with chronic heart failure
Authors: Parker John D. , Thiessen Jake J.
Published: February 2004

Endothelin-1 (ET-1) concentrations are elevated in patients with congestive heart failure (CHF), although the cause of this increase remains uncertain. We hypothesized that abnormalities in ET-1 production, clearance, or a combination of these may be the cause of elevated ET-1 concentrations in chronic CHF. The kinetics of clearance of ET-1 were measured with 125I-labeled ET-1 in eight patients with CHF and five age-matched normal individuals. In both normal subjects and the CHF group, the kinetics of ET-1 clearance were best described by a three-compartment model. The steady-state volume of distribution of ET-1 was significantly greater in the CHF group compared with normal subjects (25.2 ± 3.9 vs. 13.8 ± 2.1 l/kg; P < 0.05). The total clearance rate from plasma was greater in the CHF group (0.119 ± 0.018 vs. 0.047 ± 0.013 l·kg–1·min–1; P = 0.05). The total body production rate of ET-1 was also significantly higher in patients with CHF (0.21 ± 0.03. vs. 0.06 ± 0.02 ng·kg–1·min–1; P < 0.05). It appears that increased ET-1 production rather than decreased clearance is the cause of elevated ET-1 concentrations in patients with chronic CHF.
Inhibition of nitric oxide synthase does not alter dynamic cerebral autoregulation in humans
Authors: Zhang Rong , Wilson Thad E. , Witkowski Sarah , Cui Jian , Crandall Craig G. , Levine Benjamin D.
Published: February 2004

The aim of this study was to determine whether inhibition of nitric oxide synthase (NOS) alters dynamic cerebral autoregulation in humans. Beat-to-beat blood pressure (BP) and cerebral blood flow (CBF) velocity (transcranial Doppler) were measured in eight healthy subjects in the supine position and during 60° head-up tilt (HUT). NOS was inhibited by intravenous NG-monomethyl-l-arginine (l-NMMA) infusion. Dynamic cerebral autoregulation was quantified by transfer function analysis of beat-to-beat changes in BP and CBF velocity. Pressor effects of l-NMMA on cerebral hemodynamics were compared with those of phenylephrine infusion. In the supine position, l-NMMA increased mean BP from 83 ± 3 to 94 ± 3 mmHg ( P < 0.01). However, CBF velocity remained unchanged. Consequently, cerebrovascular resistance index (CVRI) increased by 15% ( P < 0.05). BP and CBF velocity variability and transfer function gain at the low frequencies of 0.07–0.20 Hz did not change with l-NMMA infusion. Similar changes in mean BP, CBF velocity, and CVRI were observed after phenylephrine infusion, suggesting that increase in CVRI after l-NMMA was mediated myogenically by increase in arterial pressure rather than a direct effect of cerebrovascular NOS inhibition. During baseline tilt without l-NMMA, steady-state BP increased and CBF velocity decreased. BP and CBF velocity variability at low frequencies increased in parallel by 277% and 217%, respectively ( P < 0.05). However, transfer function gain remained unchanged. During tilt with l-NMMA, changes in steady-state hemodynamics and BP and CBF velocity variability as well as transfer gain and phase were similar to those without l-NMMA. These data suggest that inhibition of tonic production of NO does not appear to alter dynamic cerebral autoregulation in humans.
Sleep-related sympathovagal imbalance in SHR
Authors: Kuo Terry B. J. , Lai Ching J. , Shaw Fu-Zen , Lai Chi-Wan , Yang Cheryl C. H.
Published: February 2004

The role of the autonomic nervous system in spontaneous hypertension during each stage of the sleep-wake cycle remains unclear. The present study attempted to evaluate the differences in cardiac autonomic modulations among spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD) across sleep-wake cycles. Continuous power spectral analysis of electroencephalogram, electromyogram, and heart rate variability was performed in unanesthetized free moving rats during daytime sleep. Frequency-domain analysis of the stationary R-R intervals (RR) was performed to quantify the high-frequency power (HF), low-frequency power (LF)-to-HF ratio (LF/HF), and normalized LF (LF%) of heart rate variability. WKY and SD had similar mean arterial pressure, which is significantly lower than that of SHR during active waking, quiet sleep, and paradoxical sleep. Compared with WKY and SD, SHR had lower HF but similar RR, LF/HF, and LF% during active waking. During quiet sleep, SHR developed higher LF/HF and LF% in addition to lower HF. SHR ultimately exhibited significantly lower RR accompanied with higher LF/HF and LF% and lower HF during paradoxical sleep compared with WKY. We concluded that significant cardiac sympathovagal imbalance with an increased sympathetic modulation occurred in SHR during sleep, although it was less evident during waking.
Concerted effect of transforming growth factor-β, cyclin inhibitor p21, and c-mycon smooth muscle cell proliferation
Authors: Khanna Ashwani
Published: February 2004

