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1.  Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin–angiotensin system 
Experimental physiology  2013;99(4):627-631.
Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin–glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin–angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd−/− mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd−/− mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of LV dysfunction and higher mortality in Sgcd−/− mice. Treatment of Sgcd−/− mice with the angiotensin type 1 receptor blocker losartan for 8–9 weeks, beginning at 3 weeks of age, decreased fibrosis and oxidative stress in skeletal muscle, increased locomotor activity and prevented autonomic dysfunction. Chronic infusion of the counter-regulatory peptide angiotensin-(1–7) resulted in similar protection. We conclude that activation of the renin–angiotensin system, at a young age, contributes to skeletal muscle and autonomic dysfunction in muscular dystrophy. We speculate that the latter is mediated via abnormal sensory nerve and/or cytokine signalling from dystrophic skeletal muscle to the brain and contributes to age-related LV dysfunction, dilated cardiomyopathy, arrhythmias and premature death. Therefore, correcting the early autonomic dysregulation and renin–angiotensin system activation may provide a novel therapeutic approach in muscular dystrophy.
doi:10.1113/expphysiol.2013.074336
PMCID: PMC4322680  PMID: 24334334
2.  [No title available] 
PMCID: PMC3925386  PMID: 24213857
3.  [No title available] 
PMCID: PMC3946674  PMID: 24142455
4.  Promising Neuroprotective Effects of the Angiotensin 1-7/ACE2 / Mas axis in Stroke 
Experimental physiology  2014;99(2):342-343.
doi:10.1113/expphysiol.2013.076836
PMCID: PMC4145408  PMID: 24487246
5.  Group III/IV muscle afferents contribute to both perception of effort and fatigue 
Experimental physiology  2014;99(5):836.
doi:10.1113/expphysiol.2014.078832
PMCID: PMC4288841  PMID: 25100796
6.  Structure and Function of Voltage-Gated Sodium Channels at Atomic Resolution 
Experimental physiology  2013;99(1):10.1113/expphysiol.2013.071969.
Voltage-gated sodium channels initiate action potentials in nerve, muscle, and other excitable cells. Early physiological studies described sodium selectivity, voltage-dependent activation, and fast inactivation, and developed conceptual models for sodium channel function. This review article follows the topics of my 2013 Sharpey-Schafer Prize Lecture and gives an overview of research using a combination of biochemical, molecular biological, physiological, and structural biological approaches that has elucidated the structure and function of sodium channels at the atomic level. Structural models for voltage-dependent activation, sodium selectivity and conductance, drug block, and both fast and slow inactivation are discussed. A perspective for the future envisions new advances in understanding the structural basis for sodium channel function and the opportunity for structure-based discovery of novel therapeutics.
doi:10.1113/expphysiol.2013.071969
PMCID: PMC3885250  PMID: 24097157
7.  Exercise reveals impairments in left ventricular systolic function in patients with metabolic syndrome 
Experimental physiology  2013;99(1):149-163.
MetS is the manifestation of a cluster of cardiovascular (CV) risk factors and is associated with a three-fold increase risk of CV morbidity and mortality, which is suggested to be mediated, in part, by resting left ventricular (LV) systolic dysfunction. However, to what extent resting LV systolic function is impaired in MetS is controversial, and there are no data indicating whether LV systolic function is impaired during exercise. Accordingly, the objective of this study was to comprehensively examine LV and arterial responses to exercise in MetS individuals without diabetes and/or overt CVD compared to a healthy control population. CV function was characterized using Doppler echocardiography and gas exchange in MetS (n=27) vs. healthy controls (n=20) at rest and during peak exercise. At rest, MetS individuals displayed normal LV systolic function but reduced LV diastolic function vs. healthy controls. During peak exercise, individuals with MetS had impaired contractility; pump performance, and vasodilator reserve capacity vs. controls. A blunted contractile reserve response resulted in diminished arterial-ventricular coupling reserve and limited aerobic capacity in MetS vs. controls. These findings possess clinical importance as they provide insight to the pathophysiological changes in MetS that may predispose this population of individuals to an increased risk of CV morbidity and mortality.
doi:10.1113/expphysiol.2013.075796
PMCID: PMC3947356  PMID: 24036595
metabolic syndrome; systolic function; exercise reserve
8.  Post-exercise syncope: Wingate syncope test and effective countermeasure 
Experimental physiology  2013;99(1):172-186.
