bluuebunny/crossref_metadata_2025 huggingface dataset:
Transient outward current carried by inwardly rectifying K+ channels in guinea pig ventricular myocytes dialyzed with low-K+ solution
Authors: Zhabyeyev Pavel , Asai Tatsuya , Missan Sergey , McDonald Terence F.
Published: October 2004

There have been periodic reports of nonclassic (4-aminopyridine insensitive) transient outward K+ current in guinea pig ventricular myocytes, with the most recent one describing a novel voltage-gated inwardly rectifying type. In the present study, we have investigated a transient outward current that overlaps inward Ca2+ current ( ICa,L) in myocytes dialyzed with 10 mM K+ solution and superfused with Tyrode’s solution. Although depolarizations from holding potential ( Vhp) −40 to 0 mV elicited relatively small inward ICa,L in these myocytes, removal of external K+ or addition of 0.2 mM Ba2+ more than doubled the amplitude of the current. The basis of the enhancement of ICa,L was the suppression of a large transient outward K+ current. Similar enhancement was observed when Vhp was moved to −80 mV and test depolarizations were preceded by short prepulses to −40 mV. Investigation of the time and voltage properties of the outward K+ transient indicated that it was inwardly rectifying and unlikely to be carried by voltage-gated channels. The outward transient was attenuated in myocytes dialyzed with high-Mg2+ solution, accelerated in myocytes dialyzed with 100 μM spermine solution, and abolished with time in myocytes dialyzed with ATP-free solution. These and other findings suggest that the outward transient is a component of classic “time-independent” inwardly rectifying K+ current.
Neural regulation of glucagon-like peptide-1 secretion in pigs
Authors: Hansen Lene , Lampert Sarah , Mineo Hitoshi , Holst Jens J.
Published: October 2004

Glucagon-like peptide (GLP)-1 is secreted rapidly from the intestine postprandially. We therefore investigated its possible neural regulation. With the use of isolated perfused porcine ileum, GLP-1 secretion was measured in response to electrical stimulation of the mixed, perivascular nerve supply and infusions of neuroactive agents alone and in combination with different blocking agents. Electrical nerve stimulation inhibited GLP-1 secretion, an effect abolished by phentolamine. Norepinephrine inhibited secretion, and phentolamine abolished this effect. GLP-1 secretion was stimulated by isoproterenol (abolished by propranolol). Acetylcholine stimulated GLP-1 secretion, and atropine blocked this effect. Dimethylphenylpiperazine stimulated GLP-1 secretion. In chloralose-anesthetized pigs, however, electrical stimulation of the vagal trunks at the level of the diaphragm had no effect on GLP-1 or GLP-2 and weak effects on glucose-dependent insulinotropic peptide and somatostatin secretion, although this elicited a marked atropine-resistant release of the neuropeptide vasoactive intestinal polypeptide to the portal circulation. Thus GLP-1 secretion is inhibited by the sympathetic nerves to the gut and may be stimulated by intrinsic cholinergic nerves, whereas the extrinsic vagal supply has no effect.
GATA-4, GATA-5, and GATA-6 activate the rat liver fatty acid binding protein gene in concert with HNF-1α
Authors: Divine Joyce K. , Staloch Lora J. , Haveri Hanna , Jacobsen Christina M. , Wilson David B. , Heikinheimo Markku , Simon Theodore C.
Published: October 2004

Transcriptional regulation by GATA-4, GATA-5, and GATA-6 in intestine and liver was explored using a transgene constructed from the proximal promoter of the rat liver fatty acid binding protein gene ( Fabpl). An immunohistochemical survey detected GATA-4 and GATA-6 in enterocytes, GATA-6 in hepatocytes, and GATA-5 in neither cell type in adult animals. In cell transfection assays, GATA-4 or GATA-5 but not GATA-6 activated the Fabpl transgene solely through the most proximal of three GATA binding sites in the Fabpl promoter. However, all three factors activated transgenes constructed from each Fabpl site upstream of a minimal viral promoter. GATA factors interact with hepatic nuclear factor (HNF)-1α, and the proximal Fabpl GATA site adjoins an HNF-1 site. GATA-4, GATA-5, or GATA-6 bounded to HNF-1α in solution, and all cooperated with HNF-1α to activate the Fabpl transgene. Mutagenizing all Fabpl GATA sites abrogated transgene activation by GATA factors, but GATA-4 activated the mutagenized transgene in the presence of HNF-1α. These in vitro results suggested GATA/HNF-1α interactions function in Fabpl regulation, and in vivo relevance was determined with subsequent experiments. In mice, the Fabpl transgene was active in enterocytes and hepatocytes, a transgene with mutagenized HNF-1 site was silent, and a transgene with mutagenized GATA sites had identical expression as the native transgene. Mice mosaic for biallelic Gata4 inactivation lost intestinal but not hepatic Fabpl expression in Gata4-deficient cells but not wild-type cells. These results demonstrate GATA-4 is critical for intestinal gene expression in vivo and suggest a specific GATA-4/HNF-1α physical and functional interaction in Fabpl activation.
Modulation of control of muscle sympathetic nerve activity during orthostatic stress in humans
Authors: Ichinose Masashi , Saito Mitsuru , Ogawa Takeshi , Hayashi Keiji , Kondo Narihiko , Nishiyasu Takeshi
Published: October 2004

