Showing papers in "American Journal of Physiology-heart and Circulatory Physiology in 2001"
TL;DR: It is concluded that hyperthermia stimulates xanthine oxidase production of reactive oxygen species that activate metals and limit heat tolerance by promoting circulatory and intestinal barrier dysfunction and intact NOS activity is required for normal stress tolerance, whereas overproduction ofNO may contribute to the nonprogrammed splanchnic dilation that precedes vascular collapse with heat stroke.
Abstract: This work tested the hypotheses that splanchnic oxidant generation is important in determining heat tolerance and that inappropriate.NO production may be involved in circulatory dysfunction with heat stroke. We monitored colonic temperature (T(c)), heart rate, mean arterial pressure, and splanchnic blood flow (SBF) in anesthetized rats exposed to 40 degrees C ambient temperature. Heating rate, heating time, and thermal load determined heat tolerance. Portal blood was regularly collected for determination of radical and endotoxin content. Elevating T(c) from 37 to 41.5 degrees C reduced SBF by 40% and stimulated production of the radicals ceruloplasmin, semiquinone, and penta-coordinate iron(II) nitrosyl-heme (heme-.NO). Portal endotoxin concentration rose from 28 to 59 pg/ml (P < 0.05). Compared with heat stress alone, heat plus treatment with the nitric oxide synthase (NOS) antagonist N(omega)-nitro-L-arginine methyl ester (L-NAME) dose dependently depressed heme-.NO production and increased ceruloplasmin and semiquinone levels. L-NAME also significantly reduced lowered SBF, increased portal endotoxin concentration, and reduced heat tolerance (P < 0.05). The NOS II and diamine oxidase antagonist aminoguanidine, the superoxide anion scavenger superoxide dismutase, and the xanthine oxidase antagonist allopurinol slowed the rates of heme-.NO production, decreased ceruloplasmin and semiquinone levels, and preserved SBF. However, only aminoguanidine and allopurinol improved heat tolerance, and only allpourinol eliminated the rise in portal endotoxin content. We conclude that hyperthermia stimulates xanthine oxidase production of reactive oxygen species that activate metals and limit heat tolerance by promoting circulatory and intestinal barrier dysfunction. In addition, intact NOS activity is required for normal stress tolerance, whereas overproduction of.NO may contribute to the nonprogrammed splanchnic dilation that precedes vascular collapse with heat stroke.
403 citations
TL;DR: It is demonstrated that overexpression of Bcl-2 renders the heart more resistant to apoptosis and I/R injury, and this protection is accompanied by a threefold decrease in lactate dehydrogenase released from the transgenic hearts.
Abstract: To test whether the antiapoptotic protein Bcl-2 prevents apoptosis and injury of cardiomyocytes after ischemia-reperfusion (I/R), we generated a line of transgenic mice that carried a human Bcl-2 t...
396 citations
TL;DR: The regional contribution of the LV wall to the ejection of blood is thus highly variable and is not fully characterized by wall thickening alone, and differences in regional LV architecture and probably local stress are possible explanations for this marked functional nonuniformity.
Abstract: Regional nonuniformity is a feature of both diseased and normal left ventricles (LV). With the use of magnetic resonance (MR) myocardial tagging, we performed three-dimensional strain analysis on 8...
383 citations
TL;DR: Opening mitochondrial K(ATP) channels has little direct effect on respiration, membrane potential, or Ca(2+) uptake but has important effects on matrix and intermembrane space volumes.
Abstract: There is an emerging consensus that pharmacological opening of the mitochondrial ATP-sensitive K+ (KATP) channel protects the heart against ischemia-reperfusion damage; however, there are widely di...
369 citations
TL;DR: Examination of whether CCE, activity of store-operated Ca(2+) channels, and human TRP1 (hTRP1) expression are essential in human pulmonary arterial smooth muscle cell (PASMC) proliferation suggests that elevated [Ca(2+)](cyt) and intracellularly stored [Ca-2+] play an important role in pulmonary vascular smooth Muscle cell growth.
Abstract: A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) due to Ca2+ release from intracellular Ca2+ stores and Ca2+ influx through plasmalemmal Ca2+ channels plays a critical role in mitogen-mediated ce...
365 citations
TL;DR: It is concluded that the MHC isoform compositions of fetal human atria are the same as those of nonfailing adult atria and that the ventricular M HC isoform composition is different between adult nonf failing and failing hearts.
