The Journal of Physiology最新文献

{"title":"The switch: the role of glucocorticoids during fetal cardiomyocyte energy metabolism.","authors":"Evani Patel, Ishita Patel","doi":"10.1113/JP282699","DOIUrl":"https://doi.org/10.1113/JP282699","url":null,"abstract":"Glucocorticoids play a crucial role in the maturation of foetal organs during pregnancy, as well as the preparation of extrauterine life and increased energy demands upon removal of the nutrient-rich placenta following birth. The administration of synthetic glucocorticoids, as either Celestone, a formulation of betamethasone acetate with betamethasone phosphate, or solely betamethasone acetate, is routine in many countries (Agnew et al. 2018). The benefits of antenatal corticosteroid treatment are vast, one of which is its ability to help with the maturation of fetal lung tissue and prevent neonatal respiratory distress syndrome in preterm babies (McGoldrick et al. 2020). Endogenously, glucocorticoids are associated with the development of the heart (Hillman et al. 2012). Cardiomyocytes undergo terminal differentiation during pregnancy, including changes to mitochondria, energy metabolism, calcium-handling, and more. Abundant literature exists on the effects of glucocorticoids on cardiomyocytes perinatally, but the direct effects of glucocorticoids, through the glucocorticoid receptor (GR), are not as well established. Furthermore, the role of synthetic glucocorticoids on thematuration of cardiomyocytes during different stages of gestation is also unknown. Elucidating the differences between endogenous and exogenous glucocorticoid administration can help clarify relationships between cardiac pathology and steroidogenesis and also provide a basis for future interventions to minimize the risk of developing cardiovascular disease, which may be influenced by synthetic glucocorticoid administration perinatally. Current research by Ivy et al. (2021), recently published in The Journal of Physiology, shows the impact of glucocorticoids on cardiomyocytes, specifically by looking at its effects on energy metabolism. This study follows a trifold experimental method to observe the effects of glucocorticoids on various levels of tissue: fetal cardiomyocytes with dexamethasone treatment depicting endogenous effects, neonatal mice with dexamethasone treatment to observe postnatal changes after birth, and pregnant dams with dexamethasone treatment to depict late-gestation effects of exogenous corticosteroids. A translational lamb model was also established to mimic the effects of synthetic corticosteroid injections.","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1291-1293"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39895773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How do Kir3.4 mutations cause hereditary hyperaldosteronism?","authors":"Yoshihiro Kubo","doi":"10.1113/JP282777","DOIUrl":"https://doi.org/10.1113/JP282777","url":null,"abstract":"The inward rectifier K+ channel subfamily (Kir) consists of seven channels (Kir1–7). Genetic mutations of Kir channels are known to induce hereditary diseases, such as Bartter syndrome (Kir1.1), Anderson syndrome (Kir2.1) and familial hypoglycaemia (Kir6.2). Kir3 is a G-protein coupled inward rectifier K+ channel which is activated by the Gβγ subunit released in response to the stimulation of Gi/o-coupled receptors. It is known to play physiological roles in various cells such as neuronal cells, cardiac muscle cells and adrenal cortex endocrine cells. Some hereditary diseases are also kinked to Kir3 channels. Mutations of Kir3.2 in the ion selectivity filter or in the pore helix are known to cause Keppen-Lubinsky syndrome (Masotti et al. 2015), and those of Kir3.4 (GIRK4) are reported to induce adrenal aldosterone producing adenoma and hyperaldosteronism (Choi et al. 2011). K+ channelsmaintain the resting potential and contribute to the repolarizing phase of the action potential. Hyperaldosteronism can be caused by the hyper-excitability of aldosterone secreting cells in adrenal cortex endocrine cells. How can this hyper-excitability be caused by an abnormality of Kir3.4? One possibility is loss of ion selectivity. If Kir3.4 also allows permeation of Na+, the resting potential cannot be maintained, and Ca2+ influx could evoke hormonal secretion. Another possibility is loss-of-function. If Kir3.4 currents are decreased, the resting potential cannot be maintained. The pathophysiological mechanisms arising from these mutations have not been solved conclusively. They may be, at least partly, due to variation of the induced abnormality depending on the position of the mutation. In this issue of The Journal of Physiology, Shalomov et al. (2022) revisited the pathophysiological