We tested the hypothesis that orthostatic stress would modulate the arterial baroreflex (ABR)-mediated beat-by-beat control of muscle sympathetic nerve activity (MSNA) in humans. In 12 healthy subjects, ABR control of MSNA (burst incidence, burst strength, and total activity) was evaluated by analysis of the relation between beat-by-beat spontaneous variations in diastolic blood pressure (DAP) and MSNA during supine rest (CON) and at two levels of lower body negative pressure (LBNP: −15 and −35 mmHg). At −15 mmHg LBNP, the relation between burst incidence (bursts per 100 heartbeats) and DAP showed an upward shift from that observed during CON, but the further shift seen at −35 mmHg LBNP was only marginal. The relation between burst strength and DAP was shifted upward at −15 mmHg LBNP (vs. CON) and further shifted upward at −35 mmHg LBNP. At −15 mmHg LBNP, the relation between total activity and DAP was shifted upward from that obtained during CON and further shifted upward at −35 mmHg LBNP. These results suggest that ABR control of MSNA is modulated during orthostatic stress and that the modulation is different between a mild (nonhypotensive) and a moderate (hypotensive) level of orthostatic stress.
Cyclooxygenase products sensitize muscle mechanoreceptors in healthy humans
Authors: Middlekauff Holly R. , Chiu Josephine
Published: October 2004

Evidence in healthy animals and humans is accumulating that the muscle mechanoreceptors play an important role in mediating sympathetic activation during exercise, especially rhythmic exercise. Furthermore, muscle mechanoreceptors appear to be sensitized acutely during exercise by metabolic by-products, although the identity of these by-products remains unknown. The purpose of this study was to determine whether the metabolic by-products 1) prostaglandins and/or 2) adenosine sensitize muscle mechanoreceptor control of muscle sympathetic nerve activity (MSNA) in normal humans during rhythmic exercise. MSNA was recorded using microneurography. Muscle mechanoreceptors were activated by low-level rhythmic forearm exercise for 3 min. In 16 healthy humans, intra-arterial indomethacin was infused into the exercising arm to inhibit synthesis of cyclooxygenase products. In 18 healthy humans, intra-arterial aminophylline was infused into the exercising arm to block adenosine receptors. During saline control, MSNA increased significantly during exercise. Inhibition of cycloxygenase during exercise dramatically and virtually completely eliminated the reflex sympathetic activation. Inhibition of adenosine receptors with aminophylline had no effect on the sympathetic activation during muscle mechanoreceptor stimulation. In conclusion, muscle mechanoreceptors are sensitized by cyclooxygenase products, but not by adenosine, during 3 min of low-level rhythmic handgrip exercise in healthy humans. Further studies of other metabolic by-products and of patients with enhanced muscle mechanoreceptor sensitivity, such as patients with heart failure, are warranted.
Loss of bone minerals and strength in rats with aldosteronism
Authors: Chhokar Vikram S. , Sun Yao , Bhattacharya Syamal K. , Ahokas Robert A. , Myers Linda K. , Xing Zhiqing , Smith Richard A. , Gerling Ivan C. , Weber Karl T.
Published: October 2004

Congestive heart failure (CHF) is a clinical syndrome with origins rooted in a salt-avid state largely mediated by effector hormones of the circulating renin-angiotensin-aldosterone system. Other participating neurohormones include catecholamines, endothelin-1, and arginine vasopressin. CHF is accompanied by a systemic illness of uncertain causality. Features include the appearance of oxidative/nitrosative stress and a wasting of tissues including bone. Herein we hypothesized that inappropriate (relative to dietary Na+) elevations in plasma aldosterone (Aldo) contribute to an altered redox state, augmented excretion of divalent cations, and in turn, a loss of bone minerals and strength. In uninephrectomized rats that received chronic Aldo and 1% NaCl treatment for 4–6 wk, we monitored plasma α1-antiproteinase activity, which is an inverse correlate of oxidative/nitrosative stress; plasma concentrations of ionized Mg2+ and Ca2+; urinary Mg2+ and Ca2+ excretion; and bone mineral composition and strength to flexure stress. Compared with controls, we found reductions in plasma α1-antiproteinase activity and ionized Mg2+ and Ca2+ together with persistently elevated urinary Mg2+ and Ca2+ excretion, a progressive loss of bone mineral density and content with reduced Mg2+ and Ca2+ concentrations, and a reduction in cortical bone strength. Thus the hypermagnesuria and hypercalciuria that accompany chronic Aldo-1% NaCl treatment contribute to the systemic appearance of oxidative/nitrosative stress and a wasting of bone minerals and strength.
Collateral damage: cardiovascular consequences of chronic sympathetic activation with human aging
Authors: Seals Douglas R. , Dinenno Frank A.
Published: October 2004

Adult aging in humans is associated with marked and sustained increases in sympathetic nervous system (SNS) activity to several peripheral tissues, including the heart, the gut-liver circulation, and skeletal muscle. This chronic activation of the peripheral SNS likely is, at least in part, a primary response of the central nervous system to stimulate thermogenesis to prevent further fat storage in the face of increasing adiposity with aging. However, as has been proposed in obesity hypertension, this tonic activation of the peripheral SNS has a number of adverse secondary cardiovascular consequences. These include chronic reductions in leg blood flow and vascular conductance, increased tonic support of arterial blood pressure, reduced limb and systemic α-adrenergic vasoconstrictor responsiveness, impaired baroreflex buffering, large conduit artery hypertrophy, and decreased vascular and cardiac responsiveness to β-adrenergic stimulation. These effects of chronic age-associated SNS activation on the structure and function of the cardiovascular system, in turn, may have important implications for the maintenance of physiological function and homeostasis, as well as the risk of developing clinical cardiovascular and metabolic diseases in middle-aged and older adults.
Mechanism of cardiac depression after trauma-hemorrhage: increased cardiomyocyte IL-6 and effect of sex steroids on IL-6 regulation and cardiac function
Authors: Yang Shaolong , Zheng Rui , Hu Shunhua , Ma Yuchen , Choudhry Mashkoor A. , Messina Joseph L. , Rue Loring W. , Bland Kirby I. , Chaudry Irshad H.
Published: October 2004