Increased aortic smooth muscle cell (SMC) proliferation is a key event in the pathogenesis of atherosclerosis. Transforming growth factor-β (TGF-β) is one of the potent inhibitors of SMC proliferation. The purpose of this study was 1) to explore the effect of TGF-β inhibition on proliferation of SMC and expression of growth regulatory molecules like p21 and c- myc and 2) to determine whether restoration of cell cycle regulatory molecules normalizes the altered proliferation. To test the role of TGF-β in SMC proliferation, using antisense plasmid DNA, we inhibited TGF-β gene from aortic SMC, which resulted in a significant increase ( P < 0.03) in proliferation (studied by quantifying new DNA synthesis with [3H]thymidine uptake assay). In TGF-β-altered SMC (TASMC), the mRNA expression (studied by RT-PCR) of c- myc was increased whereas that of the cyclin inhibitor p21 was completely inhibited. Using p21 sense plasmid DNA, we transfected p21 gene in TASMC, which restored p21 mRNA and protein expression and decreased proliferation ( P < 0.002) in TASMC. Similar treatment with c- myc antisense oligonucleotides significantly ( P < 0.001) decreased the proliferation of TASMC. TASMC also exhibited alteration in morphological changes in SMC but returned to normal with treatment of p21 and TGF-β sense plasmid DNA. Two-dimensional gel electrophoresis analysis of SMC and TASMC demonstrated differential expression of proteins relevant to cellular proliferation and atherosclerosis. This study uniquely analyzes the effect of TGF-β at the molecular level on proliferation of SMC and on cell cycle regulatory molecules, implicating their potential role in the pathogenesis of atherosclerosis.
Interaction between prostanoids and nitric oxide in regulation of systemic, pulmonary, and coronary vascular tone in exercising swine
Authors: Merkus Daphne , Houweling Birgit , Zarbanoui Alisina , Duncker Dirk J.
Published: February 2004

Prostacyclin and nitric oxide (NO) are produced by the endothelium in response to physical forces such as shear stress. Consequently, both NO and prostacyclin may increase during exercise and contribute to metabolic vasodilation. Conversely, NO has been hypothesized to inhibit prostacyclin production. We therefore investigated the effect of cyclooxygenase (COX) inhibition on exercise-induced vasodilation of the porcine systemic, pulmonary, and coronary beds before and after inhibition of NO production. Swine were studied at rest and during treadmill exercise at 1–5 km/h, before and after COX inhibition with indomethacin (10 mg/kg iv), and in the absence and presence of NO synthase inhibition with Nω-nitro-l-arginine (l-NNA; 20 mg/kg iv). COX inhibition produced systemic vasoconstriction at rest, which waned during exercise. The systemic vasoconstriction by COX inhibition was enhanced after l-NNA, particularly at rest. In the coronary circulation, COX inhibition also resulted in vasoconstriction at rest and during exercise. However, vasoconstriction was not modified by pretreatment with l-NNA. In contrast, COX inhibition had no effect on the pulmonary circulation, either at rest or during exercise. Moreover, a prostanoid influence in the pulmonary circulation could not be detected after l-NNA. In conclusion, endogenous prostanoids contribute importantly to systemic and coronary tone in awake swine at rest but are not mandatory for exercise-induced vasodilation in these beds. Endogenous prostanoids are not mandatory for the regulation of pulmonary resistance vessel tone. Finally, NO blunts the contribution of prostanoids to vascular tone regulation in the systemic but not in the coronary and pulmonary beds.
Mechanistic inquiry into decrease in probability of defibrillation success with increase in complexity of preshock reentrant activity
Authors: Hillebrenner Matthew G. , Eason James C. , Trayanova Natalia A.
Published: February 2004