mechanisms by intensively characterizing the Kir3.4 mutants. Choi et al. (2011) analyzed the ion selectivity of Kir3.1/Kir3.4 (wt or G151R or L168R or T158A) expressed in HEK293T cells, and beautifully showed that all these mutants allow Na+ to permeate as well. They discussed the loss of K+ selectivity induced depolarization and Ca2+ influx, which caused constitutive aldosterone production and cell proliferation. G151 is located in the selectivity filter, while L168 is in the pore helix behind the selectivity filter and T158 is in the extracellular loop just above the selectivity filter. Considering the location of these amino acid residues, an abnormality due to loss of ion selectivity is both understandable and acceptable. Murthy et al. (2014) characterized new disease associated Kir3.4 mutants R52H and E246K in the cytosolic region of Xenopus oocytes. They showed that the K+ selectivity, rectification and sensitivity to the block by TPN-Q were remarkably reduced. Judging from the position of the mutations, the observed phenotypes were rather unexpected and the mechanism underlying the abnormality remained to be elucidated. Shalomov and co-authors aimed to clarify the pathophy","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1277-1278"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39659947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A revised mechanism of action of hyperaldosteronism-linked mutations in cytosolic domains of GIRK4 (KCNJ5).","authors":"Boris Shalomov, Reem Handklo-Jamal, Haritha P Reddy, Neta Theodor, Amal K Bera, Nathan Dascal","doi":"10.1113/JP282690","DOIUrl":"https://doi.org/10.1113/JP282690","url":null,"abstract":"<p><p>G protein-gated, inwardly rectifying potassium channels (GIRK) mediate inhibitory transmission in brain and heart, and are present in the adrenal cortex. GIRK4 (KCNJ5) subunits are abundant in the heart and adrenal cortex. Multiple mutations of KCNJ5 cause primary aldosteronism (PA). Mutations in the pore region of GIRK4 cause loss of K<sup>+</sup> selectivity, Na<sup>+</sup> influx and depolarization of zona glomerulosa cells followed by hypersecretion of aldosterone. The concept of selectivity loss has been extended to mutations in cytosolic domains of GIRK4 channels, remote from the pore. We expressed aldosteronism-linked GIRK4<sub>R52H</sub> , GIRK4<sub>E246K</sub> and GIRK4<sub>G247R</sub> mutants in Xenopus oocytes. Whole-cell currents of heterotetrameric GIRK1/4<sub>R52H</sub> and GIRK1/4<sub>E246K</sub> channels were greatly reduced compared with GIRK1/4<sub>WT</sub> . Nevertheless, all heterotetrameric mutants retained full K<sup>+</sup> selectivity and inward rectification. When expressed as homotetramers, only GIRK4<sub>WT</sub> , but none of the mutants, produced whole-cell currents. Confocal imaging, single-channel and Förster Resonance Energy Transfer (FRET) analyses showed: (1) reduction of membrane abundance of all mutated channels, especially as homotetramers, (2) impaired interaction with Gβγ subunits, and (3) reduced open probability of GIRK1/4<sub>R52H</sub> . VU0529331, a GIRK4 opener, activated homotetrameric GIRK4<sub>G247R</sub> channels, but not GIRK4<sub>R52H</sub> or GIRK4<sub>E246K</sub> . In the human adrenocortical carcinoma cell line (HAC15), VU0529331 and overexpression of heterotetrameric GIRK1/4<sub>WT</sub> , but not overexpression of GIRK1/4 mutants, reduced aldosterone secretion. Our results suggest that, contrary to pore mutants of GIRK4, non-pore mutants R52H and E246K mutants are loss-of-function rather than gain-of-function/selectivity-loss mutants. Hence, GIRK4 openers may be a potential course of treatment for patients with cytosolic N- and C-terminal mutations. KEY POINTS: Mutations in GIRK4 (KCNJ5) G protein-gated channels cause primary aldosteronism, a major cause of secondary hypertension. The primary mechanism is believed to be loss of K<sup>+</sup> selectivity. R52H and E246K, aldosteronism-causing mutations in cytosolic N- and C- termini of GIRK4, were reported to cause loss of K<sup>+</sup> selectivity. We show that R52H, E246K and G247R mutations render homotetrameric GIRK channels non-functional. In heterotetrameric context with GIRK1, these mutations impair membrane expression, interaction with Gβγ and open probability, but do not alter K<sup>+</sup> selectivity or inward rectification. In the human aldosterone-secreting cell line, a GIRK4 opener and overexpression of heterotetrameric GIRK1/4<sub>WT</sub> , but not overexpression of GIRK1/4 mutants, reduced aldosterone secretion. Aldosteronism-causing mutations in the cytosolic domain of GIRK4 are loss-of-function mutations rather than