Abstract: The goal of this study was to test the hypothesis that the relative amounts of the cardiac myosin heavy chain (MHC) isoforms MHC-α and MHC-β change during development and transition to heart failur...
310 citations
TL;DR: The increase in diastolic diameter 1-4 wk after infarction correlated with cardiomyocyte apoptosis in the noninfarcted myocardium, which quantitatively contributed most (>50%) to the apoptotic cell loss by 4 wk.
Abstract: We investigated the role of cardiomyocyte apoptosis in the remodeling of the left ventricle from 24 h to 12 wk after myocardial infarction in the rat. Infarct size planimetry, quantification of cardiomyocyte apoptosis, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) methodology, and echocardiography (left ventricular diastolic diameter and ejection fraction) were performed. Sham-operated animals showed low rates of cardiomyocyte apoptosis (0.03%) and no change in diastolic diameter or ejection fraction during the study. Twenty-four hours after infarction, TUNEL positivity was high in the infarct areas (1.4%) and border zones (4.9%). It declined to 0.34% (P 50%) to the apoptotic cell loss by 4 wk.
305 citations
TL;DR: A valid and reproducible protocol for measuring maximal oxygen uptake (VO(2 max)), which was reached at a 25 degrees inclination with a respiratory exchange ratio > 1.05, is developed and could be used in future studies on cellular, molecular, and integrative mechanisms of improved cardiovascular function.
Abstract: Physiological studies of long-term cardiovascular adaptation to exercise require training regimens that give robust conditioning effects and adequate testing procedures to quantify the outcome. We ...
282 citations
TL;DR: The OxyLite consistently recorded large PO2 increases with hyperoxia, whereas the microelectrode response was variable, and demonstrates the importance of considering the features of the measurement device when studying tissues with heterogeneous PO2 distributions.
Abstract: In this study we compare oxygen tension (Po 2) histograms measured with O2 microelectrodes and a new optical Po 2 measurement device, the OxyLite, in normal tissues (mouse spleen and thymus) and in...
280 citations
TL;DR: The structural and electrophysiological properties of the engineered cardiac muscle, such as cellularity, conduction velocity, maximum signal amplitude, capture rate, and excitation threshold, were significantly improved compared with the authors' previous studies.
Abstract: The primary aim of this study was to relate molecular and structural properties of in vitro reconstructed cardiac muscle with its electrophysiological function using an in vitro model system based on neonatal rat cardiac myocytes, three-dimensional polymeric scaffolds, and bioreactors. After 1 wk of cultivation, we found that engineered cardiac muscle contained a 120- to 160-μm-thick peripheral region with cardiac myocytes that were electrically connected through gap junctions and sustained macroscopically continuous impulse propagation over a distance of 5 mm. Molecular, structural, and electrophysiological properties were found to be interrelated and depended on specific model system parameters such as the tissue culture substrate, bioreactor, and culture medium. Native tissue and the best experimental group (engineered cardiac muscle cultivated using laminin-coated scaffolds, rotating bioreactors, and low-serum medium) were comparable with respect to the conduction velocity of propagated electrical impulses and spatial distribution of connexin43. Furthermore, the structural and electrophysiological properties of the engineered cardiac muscle, such as cellularity, conduction velocity, maximum signal amplitude, capture rate, and excitation threshold, were significantly improved compared with our previous studies.
278 citations
TL;DR: It is suggested that VEGF increases BMEC monolayer permeability by reducing occludin expression and disrupting ZO-1 and occlUDin organization, which leads to tight junction disassembly.
Abstract: Tight junctions between brain microvessel endothelial cells (BMECs) maintain the blood-brain barrier. Barrier breakdown is associated with brain tumors and central nervous system diseases. Tumor ce...
TL;DR: The potential role of tetrahydrobiopterin in the pathogenesis of vascular endothelial dysfunction and mechanisms underlying beneficial vascular effects of tetRahydroBIopterin will be discussed.
Abstract: Tetrahydrobiopterin is one of the most potent naturally occurring reducing agents and an essential cofactor required for enzymatic activity of nitric oxide synthase (NOS). The exact role of tetrahy...
TL;DR: It is demonstrated that neutrophils are a major source of oxidants in hearts reperfused in vivo after prolonged ischemia and that antineutrophil interventions can effectively prevent the increase in oxygen radical concentration during reperfusion.