Energy requirements for successful antiarrhythmia shocks are arrhythmia specific. However, it remains unclear why the probability of shock success decreases with increasing arrhythmia complexity. The goal of this research was to determine whether a diminished probability of shock success results from an increased number of functional reentrant circuits in the myocardium, and if so, to identify the responsible mechanisms. To achieve this goal, we assessed shock efficacy in a bidomain defibrillation model of a 4-mm-thick slice of canine ventricles. Shocks were applied between a right ventricular cathode and a distant anode to terminate either a single scroll wave (SSW) or multiple scroll waves (MSWs). From the 160 simulations conducted, dose-response curves were constructed for shocks given to SSWs and MSWs. The shock strength that yielded a 50% probability of success (ED50) for SSWs was found to be 13% less than that for MSWs, which indicates that a larger number of functional reentries results in an increased defibrillation threshold. The results also demonstrate that an isoelectric window exists after both failed and successful shocks; however, shocks of strength near the ED50 value that were given to SSWs resulted in 16.3% longer isoelectric window durations than the same shocks delivered to MSWs. Mechanistic inquiry into these findings reveals that the two main factors underlying the observed relationships are 1) smaller virtual electrode polarizations in the tissue depth, and 2) differences in preshock tissue state. As a result of these factors, intramural excitable pathways leading to delayed breakthrough on the surface were formed earlier after shocks given to MSWs compared with SSWs and thus resulted in a lower defibrillation threshold for shocks given to SSWs.
A theoretical model of nitric oxide transport in arterioles: frequency- vs. amplitude-dependent control of cGMP formation
Authors: Tsoukias Nikolaos M. , Kavdia Mahendra , Popel Aleksander S.
Published: February 2004

Nitric oxide (NO) plays many important physiological roles, including the regulation of vascular smooth muscle tone. In response to hemodynamic or agonist stimuli, endothelial cells produce NO, which can diffuse to smooth muscle where it activates soluble guanylate cyclase (sGC), leading to cGMP formation and smooth muscle relaxation. The close proximity of red blood cells suggests, however, that a significant amount of NO released will be scavenged by blood, and thus the issue of bioavailability of endothelium-derived NO to smooth muscle has been investigated experimentally and theoretically. We formulated a mathematical model for NO transport in an arteriole to test the hypothesis that transient, burst-like NO production can facilitate efficient NO delivery to smooth muscle and reduce NO scavenging by blood. The model simulations predict that 1) the endothelium can maintain a physiologically significant amount of NO in smooth muscle despite the presence of NO scavengers such as hemoglobin and myoglobin; 2) under certain conditions, transient NO release presents a more efficient way for activating sGC and it can increase cGMP formation severalfold; and 3) frequency-rather than amplitude-dependent control of cGMP formation is possible. This suggests that it is the frequency of NO bursts and perhaps the frequency of Ca2+oscillations in endothelial cells that may limit cGMP formation and regulate vascular tone. The proposed hypothesis suggests a new functional role for Ca2+oscillations in endothelial cells. Further experimentation is needed to test whether and under what conditions in silico predictions occur in vivo.
Contractile reserve but not tension is reduced in monocrotaline-induced right ventricular hypertrophy
Authors: Versluis J. Pieter , Heslinga Johannes W. , Sipkema Pieter , Westerhof Nico
Published: February 2004