g","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1419-1437"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39764573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diet-induced disruption of the olfactory system: not only obesity is to blame.","authors":"Ivan Manzini","doi":"10.1113/JP282622","DOIUrl":"https://doi.org/10.1113/JP282622","url":null,"abstract":"Most animals have an olfactory system (OS) whose anatomy, organization and functioning are remarkably similar. The OS is responsible for the sense of smell, through which animals gather information about the chemical composition of the environment (Manzini et al. 2022). In most species, the sense of smell conveys essential information for finding suitable food, avoiding predators, orienting themselves in space and increasing reproductive success. This also applies to humans, where it is crucial for the enjoyment of food and strongly influences general well-being (Boesveldt & Parma, 2021). The OS also senses and responds to endogenous signals that change depending on the metabolic status. The activation of receptors expressed in cells of the OS by specific hormones and nutritional signalling molecules can influence the functioning of the OS and thus modulate the sense of smell (Fadool & Kolling, 2020). It has long been known that obesity, that is, an excessive body fat accumulation, negatively affects our health and leads to a progressive decline of several organ systems (Tchernof & Després, 2013). More recent studies have linked obesity to cellular and molecular disruption of the OS. It has been reported that obese animals have both a smaller number of olfactory sensory neurons (OSNs) and associated projections to the olfactory bulb (OB), reduced expression of olfactory receptors, lesser amounts of olfactory G-proteins and weaker odorant-induced receptor potentials. On the level of the OB, the first relay centre of the OS, obesity alters the functioning of projection neurons, neurons that transmit olfactory information to higher olfactory centres. Together, this leads to an impaired sense of smell (Fadool & Kolling, 2020). The apparent link between obesity and the alterations of the OS has been challenged by ground-breaking results obtained using transgenic mouse lines. While genetically obese animals that consumed a nutrient-balanced diet retained an intact OS, animals genetically resistant to obesity still exhibited a reduction of OSNs when fed a diet containing a higher amount of fat. These results led to the hypothesis that excess fat in the diet rather than obesity could trigger alterations of the OS (Fadool & Kolling, 2020). In the current issue of The Journal of Physiology, Chelette and coworkers (2022) have examined this hypothesis in detail and provided compelling evidence that excess fat in the diet rather than the development of obesity is the cause for loss of OSNs and associated projections to the OB. To decouple diet-induced obesity from dietary fat consumption, the authors developed a sophisticated pair-feeding method that allowed feeding a moderately high-fat (MHF) diet while keeping the total calories the same as in a nutrient-balanced (but lower fat) control diet. Using this feeding method and a transgenic mouse line in which a specific subpopulation of OSNs can be readily visualized, the authors elegantly demonstrated the follo","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1273-1274"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39799491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correlating genotype with phenotype using CFTR-mediated whole-cell Cl^- currents in human nasal epithelial cells.","authors":"Sabrina Noel,&nbsp;Nathalie Servel,&nbsp;Aurélie Hatton,&nbsp;Anita Golec,&nbsp;Mayuree Rodrat,&nbsp;Demi R S Ng,&nbsp;Hongyu Li,&nbsp;Iwona Pranke,&nbsp;Alexandre Hinzpeter,&nbsp;Aleksander Edelman,&nbsp;David N Sheppard,&nbsp;Isabelle Sermet-Gaudelus","doi":"10.1113/JP282143","DOIUrl":"https://doi.org/10.1113/JP282143","url":null,"abstract":"<p><p>Dysfunction of the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR) causes a wide spectrum of disease, including cystic fibrosis (CF) and CFTR-related diseases (CFTR-RDs). Here, we investigate genotype-phenotype-CFTR function relationships using human nasal epithelial (hNE) cells from a small cohort of non-CF subjects and individuals with CF and CFTR-RDs and genotypes associated with either residual or minimal CFTR function using electrophysiological techniques. Collected hNE cells were either studied directly with the whole-cell patch-clamp technique or grown as primary cultures at an air-liquid interface after conditional reprogramming. The properties of cAMP-activated whole-cell Cl^- currents in freshly isolated hNE cells identified them as CFTR-mediated. Their magnitude varied