Abstract: Although many studies document oxygen radical formation during ischemia-reperfusion, few address the sources of radicals in vivo or examine radical generation in the context of prolonged ischemia. In particular, the contribution of activated neutrophils remains unclear. To investigate this issue, we developed a methodology to detect radicals without interfering with blood-borne mechanisms of radical generation. Dogs underwent aorta and coronary sinus catheterization. No chemicals were infused; instead, blood was drawn into syringes prefilled with a spin trap and analyzed by electron paramagnetic resonance spectroscopy. After 90 min of coronary artery occlusion, transcardiac concentration of oxygen radicals rose severalfold 10 min after reflow and remained significantly elevated for at least 1 h. Radicals were mostly derived from neutrophils, as shown by marked reduction after the administration of 1) neutrophil NADPH oxidase inhibitors and 2) a monoclonal antibody (R15.7) against neutrophil CD18 adhesion molecule. Reduction of radical generation by R15.7 was also associated with a significantly smaller infarct size and no-reflow areas. Thus our data demonstrate that neutrophils are a major source of oxidants in hearts reperfused in vivo after prolonged ischemia and that antineutrophil interventions can effectively prevent the increase in oxygen radical concentration during reperfusion.
TL;DR: It is concluded that a larger late sodium conductance in midmyocardial cells will favor longer action potentials in these cells, and drugs that slow inactivation of sodium channels will produce a nonuniform response across the ventricular wall that is proarrhythmic.
Abstract: Action potentials and whole cell sodium current were recorded in canine epicardial, midmyocardial, and endocardial myocytes in normal sodium at 37°C. Tetrodotoxin (TTX) reduced the action potential...
TL;DR: It is shown that inflammatory-mediated pain alters both the functional and molecular properties of the BBB and may significantly alter delivery of therapeutic agents to the brain, thus affecting dosing regimens during chronic pain.
Abstract: Effects of inflammatory pain states on functional and molecular properties of the rat blood-brain barrier (BBB) were investigated. Inflammation was produced by subcutaneous injection of formalin, λ-carrageenan, or complete Freund's adjuvant (CFA) into the right hind paw. In situ perfusion and Western blot analyses were performed to assess BBB integrity after inflammatory insult. In situ brain perfusion determined that peripheral inflammation significantly increased the uptake of sucrose into the cerebral hemispheres. Capillary depletion and cerebral blood flow analyses indicated the perturbations were due to increased paracellular permeability rather than vascular volume changes. Western blot analyses showed altered tight junctional protein expression during peripheral inflammation. Occludin significantly decreased in the λ-carrageenan- and CFA-treated groups. Zonula occluden-1 expression was significantly increased in all pain models. Claudin-1 protein expression was present at the BBB and remained uncha...
TL;DR: The signaling pathways of ANG II receptor activation are a focus of intense investigative effort, and critically appraise the literature on the signaling mechanisms whereby AT(1) and AT(2) receptors elicit their respective actions.
Abstract: Angiotensin II (ANG II) is a pleiotropic vasoactive peptide that binds to two distinct receptors: the ANG II type 1 (AT1) and type 2 (AT2) receptors. Activation of the renin-angiotensin system (RAS...
TL;DR: The rate of recoil of torsion, determined wholly noninvasively, provides an isovolumic phase, preload-independent assessment of LV relaxation, and should allow the detailed study of diastolic function in states known to affect filling rates, such as aging, hypertension, and congestive heart failure.
Abstract: Most noninvasive measures of diastolic function are made during left ventricular (LV) filling and are therefore subject to “pseudonormalization,” because variation in left atrial (LA) pressure may ...
TL;DR: Data point to gender-specific autonomic responses to cardiovascular stress in women through differences in sympathetic reflex responses to head-up tilt between genders.