The objective of this study was to evaluate the role of right ventricular hypertrophy on developed tension (Fdev) and contractile reserve of rat papillary muscle by using a model of monocrotaline (Mct)-induced pulmonary hypertension. Calcium handling and the influence of bicarbonate ([Formula: see text]) were also addressed with the use of two different buffers ([Formula: see text] and HEPES). Wistar rats were injected with either Mct (40 mg/kg sc) or vehicle control (Con). Isometrically contracting right ventricular papillary muscles were studied at 80% of the length of maximal developed force. Contractile reserve (1 – Fdev/Fmax) was calculated from Fdev and maximal tension (Fmax). Calcium recirculation was determined with postextrasystolic potentiation. Both groups of muscles were superfused with either [Formula: see text] (Con-B and Mct-B, both n = 6) or HEPES (Con-H and Mct-H, both n = 6) buffer. With hypertrophy, contractions were slower but Fdev was not changed. However, Fmax was decreased ( P < 0.05). With [Formula: see text], Fmax decreased from 23.8 ± 6.5 mN·mm–2 in Con-B, to 13.7 ± 3.3 mN·mm–2 in Mct-B. With HEPES, it decreased from 16.3 ± 3.5 mN·mm–2 ( n = 6, Con-H) to 8.3 ± 1.6 mN·mm–2 (Mct-H). Contractile reserve during hypertrophy was therefore also decreased ( P < 0.05). With [Formula: see text], it decreased from 0.73 ± 0.03 (Con-B) to 0.55 ± 0.04 (Mct-B). With HEPES, it decreased ( P < 0.001) from 0.64 ± 0.07 (Con-H) to 0.19 ± 0.06 (Mct-H). The recirculation fraction decreased ( P < 0.05) from 0.59 ± 0.04 in Con-B to 0.44 ± 0.04 in Mct-B. We conclude that contractile reserve and recirculation fraction are impaired during hypertrophy, with a stronger effect under HEPES than [Formula: see text] superfusion.
Fractal properties of human muscle sympathetic nerve activity
Authors: Fadel Paul J. , Orer Hakan S. , Barman Susan M. , Vongpatanasin Wanpen , Victor Ronald G. , Gebber Gerard L.
Published: February 2004

Muscle sympathetic nerve activity (MSNA) in resting humans is characterized by cardiac-related bursts of variable amplitude that occur sporadically or in clusters. The present study was designed to characterize the fluctuations in the number of MSNA bursts, interburst interval, and burst amplitude recorded from the peroneal nerve of 15 awake, healthy human subjects. For this purpose, we used the Allan and Fano factor analysis and dispersional analysis to test whether the fluctuations were time-scale invariant (i.e., fractal) or random in occurrence. Specifically, we measured the slopes of the power laws in the Allan factor, Fano factor, and dispersional analysis curves. In addition, the Hurst exponent was calculated from the slope of the power law in the Allan factor curve. Whether the original time series contained fractal fluctuations was decided on the basis of a comparison of the values of these parameters with those for surrogate data blocks. The results can be summarized as follows. Fluctuations in the number of MSNA bursts and interburst interval were fractal in each of the subjects, and fluctuations in burst amplitude were fractal in four of the subjects. We also found that fluctuations in the number of heartbeats and heart period (R-R interval) were fractal in each of the subjects. These results demonstrate for the first time that apparently random fluctuations in human MSNA are, in fact, dictated by a time-scale-invariant process that imparts “long-term memory” to the sequence of cardiac-related bursts. Whether sympathetic outflow to the heart also is fractal and contributes to the fractal component of heart rate variability remains an open question.
Mechanisms of ADRF release from rat aortic adventitial adipose tissue
Authors: Dubrovska Galyna , Verlohren Stefan , Luft Friedrich C. , Gollasch Maik
Published: February 2004

Blood vessels are surrounded by variable amounts of adipose tissue. We showed earlier that adventitial adipose tissue inhibits rat aortic contraction by release of a transferable factor, adventitium-derived relaxing factor (ADRF), which activates smooth muscle K+ channels. However, little is known about the mechanisms of ADRF release. Using isolated rat aortic rings and isometric contraction measurements, we show that ADRF release depends on extracellular [Ca2+] (EC50 ∼ 4.7 mM). ADRF effects do not involve neuronal presynaptic N-type Ca2+ and Na+ channels or vanilloid, cannabinoid, and CGRP receptors. ADRF release is strongly inhibited by the protein tyrosine kinase inhibitors genistein and tyrphostin A25. In contrast, daidzein, an inactive genistein analog, and the protein tyrosine kinase inhibitor ST638 had no effect. Protein kinase A inhibition by H89 also inhibited ADRF release, whereas the protein kinase G inhibitor KT-5823 had no effect. We propose that ADRF release is Ca2+ dependent and is regulated by intracellular signaling pathways involving tyrosine kinase and protein kinase A. Furthermore, ADRF release does not depend on perivascular nerve endings.
Radial displacement of red blood cells during hemodilution and the effect on arteriolar oxygen profile
Authors: Briceño Juan Carlos , Cabrales Pedro , Tsai Amy G. , Intaglietta Marcos
Published: February 2004