Altered systemic hemodynamics following exercise can compromise cerebral perfusion and result in syncope. As the Wingate anaerobic test often induces pre-syncope, we hypothesized that a modified Wingate test could form the basis of a novel model for the study of post-exercise syncope and a test-bed for potential countermeasures. Along these lines, breathing through an impedance threshold device has been shown to increase tolerance to hypovolemia, and could prove beneficial in the setting of post-exercise syncope. Therefore, we hypothesized that a modified Wingate test followed by head-up tilt would produce post-exercise syncope, and that breathing through an impedance threshold device (countermeasure) would prevent post-exercise syncope in healthy individuals. Nineteen recreationally active men and women underwent a 60° head-up tilt during recovery from the Wingate test while arterial pressure, heart rate, end-tidal CO2, and cerebral tissue oxygenation were measured on a control and countermeasure day. The duration of tolerable tilt was increased by a median time of 3 min 48 sec with countermeasure compared to control (P < 0.05) and completion of the tilt test increased from 42% to 67% with countermeasure. During the tilt, mean arterial pressure was greater (108.0 ± 4.1 vs.100.4 ± 2.4 mmHg; P < 0.05) with countermeasure compared to control. These data suggest that the Wingate syncope test produces a high incidence of pre-syncope which is sensitive to countermeasures such as inspiratory impedance.
doi:10.1113/expphysiol.2013.075333
PMCID: PMC3947357  PMID: 24078670
Syncope; vasovagal; Post-exercise hypotension; Tilt-table test; Hypotension; Orthostatic; Anaerobic exercise; Orthostatic intolerance; Cerebrovascular circulation
9.  Integrative physiologic and computational approaches to understand autonomic control of cerebral autoregulation 
Experimental physiology  2013;99(1):3-15.
The brain requires steady delivery of oxygen and glucose, without which neurodegeneration occurs within minutes. Thus, the ability of the cerebral vasculature to maintain relatively steady blood flow in the face of changing systemic pressure, i.e., cerebral autoregulation, is critical to neurophysiologic health. Although the study of autoregulation dates to the early 20th century, only the recent availability of cerebral blood flow measures with high temporal resolution has allowed rapid, beat-by-beat measurements to explore the characteristics and mechanisms of autoregulation. These explorations have been further enhanced by the ability to apply sophisticated computational approaches that exploit the large amounts of data that can be acquired. These advances have led to unique insights. For example, recent studies have revealed characteristic time scales wherein cerebral autoregulation is most active, and specific regions wherein autonomic mechanisms are prepotent. However, given that effective cerebral autoregulation against pressure fluctuations results in relatively unchanging flow despite changing pressure, estimating the pressure-flow relationship can be limited by the error inherent in computational models of autoregulatory function. This review will focus on the autonomic neural control of the cerebral vasculature in health and disease from an integrative physiologic and perspective. It will also provide a critical overview of the current analytic approaches to understand cerebral autoregulation.
doi:10.1113/expphysiol.2013.072355
PMCID: PMC3947359  PMID: 24097158
sympathetic nervous system; autonomic nervous control; cerebrovasculature; human
10.  SKELETAL MUSCLE CAPILLARY FUNCTION: CONTEMPORARY OBSERVATIONS AND NOVEL HYPOTHESES 
Experimental physiology  2013;98(12):1645-1658.
The capillary bed constitutes a vast surface facilitating exchange of O2, substrates and metabolites between blood and organs. In contracting skeletal muscle capillary blood flow and O2 diffusing capacity as well as O2 flux may increase two orders of magnitude above resting. Chronic diseases such as heart failure, diabetes and also sepsis impair these processes leading to compromised energetic, metabolic and ultimately contractile function. Among researchers seeking to understand blood-myocyte exchange in health and the bases for dysfunction in disease there is a fundamental disconnect between microcirculation specialists and many physiologists and physiologist clinicians. Whereas the former observe capillaries and capillary function directly (muscle intravital microscopy) the latter generally use indirect methodologies (e.g., post-mortem tissue analysis, 1-methyl xanthine, contrast enhanced ultrasound, permeability surface area product) and interpret their findings based upon August Krogh’s observations made nearly a century ago. “Kroghian” theory holds that only a small fraction of capillaries support red blood cell (RBC) flux in resting muscle leaving the vast majority to be “recruited” (i.e., initiate RBC flux) during contractions which would constitute the basis for increasing capillary exchange surface area and reducing capillary-mitochondrial diffusion distances. Experimental techniques each have their strengths and weaknesses and often the correct or complete answer to a problem emerges from integration across multiple technologies. Today Krogh’s entrenched “capillary recruitment” hypothesis is challenged by direct observations of capillaries in contracting muscle; something that he and his colleagues could not do. Moreover, in the peer-reviewed scientific literature, application of a range of contemporary physiological technologies including intravital microscopy of contracting muscle, magnetic resonance and near infrared spectroscopy and phosphorescence quenching combined with elegant in situ and in vivo models suggest that the role of the capillary bed, at least in contracting muscle, is subserved without the necessity for de novo capillary recruitment of previously non-flowing capillaries. When viewed within the context of the capillary recruitment hypothesis, this evidence casts serious doubt on the interpretation of those data that are based upon Kroghian theory and indirect methodologies. Thus today a wealth of evidence calls for a radical revision of blood-muscle exchange theory to one in which most capillaries support RBC flux at rest and, during contractions, capillary surface area is “recruited” along the length of previously flowing capillaries. This occurs, in part, by elevating capillary hematocrit and extending the length of the capillary available for blood-myocyte exchange (i.e., longitudinal recruitment). Our understanding of blood-myocyte O2 and substrate/metabolite exchange in health and the mechanistic bases for dysfunction in disease demands no less.