between hNE cells from individuals within the same genotype and decreased in the rank order: non-CF > CFTR residual function > CFTR minimal function. CFTR-mediated whole-cell Cl^- currents in hNE cells isolated from fully differentiated primary cultures were identical to those in freshly isolated hNE cells in both magnitude and behaviour, demonstrating that conditional reprogramming culture is without effect on CFTR expression and function. For the cohort of subjects studied, CFTR-mediated whole-cell Cl^- currents in hNE cells correlated well with CFTR-mediated transepithelial Cl^- currents measured in vitro with the Ussing chamber technique, but not with those determined in vivo with the nasal potential difference assay. Nevertheless, they did correlate with the sweat Cl^- concentration of study subjects. Thus, this study highlights the complexity of genotype-phenotype-CFTR function relationships, but emphasises the value of conditionally reprogrammed hNE cells in CFTR research and therapeutic testing. KEY POINTS: The genetic disease cystic fibrosis is caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel, which controls anion flow across epithelia lining ducts and tubes in the body. This study investigated CFTR function in nasal epithelial cells from people with cystic fibrosis and CFTR variants with a range of disease severity. CFTR function varied widely in nasal epithelial cells depending on the identity of CFTR variants, but was unaffected by conditional reprogramming culture, a cell culture technique used to grow large numbers of patient-derived cells. Assessment of CFTR function in vitro in nasal epithelial cells and epithelia, and in vivo in the nasal epithelium and sweat gland highlights the complexity of genotype-phenotype-CFTR function relationships.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1515-1531"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39610887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin, Nobel laureates and The Journal of Physiology.","authors":"Bettina Mittendorfer","doi":"10.1113/JP282823","DOIUrl":"https://doi.org/10.1113/JP282823","url":null,"abstract":"The publication of the 600th volume of The Journal of Physiology coincides with the 100th anniversary of the discovery of insulin and offers the Editors an opportunity to highlight The Journal’s important contribution in disseminating critical research findings. In 1921 the surgeon Frederick Grant Banting and the biochemist and physiologist John James Rickard Macleod, with assistance from Charles Best and E. Clark Noble, isolated the ‘internal secretion’ of the pancreatic islets of Langerhans – now known as insulin – with the goal of using it for treating diabetes (Jurdjevic & Tillman, 2004). In 1922, the first patient with diabetes received insulin therapy. Only a year later, in 1923, insulin became commercially available and F. G. Banting and J. J. R. Macleod received the Nobel Prize for Physiology or Medicine for their seminal discovery. The discovery of insulin not only changed the medical care and lives of patients with diabetes but also set off a highly prolific area of research that has remained as exciting today as it was 100 years ago. Many of the very first papers dealing with insulin appeared in The Journal of Physiology and included papers by the Nobel laureates and their team (Forrest et al. 1923; Macleod et al. 1923; Noble &Macleod, 1923; Burn &Dale, 1924; Bainbridge, 1925; Raper & Smith, 1925; King et al. 1928). In total, Macleod and colleagues published 37 of their papers in The Journal of Physiology. Researchers’ interest in insulin has not waned and it is now well established that the effects of insulin reach well beyond its essential role in regulating blood glucose (James et al. 2017; Di Pino & DeFronzo, 2019; Vigneri et al. 2020). In addition, tremendous advances have been made in understanding the regulation of insulin production and secretion from beta-cells and its removal from plasma (Petersen & Shulman, 2018; Campbell & Newgard, 2021; Koh et al. 2022) and The Journal of Physiology has provided an avenue for the dissemination of this important research (e.g. Kosaka, 1933; Himsworth, 1934; Best et al. 1939; Goadby & Richardson, 1940; Best & Haist, 1941; Hinke et al. 2004; Eliasson et al. 2008; Salazar-Petres & Sferruzzi-Perri, 2022). To date, over 900 papers dealing with insulin have been published in The Journal of Physiology. Although, the focus of the research in this area has shifted, and now – driven by the ever expanding knowledge and new technologies – primarily centres on the molecular mechanisms of insulin metabolism and action. In addition, the changing population demographics and lifestyle during the last 100 years has driven the