In this study, we assessed the magnitude of the erratic deviations in the radial position of red blood cells (RBCs) in the laminar flow regime of arterioles in a hamster window preparation and the intraluminal Po2 profile to determine whether this variability affects the intraluminal distribution of oxygen in conditions of normal hematocrit and hemodilution. A gated image intensifier was used to visualize fluorescently labeled RBCs in tracer quantities and obtain multiple measurements of RBC radial and longitudinal positions at time intervals on the order of 5 ms within single arterioles (diameter range 40–95 μm). RBCs in the velocity range of 0.3–14 mm/s exhibit a mean coefficient of variation of velocity of 16.9 ± 10.5% and a SD of the radial position of 1.98 ± 0.98 μm. Both quantities were inversely related to hematocrit, and the former was significantly lowered by hemodilution. Our experimental results presented very similar values and shape compared with the intraluminal oxygen profile derived theoretically for normal hematocrit, suggesting that shear-augmented diffusion due to the measured radial displacement of RBCs did not significantly affect oxygen diffusion from blood into the arteriolar vessel wall. Po2 profiles in the arterioles assumed an increasingly parabolic configuration with increasing levels of hemodilution.
Heterotrimeric G protein Giis involved in a signal transduction pathway for ATP release from erythrocytes
Authors: Olearczyk Jeffrey J. , Stephenson Alan H. , Lonigro Andrew J. , Sprague Randy S.
Published: February 2004

Erythrocytes are reported to release ATP in response to mechanical deformation and decreased oxygen tension. Previously we proposed that receptor-mediated activation of the heterotrimeric G protein Gsresulted in ATP release from erythrocytes. Here we investigate the hypothesis that activation of heterotrimeric G proteins of the Gisubtype are also involved in a signal transduction pathway for ATP release from rabbit erythrocytes. Heterotrimeric G proteins Gαi1, Gαi2, and Gαi3but not Gαowere identified in rabbit and human erythrocyte membranes. Pretreatment of rabbit erythrocytes with pertussis toxin (100 ng/ml, 2 h), which uncouples Gi/ofrom their effector proteins, inhibited deformation-induced ATP release. Incubation of rabbit and human erythrocytes with mastoparan (Mas, 10 μM) or Mas-7 (1 μM), which are compounds that directly activate Giproteins, resulted in ATP release. However, rabbit erythrocytes did not release ATP when incubated with Mas-17 (10 μM), which is an inactive Mas analog. In separate experiments, Mas (10 μM) but not Mas-17 (10 μM) increased intracellular concentrations of cAMP when incubated with rabbit erythrocytes. Importantly, Mas-induced ATP release from rabbit erythrocytes was inhibited after treatment with pertussis toxin (100 ng/ml, 2 h). These data are consistent with the hypothesis that the heterotrimeric G protein Giis a component of a signal transduction pathway for ATP release from erythrocytes.
Gender affects calf venous compliance at rest and during baroreceptor unloading in humans
Authors: Monahan Kevin D. , Ray Chester A.
Published: February 2004

Leg venous compliance is a determinant of peripheral venous pooling during orthostatic stress such that high venous compliance could contribute to reduced orthostatic tolerance. We tested the hypotheses that 1) calf venous compliance is reduced during baroreceptor unloading, and 2) calf venous compliance is greater in women than men. Twelve men (27 ± 2 yr) and 12 women (25 ± 2 yr) were studied in the supine posture. Calf venous compliance was determined by inflating a thigh venous collecting cuff to 60 mmHg for 8 min and then decreasing cuff pressure at a rate of 1 mmHg/s to 0 mmHg. The slope of the pressure-compliance relation (compliance = β1+ 2·β2·cuff pressure), which is the first derivative of the quadratic pressure-volume relation [(Δlimb volume) = β0+ β1·(cuff pressure) + β2·(cuff pressure)2] during the reduction in collecting cuff pressure, was used to assess venous compliance at baseline and during one-legged lower body negative pressure (LBNP; —50 mmHg). At baseline, calf venous compliance was 48% lower ( P < 0.001) in women than men and decreased in men (Δ—25 ± 8%; P < 0.05) but not women (Δ1 ± 11%) during LBNP. Rhythmic ischemic handgrip (Δ6 ± 9%) and cold pressor testing (Δ—9 ± 7%) did not alter calf venous compliance in a subgroup of men ( n = 6). These data indicate gender-dependent effects on calf venous compliance under conditions associated with low sympathetic outflow (i.e., rest) and high sympathetic outflow (i.e., LBNP). However, they cannot explain gender-associated differences in orthostatic tolerance.
Evolution of activation patterns during long-duration ventricular fibrillation in dogs
Authors: Huang Jian , Rogers Jack M. , Killingsworth Cheryl R. , Singh Karan P. , Smith William M. , Ideker Raymond E.
Published: February 2004