doi:10.1113/expphysiol.2013.073874
PMCID: PMC4251469  PMID: 23995101
11.  Modulation of food intake by mTOR signaling in the dorsal motor nucleus of vagus in male rats: Focus on ghrelin and nesfatin-1 
Experimental physiology  2013;98(12):10.1113/expphysiol.2013.074930.
Previous studies demonstrate that mTOR signaling in the hypothalamus is involved in the control of energy homeostasis. The aim of this study is to characterize the effect of mTOR signaling in the dorsal motor nucleus of vagus (DMNV) on the energy intake. Phosphor-mTOR was detected in the DMNV neurons and its levels increased by energy deprivation. Rapamycin significantly inhibited mTOR activity and reduced food intake when administrated into 4th ventricle. Exposure of DMNV neurons to ghrelin increased the phosphorylation of mTOR. Fourth ventricle injection of ghrelin significantly increased food intake relative to the control vehicle. Pre-treatment with rapamycin for 15 min attenuated the orexigenic effect of ghrelin. Reduction in the phosphorylation of mTOR was observed following 4th intracerebroventricular injection of nesfatin-1. When administrated by 4th ICV injection, nesfatin-1 suppressed the food intake as compared with the control. The anorexigenic effect of nesfatin-1 was significantly attenuated by pre-treatment with leucine for 15 min. All these studies suggest that mTOR signaling in the DMNV neurons regulates both the nutrient and hormonal signals for the modulation of food intake.
doi:10.1113/expphysiol.2013.074930
PMCID: PMC3839812  PMID: 23955309
Dorsal vagal complex; ghrelin; nesfatin-1
12.  Pyridoxamine protects against mechanical defects in cardiac ageing in rats: studies on load dependence of myocardial relaxation 
Experimental Physiology  2014;99(11):1488-1498.
New Findings
What is the central question of this study?
This study aimed to investigate the hypothesis that pyridoxamine, one of the three natural forms of vitamin B6, can protect against myocardial relaxation of senescent animals by targeting arterial stiffening and contractile dysfunction of the left ventricle.
What is the main finding and its importance?
We found that treating the senescent rats with pyridoxamine for 5 months might improve myocardial relaxation rate, at least partly through its ability to enhance myocardial contractile performance, increase wave transit time and decrease wave reflection factor.
Our team demonstrated in the past that pyridoxamine attenuated arterial stiffening by targeting the pathogenic formation of glycated collagen cross-links in aged rats. Herein, we examined whether pyridoxamine therapy can protect against mechanical defects in myocardial relaxation by improving arterial wave properties and cardiac contractile performance in senescent animals. Fifteen-month-old male Fisher 344 rats were treated daily with pyridoxamine (1 g l−1 in drinking water) for 5 months and compared with age-matched untreated control animals (20 months old). Arterial wave properties were characterized by wave transit time (τw) and wave reflection factor (Rf). We measured the contractile status of the myocardium in an intact heart as the left ventricular (LV) end-systolic elastance (Ees). Myocardial relaxation was described according to the time constant of the LV isovolumic pressure decay (τe). Pyridoxamine therapy prevented the age-associated prolongation in LV τe and the diminished Ees in senescent rats. The drug also attenuated the age-related augmentation in afterload imposed on the heart, as evidenced by the increased τw and decreased Rf. We found that the LV τe was significantly influenced by both the arterial τw and Rf (τe = 16.3902 + 8.3123 × Rf − 0.4739 × τw; r = 0.7048, P < 0.005). In the meantime, the LV τe and the LV Ees showed a significant inverse linear correlation (τe = 13.9807 − 0.0068 × Ees; r = 0.6451, P < 0.0005). All these findings suggested that long-term treatment with pyridoxamine might ameliorate myocardial relaxation rate, at least partly through its ability to enhance myocardial contractile performance, increase wave transit time and decrease wave reflection factor in aged rats.
doi:10.1113/expphysiol.2014.082008
PMCID: PMC4240468  PMID: 25239923
13.  Elevated blood pressure, heart rate and body temperature in mice lacking the XLαs protein of the Gnas locus is due to increased sympathetic tone 
Experimental Physiology  2013;98(10):1432-1445.