A prolonged depression of cardiovascular function occurs in males after trauma-hemorrhagic shock (T-H). Although a correlation between increased circulatory IL-6 levels and poor outcome has been reported after T-H, it remains unknown whether T-H increases IL-6 levels locally in cardiomyocytes and whether there is a correlation between altered cardiac function and local IL-6 production after T-H. T-H was induced in normal, castrated (2 wk before T-H), and 17β-estradiol (E2)-treated (0.5 mg sc, 1 wk before T-H) adult male rats. At 2 h after T-H or sham operation, cardiac output, heart rate, mean arterial pressure, positive and negative first derivative of pressure (±dP/d t), stroke volume, and total peripheral resistance were determined. Cardiomyocytes were isolated and divided into two parts: one was used for measurements of intracellular IL-6 levels using fluorescein-activated cell sorting, and the other was used to isolate RNA to determine IL-6 gene expression by quantitative real-time PCR. In addition, cardiac IL-6 protein levels were measured in freshly isolated hearts by Western blotting. Cardiac output, stroke volume, +dP/d t, −dP/d t, and total peripheral resistance were markedly altered after T-H. These parameters, except −dP/d t, improved significantly in the castrated group; however, all these parameters were restored in E2-treated males. Cardiomyocyte IL-6 mRNA expression and intracellular IL-6 production increased after T-H. Cardiac IL-6 protein levels increased after T-H in freshly isolated heart. Castration and E2treatment attenuated cardiomyocyte intracellular IL-6 levels and cardiac IL-6 protein levels after T-H; however, only E2treatment attenuated cardiomyocyte IL-6 gene expression. Thus there is an inverse correlation between cardiomyocyte IL-6 levels and cardiac function after T-H. The salutary effects of E2on cardiac function after T-H may be due in part to decreased IL-6 synthesis in cardiomyocytes.
Functional and morphological studies of protein transcytosis in continuous endothelia
Authors: Predescu Dan , Vogel Stephen M. , Malik Asrar B.
Published: October 2004

Continuous microvascular endothelium constitutively transfers protein from vessel lumen to interstitial space. Compelling recent biochemical, ultrastructural, and physiological evidence reviewed herein demonstrates that protein transport is not the result of barrier “leakiness” but, rather, is an active process occurring primarily in a transendothelial vesicular pathway. Protein accesses the vesicular pathway by means of caveolae open to the vessel lumen. Vascular tracer proteins appear in free cytoplasmic vesicles within minutes; contents of transport vesicles are rapidly deposited into the subendothelial matrix by exocytosis. Caveolin-1 deficiency eliminates caveolae and abolishes vesicular protein transport; interestingly, exchange vessels develop a compensatory transport mode through the opening of a paracellular permeability pathway. The evidence supports the transcytosis hypothesis and the concept that transcytosis is a fundamental component of transendothelial permeability of macromolecules.
Lipopolysaccharide increases alveolar type II cell number in fetal mouse lungs through Toll-like receptor 4 and NF-κB
Authors: Prince Lawrence S. , Okoh Victor O. , Moninger Thomas O. , Matalon Sadis
Published: October 2004

Chorioamnionitis is a major cause of preterm delivery. Infants exposed to inflammation in utero and then born preterm may have improved lung function in the immediate postnatal period. We developed a mouse model of chorioamnionitis to study the inflammatory signaling mechanisms that might influence fetal lung maturation. With this in vivo model, we found that Escherichia coli lipopolysaccharide (LPS) increased the number of alveolar type II cells in the fetal mouse lung. LPS also increased type II cell number in cultured fetal lung explants, suggesting that LPS could directly signal the fetal lung in the absence of maternal influences. Using immunostaining, we localized cells within the fetal mouse lung expressing the LPS receptor molecule Toll-like receptor 4 (TLR4). Similar to the signaling pathways in inflammatory cells, LPS activated NF-κB in fetal lung explants. Activation of the TLR4/NF-κB pathway appeared to be required, as LPS did not increase the number of type II cells in C.C3H- Tlr4Lps-dmice, a congenic strain containing a loss of function mutation in tlr4. In addition, the sesquiterpene lactone parthenolide inhibited NF-κB activation following LPS exposure and blocked the LPS-induced increase in type II cells. On the basis of these data from our mouse model of chorioamnionitis, it appears that LPS specifically activated the TLR4/NF-κB pathway, leading to increased type II cell maturation. These data implicate an important signaling mechanism in chorioamnionitis and suggest the TLR4/NF-κB pathway can influence lung development.
Regulation of polymorphonuclear leukocyte apoptosis: role of lung endothelium-epithelium bilayer transmigration
Authors: Hu Maowen , Lin Xinchun , Du Qiaoting , Miller Edmund J. , Wang Ping , Simms H. Hank
Published: October 2004