Although resuscitation for sudden cardiac arrest attempts are frequently not instituted for several minutes after the onset of ventricular fibrillation (VF), previous mapping studies have examined only the first 40 s of VF or have involved isolated perfused hearts that did not become ischemic during VF. We applied quantitative pattern analysis to mapping data throughout the first 10 min of VF acquired from a 21 × 24 unipolar electrode array located on the ventricular epicardium of six open-chest dogs. The following twelve descriptors were continuously quantified: 1) number of wavefronts, 2) incidence of reentry, 3) wavefront propagation velocity, 4) incidence of breakthrough/focus, 5) incidence of block, 6) mean area activated by the wavefronts, 7) wavefront fractionations, 8) wavefront collisions, 9) multiplicity index, 10) repeatability, 11) negative peak rate of voltage change, and 12) peak frequency of activation. Cluster analysis of these descriptors divided VF into five stages ( stages i– v). The values of most descriptors (except block and breakthrough incidence) increased during stage i (1–11 s after VF induction) and maintained high values with rapid dynamic fluctuations during stage ii (12–62 s). Descriptors changed quickly to values indicating greater organization during stage iii (63–86 s), decreased steadily during stage iv (87–310 s), and approached zero during stage v (311–600 s). There was a high incidence of reentry just before, during, and after stage iii. In conclusion, during the first 10 min, VF can be divided into five stages according to the evolution of electrophysiological characteristics. All of the parameters show a rapid deterioration during VF, except for a temporary reversal ∼1 min after induction when activation briefly became more organized. Thus a quantitative description of activation does not uniformly decrease as VF progresses, but undergo rapid changes and exhibit a brief interval of increased organization after ∼1 min of VF. Further studies are warranted to determine whether these changes, particularly the increased organization of stage iii, have clinical consequences, such as an alteration in defibrillation efficacy.
Spectral analysis of muscle sympathetic nerve activity in heat-stressed humans
Authors: Cui Jian , Zhang Rong , Wilson Thad E. , Crandall Craig G.
Published: February 2004

Whole body heating increases muscle sympathetic nerve activity (MSNA); however, the effect of heat stress on spectral characteristics of MSNA is unknown. Such information may provide insight into mechanisms of heat stress-induced MSNA activation. The purpose of the present study was to test the hypothesis that heat stress-induced changes in systolic blood pressure variability parallel changes in MSNA variability. In 13 healthy subjects, MSNA, electrocardiogram, arterial blood pressure (via Finapres), and respiratory activity were recorded under both normothermic and heat stress conditions. Spectral characteristics of integrated MSNA, R-R interval, systolic blood pressure, and respiratory excursions were assessed in the low (LF; 0.03–0.15 Hz) and high (HF; 0.15–0.45 Hz) frequency components. Whole body heating significantly increased skin and core body temperature, MSNA burst rate, and heart rate, but not mean arterial blood pressure. Systolic blood pressure and R-R interval variability were significantly reduced in both the LF and HF ranges. Compared with normothermic conditions, heat stress significantly increased the HF component of MSNA, while the LF component of MSNA was not altered. Thus the LF-to-HF ratio of MSNA oscillatory components was significantly reduced. These data indicate that the spectral characteristics of MSNA are altered by whole body heating; however, heat stress-induced changes in MSNA do not parallel changes in systolic blood pressure variability. Moreover, the reduction in LF component of systolic blood pressure during heat stress is unlikely related to spectral changes in MSNA.