Abstract: We tested the hypothesis that differences in sympathetic reflex responses to head-up tilt (HUT) between males (n = 9) and females (n = 8) were associated with decrements in postural vasomotor responses in women. Muscle sympathetic nerve activity (MSNA; microneurography), heart rate, stroke volume (SV; Doppler), and blood pressure (Finapres) were measured during a progressive HUT protocol (5 min at each of supine, 20 degrees, 40 degrees, and 60 degrees ). MSNA and hemodynamic responses were also measured during the cold pressor test (CPT) to examine nonbaroreflex neurovascular control. SV was normalized to body surface area (SV(i)) to calculate the index of cardiac output (Q(i)), and total peripheral resistance (TPR). During HUT, heart rate increased more in females versus males (P < 0.001) and SV(i) and Q(i) decreased similarly in both groups. Mean arterial pressure (MAP) increased to a lesser extent in females versus males in the HUT (P < 0.01) but increases in TPR during HUT were similar. MSNA burst frequency was lower in females versus males in supine (P < 0.03) but increased similarly during HUT. Average amplitude/burst increased in 60 degrees HUT for males but not females. Both males and females demonstrated an increase in MAP as well as MSNA burst frequency, mean burst amplitude, and total MSNA during the CPT. However, compared with females, males demonstrated a greater neural response (DeltaTotal MSNA) due to a larger increase in mean burst amplitude (P < 0.05). Therefore, these data point to gender-specific autonomic responses to cardiovascular stress. The different MSNA response to postural stress between genders may contribute importantly to decrements in blood pressure control during HUT in females.
TL;DR: Results indicate a possible mechanism for increased venous resistance at reduced flows by testing the hypothesis that red blood cell aggregation alters flow patterns in vivo and leads to bluntedred blood cell velocity profiles at reduced shear rates.
Abstract: A recent whole organ study in cat skeletal muscle showed that the increase in venous resistance seen at reduced arterial pressures is nearly abolished when the muscle is perfused with a nonaggregat...
TL;DR: In this paper, the authors examined modulation of respiratory sinus arrhythmia by sympathetic outflow and fitted changes of respiratory frequency R-R interval spectral power with a damped oscillator model: frequency-dependent oscillations with a resonant frequency, generated by driving forces and modified by damping influences.
Abstract: Clinicians and experimentalists routinely estimate vagal-cardiac nerve traffic from respiratory sinus arrhythmia. However, evidence suggests that sympathetic mechanisms may also modulate respiratory sinus arrhythmia. Our study examined modulation of respiratory sinus arrhythmia by sympathetic outflow. We measured R-R interval spectral power in 10 volunteers that breathed sequentially at 13 frequencies, from 15 to 3 breaths/min, before and after beta-adrenergic blockade. We fitted changes of respiratory frequency R-R interval spectral power with a damped oscillator model: frequency-dependent oscillations with a resonant frequency, generated by driving forces and modified by damping influences. beta-Adrenergic blockade enhanced respiratory sinus arrhythmia at all frequencies (at some, fourfold). The damped oscillator model fit experimental data well (39 of 40 ramps; r = 0.86 +/- 0.02). beta-Adrenergic blockade increased respiratory sinus arrhythmia by amplifying respiration-related driving forces (P < 0.05), without altering resonant frequency or damping influences. Both spectral power data and the damped oscillator model indicate that cardiac sympathetic outflow markedly reduces heart period oscillations at all frequencies. This challenges the notion that respiratory sinus arrhythmia is mediated simply by vagal-cardiac nerve activity. These results have important implications for clinical and experimental estimation of human vagal cardiac tone.
TL;DR: The results demonstrate that shear level influences the rate of luminal expansion, specific remodeling events within each wall layer, and the degree of endothelial gene expression.
Abstract: The magnitude of shear stimulus has been shown to determine the level of growth factor expression in cell culture. However, little is known regarding what effect shear level has on specific arteria...
TL;DR: A new model is developed that accurately represents the cardiopulmonary system and can explain how the heart, lung, and autonomic tone interact during the Valsalva maneuver and is likely that with further refinement it could describe various physiological states and help investigators to better understand the biophysics of cardiopULmonary disease.
Abstract: Previous models combining the human cardiovascular and pulmonary systems have not addressed their strong dynamic interaction. They are primarily cardiovascular or pulmonary in their orientation and do not permit a full exploration of how the combined cardiopulmonary system responds to large amplitude forcing (e.g., by the Valsalva maneuver). To address this issue, we developed a new model that represents the important components of the cardiopulmonary system and their coupled interaction. Included in the model are descriptions of atrial and ventricular mechanics, hemodynamics of the systemic and pulmonic circulations, baroreflex control of arterial pressure, airway and lung mechanics, and gas transport at the alveolar-capillary membrane. Parameters of this combined model were adjusted to fit nominal data, yielding accurate and realistic pressure, volume, and flow waveforms. With the same set of parameters, the nominal model predicted the hemodynamic responses to the markedly increased intrathoracic (pleural) pressures during the Valsalva maneuver. In summary, this model accurately represents the cardiopulmonary system and can explain how the heart, lung, and autonomic tone interact during the Valsalva maneuver. It is likely that with further refinement it could describe various physiological states and help investigators to better understand the biophysics of cardiopulmonary disease.