Delayed polymorphonuclear leukocyte (PMN) apoptosis exacerbates acute lung injury. To reach the alveolar spaces, PMNs must migrate across both pulmonary endothelial and epithelial cell layers. We hypothesized that transmigration across the endothelium-epithelium bilayer suppresses PMN apoptosis and sought to elucidate the underlying mechanisms. PMNs freshly isolated from normal volunteers were allowed to migrate across polycarbonate membranes alone or membranes coated with a bilayer of human lung endothelial and epithelial cells. After migration toward different chemoattractants (IL-8, formyl-Met-Leu-Phe, or leukotriene B4), PMN apoptosis and caspase activities were assessed by annexin V, histology, and enzymatic assays, respectively. Messenger RNA and specific protein expression in three receptor ligand-mediated, apoptosis-inducing pathways (Fas, TNF-α, and TNF-related apoptosis-inducing ligand) were further examined by gene array, RT-PCR, flow cytometry, and Western blot analyses. The data demonstrated that transbilayer migration suppressed PMN apoptosis, and this effect was not chemoattractant type specific. Kinetic analyses further showed that the delay of apoptosis was sustained to at least 18 h. Transbilayer migration caused significant decreases in caspase (-3, -8, and -9) activities. The changes in apoptosis-related gene expression support the survival role of transbilayer migration. Furthermore, the reduced apoptosis was correlated with downregulation of Fas ligand and TNF receptor 1 expression. Our data reveal that migration across a lung endothelium-epithelium bilayer suppresses PMN apoptosis. The decreased activity and/or expression of proapoptotic proteins may provide possible targets for the regulation of inappropriate delay in PMN apoptosis during lung inflammation and injury.
p38 MAP kinase-dependent regulation of endothelial cell permeability
Authors: Borbiev Talaibek , Birukova Anna , Liu Feng , Nurmukhambetova Saule , Gerthoffer William T. , Garcia Joe G. N. , Verin Alexander D.
Published: October 2004

We have previously shown that thrombin induces endothelial cell barrier dysfunction via cytoskeleton activation and contraction and have determined the important role of endothelial cell myosin light chain kinase (MLCK) in this process. In the present study we explored p38 MAP kinase as a potentially important enzyme in thrombin-mediated endothelial cell contractile response and permeability. Thrombin induces significant p38 MAP kinase activation in a time-dependent manner with maximal effect at 30 min, which correlates with increased phosphorylation of actin- and myosin-binding protein, caldesmon. Both SB-203580 and dominant negative p38 adenoviral vector significantly attenuated thrombin-induced declines in transendothelial electrical resistance. Consistent with these data SB-203580 decreased actin stress fiber formation produced by thrombin in endothelium. In addition, dominant negative p38 had no effect on thrombin-induced myosin light chain diphosphorylation. Thrombin-induced total and site-specific caldesmon phosphorylation (Ser789) as well as dissociation of caldesmon-myosin complex were attenuated by SB-203580 pretreatment. These results suggest the involvement of p38 MAP kinase activities and caldesmon phosphorylation in the MLCK-independent regulation of thrombin-induced endothelial cell permeability.
Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology
Authors: Li Jian-Mei , Shah Ajay M
Published: October 2004

The endothelial generation of reactive oxygen species (ROS) is important both physiologically and in the pathogenesis of many cardiovascular disorders. ROS generated by endothelial cells include superoxide (O2−·), hydrogen peroxide (H2O2), peroxynitrite (ONOO−·), nitric oxide (NO), and hydroxyl (·OH) radicals. The O2−· radical, the focus of the current review, may have several effects either directly or through the generation of other radicals, e.g., H2O2and ONOO−·. These effects include 1) rapid inactivation of the potent signaling molecule and endothelium-derived relaxing factor NO, leading to endothelial dysfunction; 2) the mediation of signal transduction leading to altered gene transcription and protein and enzyme activities (“redox signaling”); and 3) oxidative damage. Multiple enzymes can generate O2−·, notably xanthine oxidase, uncoupled NO synthase, and mitochondria. Recent studies indicate that a major source of endothelial O2−· involved in redox signaling is a multicomponent phagocyte-type NADPH oxidase that is subject to specific regulation by stimuli such as oscillatory shear stress, hypoxia, angiotensin II, growth factors, cytokines, and hyperlipidemia. Depending on the level of oxidants generated and the relative balance between pro- and antioxidant pathways, ROS may be involved in cell growth, hypertrophy, apoptosis, endothelial activation, and adhesivity, for example, in diabetes, hypertension, atherosclerosis, heart failure, and ischemia-reperfusion. This article reviews our current knowledge regarding the sources of endothelial ROS generation, their regulation, their involvement in redox signaling, and the relevance of enhanced ROS generation and redox signaling to the pathophysiology of cardiovascular disorders where endothelial activation and dysfunction are implicated.
Nerve regeneration-induced recovery of quinine avoidance after complete gustatory deafferentation of the tongue
Authors: Geran Laura C. , Garcea Mircea , Spector Alan C.
Published: October 2004

The concentration-dependent decrease in quinine licking by rats is substantially attenuated by combined bilateral transection of the chorda tympani (CT) and glossopharyngeal (GL) nerves, but transection of either nerve alone produces marginal impairments at most. Here we tested whether regeneration of one or both of these nerves after combined transection would result in recovery of taste avoidance. Water-restricted rats were presented with a series of brief-access (5 s) taste trials (water and 0.003–3.0 mM quinine-HCl) in a 5-day test block of 40-min sessions both before nerve transection and starting 75–77 days after transection. Licking avoidance returned to presurgical levels when both nerves were allowed to regenerate. When only the GL was allowed to regenerate, performance did not differ from that of sham-transected animals. This suggests that even after considerable gustatory deafferentation, regeneration has the capacity to restore normal taste-guided behavior. Surprisingly, when only the CT was allowed to regenerate, avoidance behavior was severely impaired and was not different from that of rats in which regeneration of both nerves was prevented. Taking into account prior findings, it appears that the absence of the GL in the presence of an intact CT is fundamentally different from the absence of the GL in the presence of a regenerated CT with respect to some taste functions. This represents the first reported instance to our knowledge in which the capacity of a regenerated nerve to maintain taste-guided behavior was distinctly different from that of an intact nerve in a rodent model.
Obesity-prone rats have preexisting defects in their counterregulatory response to insulin-induced hypoglycemia
Authors: Tkacs Nancy C. , Levin Barry E.
Published: October 2004