New Findings
What is the central question of this study?Previously, we showed that Gnasxl knock-out mice are lean and hypermetabolic, with increased sympathetic stimulation of adipose tissue. Do these mice also display elevated sympathetic cardiovascular tone? Is the brain glucagon-like peptide-1 system involved?What is the main finding and its importance?Gnasxl knock-outs have increased blood pressure, heart rate and body temperature. Heart rate variability analysis suggests an elevated sympathetic tone. The sympatholytic reserpine had stronger effects on blood pressure, heart rate and heart rate variability in knock-out compared with wild-type mice. Stimulation of the glucagon-like peptide-1 system inhibited parasympathetic tone to a similar extent in both genotypes, with a stronger associated increase in heart rate in knock-outs. Deficiency of Gnasxl increases sympathetic cardiovascular tone.
Imbalances of energy homeostasis are often associated with cardiovascular complications. Previous work has shown that Gnasxl-deficient mice have a lean and hypermetabolic phenotype, with increased sympathetic stimulation of adipose tissue. The Gnasxl transcript from the imprinted Gnas locus encodes the trimeric G-protein subunit XLαs, which is expressed in brain regions that regulate energy homeostasis and sympathetic nervous system (SNS) activity. To determine whether Gnasxl knock-out (KO) mice display additional SNS-related phenotypes, we have now investigated the cardiovascular system. The Gnasxl KO mice were ∼20 mmHg hypertensive in comparison to wild-type (WT) littermates (P≤ 0.05) and hypersensitive to the sympatholytic drug reserpine. Using telemetry, we detected an increased waking heart rate in conscious KOs (630 ± 10 versus 584 ± 12 beats min−1, KO versus WT, P≤ 0.05). Body temperature was also elevated (38.1 ± 0.3 versus 36.9 ± 0.4°C, KO versus WT, P≤ 0.05). To investigate autonomic nervous system influences, we used heart rate variability analyses. We empirically defined frequency power bands using atropine and reserpine and verified high-frequency (HF) power and low-frequency (LF) LF/HF power ratio to be indicators of parasympathetic and sympathetic activity, respectively. The LF/HF power ratio was greater in KOs and more sensitive to reserpine than in WTs, consistent with elevated SNS activity. In contrast, atropine and exendin-4, a centrally acting agonist of the glucagon-like peptide-1 receptor, which influences cardiovascular physiology and metabolism, reduced HF power equally in both genotypes. This was associated with a greater increase in heart rate in KOs. Mild stress had a blunted effect on the LF/HF ratio in KOs consistent with elevated basal sympathetic activity. We conclude that XLαs is required for the inhibition of sympathetic outflow towards cardiovascular and metabolically relevant tissues.
doi:10.1113/expphysiol.2013.073064
PMCID: PMC4223506  PMID: 23748904
14.  Role of Oxidative Stress Induced Endothelin Converting Enzyme Activity in the Alteration of Carotid Body Function by Chronic Intermittent Hypoxia 
Experimental physiology  2013;98(11):10.1113/expphysiol.2013.073700.
Chronic intermittent hypoxia (CIH) leads to remodeling of the carotid body function manifested by augmented sensory response to hypoxia and induction of sensory long-term facilitation (LTF). It was proposed that endothelin-1 (ET-1) contributes to CIH-induced hypoxic hypersensitivity of the carotid body. The objectives of the present study were: a) to delineate the mechanisms by which CIH up regulates ET-1 expression in the carotid body, and b) to assess whether ET-1 also contributes to sensory LTF. Experiments were performed on adult, male rats exposed to alternating cycles of 5% O2 (15s) and room air (5min), 9 episodes/hr and 8hr/day for 10 days. CIH increased ET-1 levels in glomus cells without significantly altering preproendothelin-1 mRNA levels. The activity of endothelin-converting enzyme (ECE) increased with concomitant elevation of ET-1 levels in CIH exposed carotid bodies, and MnTMPyP, a membrane permeable antioxidant prevented these effects. Hypoxia facilitated ET-1 release from CIH-treated carotid body, a requisite for activation of ET receptors; however, hypoxia had no effect on ET-1 release from control carotid bodies. In CIH exposed carotid bodies, mRNAs encoding ETA receptor were up regulated and an ETA receptor specific antagonist abolished CIH-induced hypersensitivity of the hypoxic response, whereas it had no effect on the sensory LTF. These results suggest that ECE-dependent increased production of ET-1 coupled with hypoxia-evoked ET-1 release and the ensuing ETA receptor activation mediate the CIH-induced carotid body hypersensitivity to hypoxia, but the ETA signaling pathway is not associated with sensory LTF elicited by CIH.
doi:10.1113/expphysiol.2013.073700
PMCID: PMC3808500  PMID: 23913764
Recurrent apnea; endothelin-converting enzyme; endothelin-1 release; ETA receptors
15.  Utilizing Genetic Models of Idiopathic Hypogonadotropic Hypogonadism in Mice and Men to Understand Mechanism of Disease 
Experimental physiology  2013;98(11):10.1113/expphysiol.2013.071910.