TL;DR: Reduced carotid artery compliance may play an important mechanistic role in age-associated decrease in cardiovagal BRS in healthy sedentary humans.
Abstract: Cardiovagal baroreflex sensitivity (BRS) declines with advancing age in humans, but the underlying mechanism has not been established. Using two different approaches, we determined the relation bet...
TL;DR: A computational model of the Norwood circulation was constructed on the basis of compartmental analysis and showed that a pulmonary-to-systemic blood flow ratio of 1 resulted in optimal O2 delivery in all physiological states and shunt sizes.
Abstract: Hypoplastic left heart syndrome is the most common lethal cardiac malformation of the newborn. Its treatment, apart from heart transplantation, is the Norwood operation. The initial procedure for t...
TL;DR: Results support the hypothesis that the release of ATP from RBC is linked to ATP production through the oxygenation state of the hemoglobin molecule and CO and O2 bind competitively to heme.
Abstract: The release of ATP from red blood cells (RBC) in response to low O2 levels is linked to ATP production and the oxygenation state of hemoglobin. Because O2 is unloaded from the RBC, the concentratio...
TL;DR: Results indicate that testosterone relaxes porcine coronary arteries predominantly by opening BK(Ca) channels in coronary myocytes, and this response may be associated with accumulation of cGMP, and may provide a better understanding of testosterone-induced vasorelaxation reported in recent experimental and early clinical studies.
Abstract: Cardiovascular diseases are often considered to be a predominantly male health problem, and it has been suggested that testosterone exerts deleterious effects on cardiovascular function; however, f...
TL;DR: It is demonstrated that MnSOD may play an important role in the induction of the mitochondrial pathway of apoptosis in the heart, and this appears to occur primarily through the permeability transition.
Abstract: Heart mitochondria from heterozygous (Sod2 −/+) knockout mice have a 50% reduction in manganese superoxide dismutase (MnSOD) activity. The decrease in MnSOD activity was associated with increased m...
TL;DR: Cyclic stretch of cardiac myocytes and CMEC appears to be an important primary stimulus for coronary angiogenesis through both paracrine and autocrine VEGF pathways.
Abstract: To test the hypotheses that cyclic stretch of1) cardiac myocytes produces factors that trigger angiogenic events in coronary microvascular endothelial cells (CMEC) and2) CMEC enhances the expressio...
TL;DR: Exercise and passive tilt result in an increase of short-term fractal correlation properties of HR dynamics, which is related to changes in the balance between the low- and high-frequency oscillations in controlled situations.
Abstract: tk;1Passive head-up tilt and exercise result in specific changes in the spectral characteristics of heart rate (HR) variability as a result of reduced vagal and enhanced sympathetic outflow. Recent...
TL;DR: Evidence that integrin-linked signaling pathways, such as those involving protein tyrosine phosphorylation cascades and mitogen-activated protein kinases, are required for myogenic tone is analyzed.
Abstract: This review summarizes what is currently known about the role of integrins in the vascular myogenic response. The myogenic response is the rapid and maintained constriction of a blood vessel in response to pressure elevation. A role for integrins in this process has been suggested because these molecules form an important mechanical link between the extracellular matrix and the vascular smooth muscle cytoskeleton. We briefly summarize evidence for a general role of integrins in mechanotransduction. We then describe the integrin subunit combinations known to exist in smooth muscle and the vascular wall matrix proteins that may interact with these integrins. We then discuss the effects of integrin-specific peptides and antibodies on vascular tone and on calcium entry mechanisms in vascular smooth muscle. Because integrin function is linked to the cytoskeleton, we discuss evidence for the role of the cytoskeleton in determining myogenic responsiveness. Finally, we analyze evidence that integrin-linked signaling pathways, such as those involving protein tyrosine phosphorylation cascades and mitogen-activated protein kinases, are required for myogenic tone.