Rats that develop diet-induced obesity (DIO) on a 31% fat [high-energy (HE)] diet have defective sensing and responding to altered glucose levels compared with diet-resistant (DR) rats. Thus we postulated that they would also have defective counterregulatory responses (CRR) to insulin-induced hypoglycemia (IIH). Chow-fed selectively bred DIO and DR rats underwent three sequential 60-min bouts of IIH separated by 48 h. Glucose levels fell comparably, but DIO rats had 22–29% lower plasma epinephrine (Epi) levels during the first two bouts than DR rats. By the third trial, despite comparable Epi levels, DIO rats had lower 30-min glucose levels and rebounded less than DR rats 85 min after intravenous glucose. Although DIO rats gained more carcass and fat weight after 4 wk on an HE diet than DR rats, they were unaffected by prior IIH. Compared with controls, DR rats with prior IIH and HE diet had higher arcuate nucleus neuropeptide Y (50%) and proopiomelanocortin (POMC; 37%) mRNA and an inverse correlation ( r = 0.85; P = 0.004) between POMC expression and body weight gain on the HE diet. These data suggest that DIO rats have a preexisting defect in their CRR to IIH but that IIH does not affect the expression of their hypothalamic neuropeptides or weight gain as it does in DR rats.
Adrenal cortex: scalpels, syringes, and separatory funnels
Authors: Akana Susan F.
Published: October 2004

This essay looks at the historical significance of three APS classic papers that are freely available online:

Houssay BA and Lewis JT. The relative importance to life of cortex and medulla of the adrenal glands. Am J Physiol 64: 512—521, 1923 ( http://ajplegacy.physiology.org/cgi/reprint/64/3/512 ).

Marine D and Baumann EJ. Duration of life after suprarenalectomy in cats and attempts to prolong it by injections of solutions containing sodium salts, glucose and glycerol. Am J Physiol 81: 86—100, 1927 ( http://ajplegacy.physiology.org/cgi/reprint/81/1/86 ).

Swingle WW and Pfiffner JJ. Studies on the adrenal cortex. I. The effect of a lipid fraction upon the life-span of adrenalectomized cats. Am J Physiol 96: 153—163, 1931 ( http://ajplegacy.physiology.org/cgi/reprint/96/1/153 ).
Berne's adenosine hypothesis of coronary blood flow control
Authors: Feigl Eric O.
Published: October 2004

This essay looks at the historical significance of an APS classic paper that is freely available online:

Berne RM. Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Physiol 204: 317–322, 1963 ( http://ajplegacy.physiology.org/cgi/reprint/204/2/317 ).
Two classic papers in acid-base physiology: contributions of R. F. Pitts, R. S. Alexander, and W. D. Lotspeich
Authors: Giebisch Gerhard
Published: October 2004

This essay looks at the historical significance of two APS classic papers that are freely available online:

Pitts RF and Alexander RS. The nature of the renal tubular mechanism for acidifying the urine. Am J Physiol 144: 239—254, 1945 ( http://ajplegacy.physiology.org/cgi/reprint/144/2/239 ).

Pitts RF and Lotspeich WD. Bicarbonate and the renal regulation of acid base balance. Am J Physiol 147: 138—154, 1946 ( http://ajplegacy.physiology.org/cgi/reprint/147/1/138 ).
Ca-induced Ca release: lessons regarding cell models
Authors: Harder David R.
Published: October 2004

This essay looks at the historical significance of an APS classic paper that is freely available online:

Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol Cell Physiol 245: C1–C14, 1983 ( http://ajpcell.physiology.org/cgi/reprint/245/1/C1 ).
Nature vs. nurture: can exercise really alter fiber type composition in human skeletal muscle?
Authors: Ingalls Christopher P.
Published: October 2004

This essay looks at the historical significance of two APS classic papers that are freely available online:

Gollnick PD, Armstrong RB, Saubert CW IV, Piehl K, and Saltin B. Enzyme activity and fiber composition in skeletal muscle of untrained and trained men. J Appl Physiol 33: 312—319, 1972 ( http://jap.physiology.org/cgi/reprint/33/3/312 ).

Gollnick PD, Armstrong RB, Saltin B, Saubert CW IV, Sembrowich WL, and Shepherd RE. Effect of training on enzyme activity and fiber composition of human skeletal muscle. J Appl Physiol 34: 107—111, 1973 ( http://jap.physiology.org/cgi/reprint/34/1/107 ).
Hypothalamic control of body temperature: insights from the past
Authors: Mack Gary W.
Published: October 2004

This essay looks at the historical significance of three APS classic papers that are freely available online:

Hammel HT, Hardy JD, and Fusco MM. Thermoregulatory responses to hypothalamic cooling in unanesthetized dogs. Am J Physiol 198: 481—486, 1960 ( http://ajplegacy.physiology.org/cgi/reprint/198/3/481 ).

Hammel HT, Jackson DC, Stolwijk JAJ, Hardy JD, and Strømme SB. Temperature regulation by hypothalamic proportional control with an adjustable set point. J Appl Physiol 18: 1146—1154, 1963 ( http://jap.physiology.org/cgi/reprint/18/6/1146 ).

Hellstrøm B and Hammel HT. Some characteristics of temperature regulation in the unanesthetized dog. Am J Physiol 213: 547—556, 1967 ( http://ajplegacy.physiology.org/cgi/reprint/213/2/547 ).
Eugene M. Landis and the physiology of the microcirculation
Authors: Renkin E. M.
Published: October 2004

This essay looks at the historical significance of two APS classic papers that are freely available online:

Landis EM. The capillary pressure in frog mesentery as determined by micro-injection methods. Am J Physiol 75: 548–570, 1926 ( http://ajplegacy.physiology.org/cgi/reprint/75/3/548 ).