Mutations in the genes encoding the neuropeptides, kisspeptin and neurokinin B, as well as their receptors, are associated with gonadotropin-releasing hormone (GnRH) deficiency and a failure to initiate and/or progress through puberty. Although the total number of patients studied to date is small, mutations in the kisspeptin pathway appear to result in lifelong GnRH deficiency. Mice with mutations in kisspeptin and the kisspeptin receptor, Kiss1−/− and Kiss1r−/− respectively, appear to be phenocopies of the human with abnormal sexual maturation and infertility. In contrast, mutations in the neurokinin B pathway lead to a more variable adult reproductive phenotype, with a subset of hypogonadotropic individuals demonstrating paradoxical recovery of reproductive function later in life. While “reversal” remains poorly understood, the ability to recover reproductive function indicates that neurokinin B may play different roles in the initiation of sexual maturation compared to the maintenance of adult reproductive function. Mice with mutations in the gene encoding the neurokinin B receptor, Tacr3, have abnormal estrous cycles and subfertility but similar to their human counterparts appear less severely affected than mice with kisspeptin deficiency. Further investigations into the interaction between the kisspeptin and neurokinin B pathways will reveal key insights into how GnRH neuronal modulation occurs at puberty and throughout reproductive life.
doi:10.1113/expphysiol.2013.071910
PMCID: PMC3808847  PMID: 23955308
neurokinin B; kisspeptin; idiopathic hypogonadotropic hypogonadism; GnRH
16.  Influence of regular physical activity and caloric restriction on β-adrenergic and natriuretic peptide receptor expression in retroperitoneal adipose tissue of OLETF rats 
Experimental physiology  2013;98(11):10.1113/expphysiol.2013.074658.
The mechanisms underlying exercise-induced increases in adipose tissue blood flow and lipolysis involve both β-adrenergic receptor (βAR)- and natriuretic peptide receptor (NPR)-dependent mechanisms. We hypothesied that daily wheel running (RUN) would increase the expression of NPR1, NPR2, βAR2, and βAR3 in retroperitoneal (RP) and epididymal (EPI) adipose tissues of obese Otsuka Long Evans Tokushima Fatty (OLETF) rats. Four-week old OLETF rats were assigned to sedentary (SED, n = 6), caloric restriction (CR, n = 8; fed 70% of SED), or RUN (n = 8) groups. Rats were sacrificed at 40 weeks of age. By design, body weight and adiposity were similar between RUN and CR animals, but each were lower than SED (P < 0.01). Compared to SED, RP depots of RUN rats exhibited 1.7-3.2-fold greater NPR1, NPR2, βAR2, and βAR3 mRNA levels (all P < 0.05). There were no differences between CR and SED in the expression of these genes in RP, and there were no differences in gene expression among groups in EPI. At the protein level, βAR2 and βAR3 were elevated in RUN and CR relative to SED in RP. To gain insights into mechanisms underlying the activity-induced increases in NPR and βAR mRNAs, RP explants from Wistar rats were treated with atrial natriuretic peptide (ANP), epinephrine, and/or S-Nitroso-N-acetyl-DL-penicillamine [SNAP; a nitric oxide (NO) donor] in organ culture experiments. SNAP synergistically enhanced epinephrine- and ANP-stimulated increases in NPR2 and βAR2 mRNA levels. Our data suggest that physical activity-induced increases in NO interact with epinephrine and ANP to trigger the induction of NPR and βAR mRNAs in the RP depot of the OLETF rat.
doi:10.1113/expphysiol.2013.074658
PMCID: PMC3839103  PMID: 23833052
obesity; lipolysis; blood flow; sympathetic nervous system
17.  Pacemaking Kisspeptin Neurons 
Experimental physiology  2013;98(11):10.1113/expphysiol.2013.074559.
Kisspeptin (Kiss1) neurons are vital for reproduction. GnRH neurons express the kisspeptin receptor, GPR 54, and kisspeptins potently stimulate the release of GnRH by depolarising and inducing sustained action potential firing in GnRH neurons. As such Kiss1 neurons may be the pre-synaptic pacemaker neurons in the hypothalamic circuitry that controls reproduction. There are at least two different populations of Kiss1 neurons: one in the rostral periventricular area (RP3V) that is stimulated by oestrogens and the other in the arcuate nucleus that is inhibited by oestrogens. How each of these Kiss1 neuronal populations participate in the regulation of the reproductive cycle is currently under intense investigation. Based on electrophysiological studies in the guinea pig and mouse, Kiss1 neurons in general are capable of generating burst firing behavior. Essentially all Kiss1 neurons, which have been studied thus far in the arcuate nucleus, express the ion channels necessary for burst firing, which include hyperpolarization-activated, cyclic nucleotide gated cation (HCN) channels and the T-type calcium (Cav3.1) channels. Under voltage clamp conditions, these channels produce distinct currents that under current clamp conditions can generate burst firing behavior. The future challenge is to identify other key channels and synaptic inputs involved in the regulation of the firing properties of Kiss1 neurons and the physiological regulation of the expression of these channels and receptors by oestrogens and other hormones. The ultimate goal is to understand how Kiss1 neurons control the different phases of GnRH neurosecretion and hence reproduction.