science, and much of today’s research in the area is dedicated to understanding the alterations in insulin metabolism and action associated with ageing, obesity and inactivity. Moving forward, The Journal of Physiology remains committed to publish the most timely research results in this and all other areas of physiology and strives to remain prominent in the dissemination of data that ","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1269-1270"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39845443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Do those with type 1 diabetes need more exercise to maintain skeletal muscle health?","authors":"Thomas J Hawke","doi":"10.1113/JP282800","DOIUrl":"https://doi.org/10.1113/JP282800","url":null,"abstract":"Figure 1. Recent studies have reported that despite similarities in baseline physical activity, those with type 1 diabetes (T1D) exhibit many alterations to skeletal muscle health The latest study by Minnock and colleagues extends the field of work by demonstrating that while exercise training in those with T1D was effective in reducing glycaemic fluctuations and hypoglycaemic events, the degree of improvements in skeletal muscle health metrics is reduced compared to those without the disease. This work highlights the limitations of current exercise guidelines and suggests that future studies are necessary to define the exercise requirements necessary to achieve optimal muscle health and maximize the physical and metabolic capacities of those with T1D. key determinant of whole-body insulin sensitivity. Importantly, these metabolic contributions to whole body health, when dysregulated (dysglycaemia, dyslipidaemia, insulin resistance), have been identified as primary contributors to the development of complications in those with type 1 diabetes (T1D). Thus, it is reasonable to consider that impairments to the health of skeletal muscle would expedite the progression of T1D complications. Moreover, increasing evidence is emerging that skeletal muscle health is a well-established determinant of quality of life and survival (McLeod et al. 2016). Several recent human studies have demonstrated that the skeletal muscles of those with T1D exhibit numerous deficits, relative to matched non-T1D subjects, leading to the proposal that muscles of those with T1D exhibit accelerated ageing. These changes include decreases in strength (Dial et al. 2021), changes in myofibre morphology and size (Dial et al. 2021), impaired mitochondrial function (Monaco et al. 2018, 2021), ultrastructural abnormalities in mitochondria (Monaco et al. 2018), increased mitochondrial ROS emission (Monaco et al. 2018), and alterations to skeletal muscle repair following exercise (Dial et al. 2021). Notably, many of these alterations in muscle health were sexually dimorphic, present across a variety of ages, and evident despite similarities in self-reported physical activity levels with non-T1D matched subjects. Despite the aforementioned differences in muscle health, persons with T1D are able to effectively undertake exercise training. However, what has yet to be fully examined is whether exercise training is capable of eliciting the same skeletal muscle adaptations in those with T1D as it is in their non-T1D matched counterparts. This makes the publication from Minnock and colleagues (2022) in this issue of The Journal of Physiology a valuable contribution to the study of diabetic myopathy and exercise training (Fig. 1). Using males and females with and without T1D, the authors had subjects undertake 12weeks of combined exercise training with preand post-training measurements including systemic measures (body composition, aerobic capacity, muscle strength), glycaemic variability and mu","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1281-1282"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39802216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide.","authors":"Ryan L Hoiland,&nbsp;Hannah G Caldwell,&nbsp;Jay M J R Carr,&nbsp;Connor A Howe,&nbsp;Benjamin S Stacey,&nbsp;Tony Dawkins,&nbsp;Denis J Wakeham,&nbsp;Joshua C Tremblay,&nbsp;Michael M Tymko,&nbsp;Alexander Patrician,&nbsp;Kurt J Smith,&nbsp;Mypinder S Sekhon,&nbsp;David B MacLeod,&nbsp;Daniel J Green,&nbsp;Damian M Bailey,&nbsp;Philip N Ainslie","doi":"10.1113/JP282427","DOIUrl":"https://doi.org/10.1113/JP282427","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Cerebrovascular CO&lt;sub&gt;2&lt;/sub&gt; reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear-mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)-dependency of CVR and cSMD. Eleven volunteers underwent a steady-state CVR test and transient CO&lt;sub&gt;2&lt;/sub&gt; test of cSMD during intravenous infusion