Landis EM. Micro-injection studies of capillary permeability. II. The relation between capillary pressure and the rate at which fluid passes through the walls of single capillaries. Am J Physiol 82: 217–238, 1927 ( http://ajplegacy.physiology.org/cgi/reprint/82/2/217 ).
Experimental validation of the countercurrent model of urinary concentration
Authors: Schafer James A.
Published: October 2004

This essay looks at the historical significance of four APS classic papers that are freely available online:

Jolliffe N, Shannon JA, and Smith HW. The excretion of urine in the dog. III. The use of non-metabolized sugars in the measurement of the glomerular filtrate. Am J Physiol 100: 301—312, 1932 ( http://ajplegacy.physiology.org/cgi/reprint/100/2/301 ).

Shannon JA. The excretion of inulin by the dog. Am J Physiol 112: 405—413, 1935 ( http://ajplegacy.physiology.org/cgi/reprint/112/3/405 ).

Shannon JA and Fisher S. The renal tubular reabsorption of glucose in the normal dog. Am J Physiol 122: 765—774, 1938 ( http://ajplegacy.physiology.org/cgi/reprint/122/3/765 ).

Shannon JA, Farber S, and Troast L. The measurement of glucose Tm in the normal dog. Am J Physiol 133: 752—761, 1941 ( http://ajplegacy.physiology.org/cgi/reprint/133/3/752 ).
Physical exercise decreases neuronal activity in the posterior hypothalamic area of spontaneously hypertensive rats
Authors: Beatty Joseph A. , Kramer Jeffery M. , Plowey Edward D. , Waldrop Tony G.
Published: October 2004

Recently, physical exercise has been shown to significantly alter neurochemistry and neuronal function and to increase neurogenesis in discrete brain regions. Although we have documented that physical exercise leads to molecular changes in the posterior hypothalamic area (PHA), the impact on neuronal activity is unknown. The purpose of the present study was to determine whether neuronal activity in the PHA is altered by physical exercise. Spontaneously hypertensive rats (SHR) were allowed free access to running wheels for a period of 10 wk (exercised group) or no wheel access at all (nonexercised group). Single-unit extracellular recordings were made in anesthetized in vivo whole animal preparations or in vitro brain slice preparations. The spontaneous firing rates of PHA neurons in exercised SHR in vivo were significantly lower (8.5 ± 1.6 Hz, n = 31 neurons) compared with that of nonexercised SHR in vivo (13.7 ± 1.8 Hz, n = 38 neurons; P < 0.05). In addition, PHA neurons that possessed a cardiac-related rhythm in exercised SHR fired significantly lower (6.0 ± 1.8 Hz, n = 11 neurons) compared with nonexercised SHR (12.1 ± 2.4 Hz, n = 18 neurons; P < 0.05). Similarly, the spontaneous in vitro firing rates of PHA neurons from exercised SHR were significantly lower (3.5 ± 0.3 Hz, n = 67 neurons) compared with those of nonexercised SHR (5.6 ± 0.5 Hz, n = 58 neurons; P < 0.001). Both the in vivo and in vitro findings support the hypothesis that physical exercise can lower spontaneous activity of neurons in a cardiovascular regulatory region of the brain. Thus physical exercise may alter central neural control of cardiovascular function by inducing lasting changes in neuronal activity.
Vascular endothelial growth factor and related molecules in acute lung injury
Authors: Mura Marco , dos Santos Claudia C. , Stewart Duncan , Liu Mingyao
Published: October 2004

VEGFs and their receptors have been implicated in the regulation of vascular permeability in many organ systems, including the lung. Increased permeability and interstitial and pulmonary edema are prominent features of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Extrapolating data from other organ systems and animal experiments have suggested that overexpression of VEGF functions primarily as proinjurious molecules in the lung. Recent data, from animal models as well as from patients with ARDS, have shown decreased levels of VEGF in the lung. The role of VEGF and related molecules in ALI/ARDS is, therefore, controversial: what has become clear is that there are many unique features in the regulation of pulmonary vascular permeability and in VEGF expression in the lung. In this review, we explore a growing body of literature looking at the expression and function of VEGF and related molecules in different models of ALI and in patients with ALI/ARDS. Novel evidence points to a potential role of VEGF in promoting repair of the alveolar-capillary membrane during recovery from ALI/ARDS. Understanding the role of VEGF in this disease process is crucial for developing new therapeutic strategies for ALI/ARDS.
Inflammatory, hemostatic, and clinical changes in a baboon experimental model for heatstroke
Authors: Bouchama A. , Roberts G. , Al Mohanna F. , El-Sayed R. , Lach B. , Chollet-Martin S. , Ollivier V. , Al Baradei R. , Loualich A. , Nakeeb S. , Eldali A. , de Prost D.
Published: October 2004

The mortality and neurological morbidity in heatstroke have been attributed to the host's inflammatory and hemostatic responses to heat stress, suggesting that immunomodulation may improve outcome. We postulated that an experimental baboon model of heatstroke will reproduce human responses and clinical outcome to allow testing of new therapeutic strategies. Eight anesthetized juvenile baboons ( Papio hamadryas) were subjected to heat stress in an incubator maintained at 44–47°C until rectal temperature attained 42.5°C (moderate heatstroke; n = 4) or systolic arterial pressure fell to <90 mmHg (severe heatstroke; n = 4) and were allowed to recover at room temperature. Four sham-heated animals served as a control group. Rectal temperature at the end of heat stress was 42.5 ± 0.0 and 43.3 ± 0.1°C, respectively. All heat-stressed animals had systemic inflammation and activated coagulation, indicated by increased plasma IL-6, prothrombin time, activated partial thromboplastin time, and D-dimer levels, and decreased platelet count. Biochemical markers and/or histology evidenced cellular injury/dysfunction: plasma levels of thrombomodulin, creatinine, creatine kinase, lactic dehydrogenase, and alanine aminotransferase were increased, and varying degrees of tissue damage were present in liver, brain, and gut. No baboon with severe heatstroke survived. Neurological morbidity but no mortality was observed in baboons with moderate heatstroke. Nonsurvivors displayed significantly greater coagulopathy, inflammatory activity, and tissue injury than survivors. Sham-heated animals had an uneventful course. Heat stress elicited distinct patterns of inflammatory and hemostatic responses associated with outcome. The baboon model of heatstroke appears suitable for testing whether immunomodulation of the host's responses can improve outcome.
Vascular remodeling in the circulations of the lung
Authors: Mitzner Wayne , Wagner Elizabeth M.
Published: October 2004