doi:10.1113/expphysiol.2013.074559
PMCID: PMC3842911  PMID: 23884368
18.  Sex-specific Effects of Exercise Ancestry on Metabolic, Morphological, and Gene Expression Phenotypes in Multiple Generations of Mouse Offspring 
Experimental physiology  2013;98(10):1469-1484.
Early life and pre-conception environmental stimuli can affect adult health-related phenotypes. Exercise training is an environmental stimulus affecting many systems throughout the body and appears to alter offspring phenotypes. The aim of this study was to examine the influence of parental exercise training, or “exercise ancestry,” on morphological and metabolic phenotypes in two generations of mouse offspring. F0 C57BL/6 mice were exposed to voluntary exercise or sedentary lifestyle and bred with like-exposed mates to produce an F1 generation. F1 mice of both ancestries were sedentary and sacrificed at 8 wk or bred with littermates to produce an F2 generation, which was also sedentary and sacrificed at 8 wk. Small, but broad generation- and sex-specific effects of exercise ancestry were observed for body mass, fat and muscle mass, serum insulin, glucose tolerance, and muscle gene expression. F1 EX females were lighter than F1 SED females, and had lower absolute tibialis anterior and omental fat masses. Serum insulin was higher in F1 EX females compared to F1 SED females. F2 EX females had impaired glucose tolerance compared to F2 SED females. Analysis of skeletal muscle mRNA levels revealed several generation- and sex-specific differences in mRNA levels for multiple genes, especially those related to metabolic genes (e.g., F1 EX males had lower mRNA levels of Hk2, Ppard, Ppargc1α, Adipoq, and Scd1 than F1 SED males). These results provide preliminary evidence that parental exercise training can influence health-related phenotypes in mouse offspring.
doi:10.1113/expphysiol.2012.070300
PMCID: PMC3783594  PMID: 23771910
Exercise; Pregnancy; Metabolism
19.  Oxytocin projections to the nucleus of the solitary tract contribute to the increased meal-related satiety responses in primary adrenal insufficiency 
Experimental physiology  2013;98(10):1495-1504.
Anorexia is a common clinical manifestation of primary adrenal gland failure. Adrenalectomy (ADX)-induced hypophagia is reversed by oxytocin (OT) receptor antagonist and is associated with increased activation of satiety-related responses in the nucleus of the solitary tract (NTS). This study evaluated OT projections from the paraventricular nucleus of the hypothalamus (PVN) to NTS after ADX and the effect of pretreatment with intracerebroventricular injection of OT receptor antagonist ([d(CH2)5,Tyr(Me)2,Orn8]-vasotocin, OVT) on the activation of NTS neurons induced by feeding in adrenalectomized rats. Adrenalectomized animals showed higher OT labeling in the NTS than sham and ADX with corticosterone replacement (ADX+B) groups. Adrenalectomized animals exhibited co-localization of the anterograde tracer Phaseolus vulgaris-leucoagglutinin and OT in axons in the NTS as well as OT fibers apposing NTS neurons activated by refeeding. After vehicle pretreatment, compared to fasting, refeeding increased the numbers of Fos− and Fos+TH-immunoreactive neurons in the NTS in sham, ADX and ADX+B groups, with a higher number of these immunolabeled neurons in adrenalectomized animals. Compared to fasting condition, refeeding also increased the activation of NTS neurons in OVT pretreated sham, ADX and ADX+B groups, however there was no difference among the three experimental groups. These data demonstrate that OT is up-regulated in projections to the NTS following ADX and that OT receptor antagonist reverses the greater activation of NTS neurons induced by feeding after ADX. The data indicate that OT pathways to the NTS contribute to higher satiety-related responses and, thus, to reduce meal size in primary adrenal insufficiency.
doi:10.1113/expphysiol.2013.073726
PMCID: PMC3786458  PMID: 23813803
Adrenalectomy; oxytocin; nucleus of the solitary tract
20.  TREATMENT OF MUSCLE MECHANOREFLEX DYSFUNCTION IN HYPERTENSION: EFFECTS OF L-ARGININE DIALYSIS IN THE NUCLEUS TRACTUS SOLITARII 
Experimental physiology  2013;98(9):1337-1348.
The blood pressure response to exercise is exaggerated in hypertension. Recent evidence suggests that an overactive skeletal muscle mechanoreflex contributes significantly to this augmented circulatory responsiveness. Sensory information from the mechanoreflex is processed within the nucleus tractus solitarii (NTS) of the medulla oblongata. Normally, endogenously produced nitric oxide (NO) within the NTS attenuates the increase in mean arterial pressure (MAP) induced by mechanoreflex stimulation. Thus, it has been suggested that decreases in NTS-NO production underlie the generation of mechanoreflex dysfunction in hypertension. Supporting this postulate, it has been shown that blocking NO production within the NTS of normotensive rats reproduces the exaggerated pressor response elicited by mechanoreflex activation in hypertensive animals. What is not known is whether increasing NO production within the NTS of hypertensive rats mitigates mechanoreflex overactivity. In this study, the mechanoreflex was selectively activated by passively stretching hindlimb muscle before and after the dialysis of 1 and 10 μM L-arginine (a NO precursor) within the NTS of decerebrate normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Stretch induced larger elevations in MAP in SHR compared to WKY. In both groups, dialysis of 1 μM L-arginine significantly attenuated the pressor response to stretch. However, at the 10 μM dose, L-arginine had no effect on the MAP response to stretch in WKY while it enhanced the response in SHR. The data demonstrate that increasing NO availability within the NTS using lower doses of L-arginine partially normalizes mechanoreflex dysfunction in hypertension whereas higher doses do not. The findings could prove valuable in the development of treatment options for mechanoreflex overactivity in this disease.
doi:10.1113/expphysiol.2012.071563
PMCID: PMC3750060  PMID: 23771911
blood pressure; heart rate; exercise
21.  Impaired Pancreatic Beta Cell Function by Chronic Intermittent Hypoxia 
Experimental physiology  2013;98(9):1376-1385.
Breathing disorders with recurrent apnea produce periodic decreases in arterial blood O2 or chronic intermittent hypoxia (CIH). Recurrent apnea patients and CIH-exposed rodents exhibit several co-morbidities including diabetes. However, the effects of CIH on pancreatic beta cell function are not known. In the present study, we investigated pancreatic beta cell function in C57BL6 mice exposed to 30 days of CIH. CIH-exposed mice exhibited elevated levels of fasting plasma insulin, but comparable glucose levels, and higher homeostasis model assessment (HOMA), indicating insulin resistance. Pancreatic beta cell morphology was unaltered in CIH- exposed mice. Insulin content was decreased in CIH-exposed beta cells, and this effect was associated with increased proinsulin levels. mRNA and protein levels of the enzyme pro-hormone convertase 1 (PC1) which converts proinsulin to insulin were down regulated in CIH-treated islets. More importantly, glucose-stimulated insulin secretion (GSIS) was impaired in CIH-exposed mice and in isolated islets. Mitochondrial reactive oxygen species (ROS) levels were elevated in CIH-exposed pancreatic islets. Treatment of mice with mito-tempol, a scavenger of mitochondrial ROS during CIH exposure, prevented the augmented insulin secretion and restored the proinsulin as well as HOMA values to control levels. These results demonstrate that CIH leads to pancreatic beta cell dysfunction manifested by augmented basal insulin secretion, insulin resistance, defective proinsulin processing, impaired GSIS and mitochondrial ROS mediates the effects of CIH on pancreatic beta cell function.
doi:10.1113/expphysiol.2013.072454
PMCID: PMC3756548  PMID: 23709585
Intermittent hypoxia; Beta cells; Reactive oxygen species
22.  Pulmonary vascular mechanics: Important contributors to the increased right ventricular afterload of pulmonary hypertension 
Experimental physiology  2013;98(8):1267-1273.
Chronic hypoxia causes pulmonary vasoconstriction and vascular remodeling, which lead to hypoxic pulmonary hypertension (HPH). HPH is associated with living at high altitudes and is a complication of many lung diseases, including chronic obstructive pulmonary disease, cystic fibrosis, and obstructive sleep apnea. Pulmonary vascular changes that occur with HPH include stiffening and narrowing of the pulmonary arteries that appear to involve all vascular cell types and sub-layers of the arterial wall. Right ventricular (RV) changes that occur with HPH include RV hypertrophy and RV fibrosis, often with preserved systolic and diastolic function and ventricular-vascular coupling efficiency. Both vascular stiffening and narrowing are important contributors to RV afterload via increases in oscillatory and steady ventricular work, respectively. The increased blood viscosity that occurs in HPH can be quite dramatic and is another important contributor to RV afterload. However, the viscosity, vascular mechanics and ventricular changes that occur with HPH are all reversible. Furthermore, even with continued hypoxia vascular remodeling does not progress to the obliterative, plexiform lesions that are seen clinically in severe pulmonary hypertension. In animal models, the RV changes appear adaptive, not maladaptive. In summary, HPH-induced vascular mechanical changes affect ventricular function but both are adaptive and reversible, which differentiates HPH from severe pulmonary hypertension. The mechanisms of adaptation and reversibility may provide useful insight into therapeutic targets for the clinical disease state.
doi:10.1113/expphysiol.2012.069096
PMCID: PMC3720829  PMID: 23666792
Hypoxia; pulmonary artery; ventricle
23.  Interleukin-4 activates large-conductance, calciumactivated potassium (BKCa) channels in human airway smooth muscle cells 
Experimental physiology  2008;93(7):908-918.