The lung is unique in its double sources of perfusion from the pulmonary and systemic circulations. One striking difference between the two circulations is the capacity for angiogenesis. The bronchial circulation has a capacity that seems quite similar to all systemic arteries, whereas the pulmonary circulation seems relatively inert in this regard. Extra-alveolar pulmonary arteries can grow somewhat in length, and septal capillaries seem to have the capability of reforming, but these processes do not seem to occur with nearly the same intensity associated with the bronchial arteries. In this review, we emphasize these differences between the two circulations of the lung, anticipating that future research will allow more focused probing into the molecular signaling that regulates the novel mechanistic and pathological pathways of each.
Signals and mechanisms of compensatory lung growth
Authors: Hsia Connie C. W.
Published: October 2004

Growth of the lung involves unique structure-function interactions not seen in solid organs. Mechanical feedback between the lung and thorax constitutes a major signal that sustains developmental as well as compensatory lung growth. After the loss of lung units as by pneumonectomy (PNX), increased mechanical stress and strain on the remaining units induce adaptive responses to augment oxygen transport, including 1) recruitment of alveolar-capillary reserves, 2) remodeling of existing tissue, and 3) regenerative growth of acinar tissue when strain exceeds a critical threshold. Alveolar hypoxia, hormones, and growth factors may feed into the mechanical feedback system to modify an existing growth response but are unlikely to initiate compensatory growth in the absence of sufficient mechanical signals. Whereas endogenous post-PNX alveolar growth preserves normal structure-function relationships, experimental manipulation of selected metabolic pathways can distort these relationships. Finally, PNX widens the disparity between the rapidly adapting acini and slowly adapting conducting airways and blood vessels, leading to disproportionate airflow and hemodynamic dysfunction and secondary hypertrophy of the right ventricle and respiratory muscles that limits overall organ function despite regeneration of gas exchange tissue. These are key concepts to consider when formulating approaches to stimulate or augment compensatory growth in chronic lung disease.
Hemodynamic effects of leg crossing and skeletal muscle tensing during free standing in patients with vasovagal syncope
Authors: van Dijk Nynke , de Bruin Ivar G. J. M. , Gisolf Janneke , de Bruin-Bon H. A. C. M. Rianne , Linzer Mark , van Lieshout Johannes J. , Wieling Wouter
Published: October 2004

Physical maneuvers can be applied to abort or delay an impending vasovagal faint. These countermaneuvers would be more beneficial if applied as a preventive measure. We hypothesized that, in patients with recurrent vasovagal syncope, leg crossing produces a rise in cardiac output (CO) and thereby in blood pressure (BP) with an additional rise in BP by muscle tensing. We analyzed the age and gender effect on the BP response. To confirm that, during the maneuvers, Modelflow CO changes in proportion to actual CO, 10 healthy subjects performed the study protocol with CO evaluated simultaneously by Modelflow and by inert gas rebreathing. Changes in Modelflow CO were similar in direction and magnitude to inert gas rebreathing-determined CO changes. Eighty-eight patients diagnosed with vasovagal syncope applied leg crossing after a 5-min free-standing period. Fifty-four of these patients also applied tensing of leg and abdominal muscles. Leg crossing produced a significant rise in CO (+9.5%; P < 0.01) and thereby in mean arterial pressure (+3.3%; P < 0.01). Muscle tensing produced an additional increase in CO (+8.3%; P < 0.01) and mean arterial pressure (+7.8%; P < 0.01). The rise in BP during leg crossing was larger in the elderly.
Egr-1 antisense oligonucleotides inhibit hypoxia-induced proliferation of pulmonary artery adventitial fibroblasts
Authors: Banks Mark F. , Gerasimovskaya Evgenia V. , Tucker Doug A. , Frid Maria G. , Carpenter Todd C. , Stenmark Kurt R.
Published: October 2004

In most mammalian species, chronic exposure to hypoxia leads to pulmonary hypertension and vascular remodeling. The adventitial fibroblast, because of its ability to proliferate in response to hypoxia, is thought to be a critical cell in the remodeling process. However, the transcription factors driving hypoxia-induced fibroblast proliferation have yet to be elucidated. The early growth response-1 (Egr-1) transcription factor has been shown to be upregulated by hypoxia in pulmonary artery adventitial fibroblasts. We therefore hypothesized that Egr-1 is directly involved in hypoxia-induced adventitial fibroblast proliferation. Immunohistochemical analysis of in vivo lung tissue from animals exposed to chronic hypoxia revealed increased expression of Egr-1 in the pulmonary artery fibroblasts vs. expression shown in normoxic controls. In fibroblasts cultured from chronically hypoxic animals, exposure to 1% oxygen upregulated Egr-1 protein and cell proliferation. To evaluate the role of Egr-1 in hypoxia-induced proliferation, we employed an Egr-1 antisense strategy. Addition of antisense Egr-1 oligonucleotides, but not sense oligonucleotides, attenuated the hypoxia-induced upregulation of Egr-1 protein and reduced hypoxia-induced DNA synthesis by 50%. Cell proliferation was also significantly inhibited by the addition of antisense Egr-1 oligonucleotides but not the sense oligonucleotides. In addition, hypoxia-induced upregulations of cyclin D and epidermal growth factor receptor were attenuated by Egr-1 antisense oligonucleotides. We conclude that Egr-1 protein expression is very sensitive to upregulation by hypoxia in pulmonary artery adventitial fibroblasts and that it plays an important role in the autonomous growth phenotype induced by hypoxia in these cells.
Effects of bilateral vestibular nucleus lesions on cardiovascular regulation in conscious cats
Authors: Mori R. L. , Cotter L. A. , Arendt H. E. , Olsheski C. J. , Yates B. J.
Published: October 2004

The vestibular system participates in cardiovascular regulation during postural changes. In prior studies (Holmes MJ, Cotter LA, Arendt HE, Cas SP, and Yates BJ. Brain Res 938: 62–72, 2002, and Jian BJ, Cotter LA, Emanuel BA, Cass SP, and Yates BJ. J Appl Physiol 86: 1552–1560, 1999), transection of the vestibular nerves resulted in instability in blood pressure during nose-up body tilts, particularly when no visual information reflecting body position in space was available. However, recovery of orthostatic tolerance occurred within 1 wk, presumably because the vestibular nuclei integrate a variety of sensory inputs reflecting body location. The present study tested the hypothesis that lesions of the vestibular nuclei result in persistent cardiovascular deficits during orthostatic challenges. Blood pressure and heart rate were monitored in five conscious cats during nose-up tilts of varying amplitude, both before and after chemical lesions of the vestibular nuclei. Before lesions, blood pressure remained relatively stable during tilts. In all animals, the blood pressure responses to nose-up tilts were altered by damage to the medial and inferior vestibular nuclei; these effects were noted both when animals were tested in the presence and absence of visual feedback. In four of the five animals, the lesions also resulted in augmented heart rate increases from baseline values during 60° nose-up tilts. These effects persisted for longer than 1 wk, but they gradually resolved over time, except in the animal with the worst deficits. These observations suggest that recovery of compensatory cardiovascular responses after loss of vestibular inputs is accomplished at least in part through plastic changes in the vestibular nuclei and the enhancement of the ability of vestibular nucleus neurons to discriminate body position in space by employing nonlabyrinthine signals.
Kinin peptides in human trapezius muscle during sustained isometric contraction and their relation to pain
Authors: Boix Fernando , Røe Cecilie , Rosenborg Laila , Knardahl Stein
Published: October 2004

To determine the muscular concentration of bradykinin and kallidin during static contraction, microdialysis probes were implanted bilaterally in the trapezius muscles of healthy women. Three hours after probe implantation, 200 μM of the angiotensin-converting enzyme (ACE) inhibitor enalaprilat were added to the perfusion solution in one of the sides for 30 min. Thirty minutes later, the subjects performed a sustained bilateral shoulder abduction at 10% of the maximal voluntary contraction until exhaustion. This protocol was repeated twice, with an interval of at least 17 days. High intersession repeatability was observed in the concentration of bradykinin but not of kallidin. Enalaprilat induced a significant increase in bradykinin levels in the dialysate, without affecting kallidin levels. The sustained contraction induced a significant increase in dialysate levels of both kinin peptides. The contraction also induced a significant increase in pain ratings, as measured by a visual analog scale. During contraction, positive correlations were found between pain ratings and levels of kinin peptides in dialysate, predominantly in the side previously perfused with enalaprilat. Subjects with the higher pain ratings also showed larger increases in kinin peptides in the side previously perfused with enalaprilat. The present results show that both plasma and tissue kinin-kallikrein are activated during muscle contraction, but that their metabolic pathways are differently regulated during rest and contraction, because they showed a different response to ACE inhibition. They also indicate that intramuscular kinin peptides levels, and ACE activity, may contribute to muscle pain.
Prevalence of the Metabolic Syndrome in American Adolescents
Authors: de Ferranti Sarah D. , Gauvreau Kimberlee , Ludwig David S. , Neufeld Ellis J. , Newburger Jane W. , Rifai Nader
Published: October 2004

Background—

Metabolic syndrome (MetS) is defined by the Third Report of the Adult Treatment Panel (ATP III) using criteria easily applied by clinicians and researchers. There is no standard pediatric definition.

Methods and Results—

We defined pediatric MetS using criteria analogous to ATP III as ≥3 of the following: (1) fasting triglycerides ≥1.1 mmol/L (100 mg/dL); (2) HDL <1.3 mmol/L (50 mg/dL), except in boys aged 15 to 19 years, in whom the cutpoint was <1.2 mmol/L (45 mg/dL); (3) fasting glucose ≥6.1 mmol/L (110 mg/dL); (4) waist circumference >75th percentile for age and gender; and (5) systolic blood pressure >90th percentile for gender, age, and height. MetS prevalence in US adolescents was estimated with the Third National Health and Nutritional Survey 1988 to 1994. Among 1960 children aged ≥12 years who fasted ≥8 hours, two thirds had at least 1 metabolic abnormality, and nearly 1 in 10 had MetS. The racial/ethnic distribution was similar to adults: Mexican-Americans, followed by non-Hispanic whites, had a greater prevalence of MetS compared with non-Hispanic blacks (12.9%, [95% CI 10.4% to 15.4%]; 10.9%, [95% CI 8.4% to 13.4%]; and 2.5%, [95% CI 1.3% to 3.7%], respectively). Nearly one third (31.2% [95% CI 28.3% to 34.1%]) of overweight/obese adolescents had MetS.

Conclusions—

Our definition of pediatric MetS, designed to be closely analogous to ATP III, found MetS is common in adolescents and has a similar racial/ethnic distribution to adults in this representative national sample. Because childhood MetS likely tracks into adulthood, early identification may help target interventions to improve future cardiovascular health.