Large-conductance, calcium-activated potassium (BKCa) channels are regulated by voltage and near-membrane calcium concentrations and are determinants of membrane potential and excitability in airway smooth muscle cells. Since the T helper–2 (Th2) cytokine, interleukin (IL)-4, is an important mediator of airway inflammation, we investigated whether IL-4 rapidly regulated BKCa activity in normal airway smooth muscle cells. On-cell voltage clamp recordings were made on subconfluent, cultured human bronchial smooth muscle cells (HBSMC). Interleukin-4 (50 ng ml−1), IL-13 (50 ng ml−1) or histamine (10 μm) was added to the bath during the recordings. Immunofluorescence studies with selective antibodies against the α and β1 subunits of BKCa were also performed. Both approaches demonstrated that HBSMC membranes contained large-conductance channels (>200 pS) with both calcium and voltage sensitivity, all of which is characteristic of the BKCa channel. Histamine caused a rapid increase in channel activity, as expected. A new finding was that perfusion with IL-4 stimulated rapid, large increases in BKCa channel activity (77.2 ± 63.3-fold increase, P < 0.05, n = 18). This large potentiation depended on the presence of external calcium. In contrast, IL-13 (50 ng ml−1) had little effect on BKCa channel activity, but inhibited the effect of IL-4. Thus, HBSMC contain functional BKCa channels whose activity is rapidly potentiated by the cytokine, IL-4, but not by IL-13.These findings are consistent with a model in which IL-4 rapidly increases near-membrane calcium concentrations to regulate BKCa activity.
doi:10.1113/expphysiol.2008.042432
PMCID: PMC4115791  PMID: 18403443
24.  Resolution of hypo-osmotic stress in isolated mouse ventricular myocytes causes sealing of t-tubules 
Experimental physiology  2013;98(7):1164-1177.
It has been recently shown that various stress-inducing manipulations in isolated ventricular myocytes may lead to significant remodeling of t-tubules. Osmotic stress is one of the most common complications in various experimental and clinical settings. Therefore, this study was designed to determine the effects of a physiologically relevant type of osmotic stress, hypo-osmotic challenge, to the integrity of t-tubular system in mouse ventricular myocytes using two approaches: (1) electrophysiological measurements of membrane capacitance and inward rectifier (IK1) tail currents originating from K+ accumulation in t-tubules, and (2) confocal microscopy of fluorescent dextrans trapped in sealed t-tubules. Importantly, we found that removal of 0.6 Na (60% NaCl) hypo-osmotic solution, but not its application to myocytes, led to ~27% reduction in membrane capacitance, ~2.5-fold reduction in the amplitude of IK1 tail current and ~2-fold reduction in so-called IK1 ‘inactivation’ (due to depletion of t-tubular K+) at negative membrane potentials – all data being consistent with significant detubulation. Confocal imaging experiments also demonstrated that extracellularly applied dextrans become trapped in sealed t-tubules only upon removal of hypo-osmotic solutions, i.e. during shrinking phase, but not during initial swelling period. In light of these data, relevant previous studies, including those on EC coupling phenomena during hypo-osmotic stress, may need to be reinterpreted and the experimental design of future experiments should take into account the novel findings.
doi:10.1113/expphysiol.2013.072470
PMCID: PMC3746342  PMID: 23585327
cardiac myocytes; t-tubules; inward rectifier potassium channels
25.  Memory consolidation in humans: new evidence and opportunities 
Experimental Physiology  2014;99(3):471-486.
We are endlessly fascinated by memory; we desire to improve it and fear its loss. While it has long been recognized that brain regions such as the hippocampus are vital for supporting memories of our past experiences (autobiographical memories), we still lack fundamental knowledge about the mechanisms involved. This is because the study of specific neural signatures of autobiographical memories in vivo in humans presents a significant challenge. However, recent developments in high-resolution structural and functional magnetic resonance imaging coupled with advanced analytical methods now permit access to the neural substrates of memory representations that has hitherto been precluded in humans. Here, I describe how the application of ‘decoding’ techniques to brain-imaging data is beginning to disclose how individual autobiographical memory representations evolve over time, deepening our understanding of systems-level consolidation. In particular, this prompts new questions about the roles of the hippocampus and ventromedial prefrontal cortex and offers new opportunities to interrogate the elusive memory trace that has for so long confounded neuroscientists.
doi:10.1113/expphysiol.2013.072157
PMCID: PMC4015368  PMID: 24414174

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