of the NO synthase inhibitor N&lt;sup&gt;G&lt;/sup&gt; -monomethyl-l-arginine (l-NMMA) or volume-matched saline (placebo; single-blinded and counter-balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra-arterial blood pressure and &lt;math&gt;&lt;semantics&gt;&lt;msub&gt;&lt;mi&gt;P&lt;/mi&gt;&lt;mrow&gt;&lt;mi&gt;aC&lt;/mi&gt;&lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt;&lt;mn&gt;2&lt;/mn&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;annotation&gt;${P_{{rm{aC}}{{rm{O}}_{rm{2}}}}}$&lt;/annotation&gt;&lt;/semantics&gt;&lt;/math&gt; . Paired arterial and jugular venous blood sampling allowed for the determination of trans-cerebral NO&lt;sub&gt;2&lt;/sub&gt;&lt;sup&gt;-&lt;/sup&gt; exchange (ozone-based chemiluminescence). l-NMMA reduced arterial NO&lt;sub&gt;2&lt;/sub&gt;&lt;sup&gt;-&lt;/sup&gt; by ∼25% versus saline (74.3 ± 39.9 vs. 98.1 ± 34.2 nM; P = 0.03). The steady-state CVR (20.1 ± 11.6 nM/min at baseline vs. 3.2 ± 16.7 nM/min at +9 mmHg &lt;math&gt;&lt;semantics&gt;&lt;msub&gt;&lt;mi&gt;P&lt;/mi&gt;&lt;mrow&gt;&lt;mi&gt;aC&lt;/mi&gt;&lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt;&lt;mn&gt;2&lt;/mn&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;annotation&gt;${P_{{rm{aC}}{{rm{O}}_{rm{2}}}}}$&lt;/annotation&gt;&lt;/semantics&gt;&lt;/math&gt; ; P = 0.017) and transient cSMD tests (3.4 ± 5.9 nM/min at baseline vs. -1.8 ± 8.2 nM/min at 120 s post-CO&lt;sub&gt;2&lt;/sub&gt; ; P = 0.044) shifted trans-cerebral NO&lt;sub&gt;2&lt;/sub&gt;&lt;sup&gt;-&lt;/sup&gt; exchange towards a greater net release (a negative value indicates release). Although this trans-cerebral NO&lt;sub&gt;2&lt;/sub&gt;&lt;sup&gt;-&lt;/sup&gt; release was abolished by l-NMMA, CVR did not differ between the saline and l-NMMA trials (57.2 ± 14.6 vs. 54.1 ± 12.1 ml/min/mmHg; P = 0.49), nor did l-NMMA impact peak internal carotid artery dilatation during the steady-state CVR test (6.2 ± 4.5 vs. 6.2 ± 5.0% dilatation; P = 0.960). However, l-NMMA reduced cSMD by ∼37% compared to saline (2.91 ± 1.38 vs. 4.65 ± 2.50%; P = 0.009). Our findings indicate that NO is not an obligatory regulator of steady-state CVR. Further, our novel transient CO&lt;sub&gt;2&lt;/sub&gt; test of cSMD is largely NO-dependent and provides an in vivo bioassay of NO-mediated cerebrovascular function in humans. KEY POINTS: Emerging evidence indicates that a transient CO&lt;sub&gt;2&lt;/sub&gt; stimulus elicits shear-mediated dilatation of the internal carotid artery, termed cerebral shear-mediated dilatation. Whether or not cerebrovascular reactivity to a steady-state CO&lt;sub&gt;2&lt;/sub&gt; stimulus is NO-dependent remains unclear in humans. During both a steady-state cerebrovascular reactivity test and a transient CO&lt;sub&gt;2&lt;/sub&gt; test of cerebral shear-mediated dilatation, trans-cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non-selective NO synthase ","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1385-1403"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39835633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probing shear-stress-mediated cerebral vasodilatation in humans - it's a NO brainer.","authors":"Jui-Lin Fan,&nbsp;James P Fisher","doi":"10.1113/JP282707","DOIUrl":"https://doi.org/10.1113/JP282707","url":null,"abstract":"The burden of brain diseases (e.g. stroke, dementia, Alzheimer’s disease) is considerable and has grown substantially alongside the increased life expectancy of western industrialised nations. Disrupted cerebrovascular endothelial function contributes significantly to the pathogenesis and neurodegeneration of several of these conditions. The early identification of individuals with or at risk of cerebrovascular impairments, using tests with a robust mechanistic basis, may have clinical utility for guiding interventional strategies, thereby helping to ameliorate disease progression before it becomes firmly established. Some of the earliest measurements of cerebral blood flow in humans quantified the “striking and consistent” steady-state hyperaemic response to the inhalation of carbon dioxide (CO2) (5–7%) (Kety & Schmidt 1948), which is important for pH and thus neuronal homeostasis. Subsequently, the cerebrovascular response to a steady-state CO2 stimulus test has been reported to be diminished in several clinical conditions and has prognostic value (Juttukonda & Donahue 2019). In a recent issue of the Journal of Physiology, Hoiland and colleagues provided important new mechanistic insights into a novel test that potentially provides a targeted assessment of cerebrovascular endothelial function. A transient CO2 stimulus – provided by inspiring a CO2-enriched gas mixture to raise PETCO2 by +9 mmHg for 30 s – evokes an increase in shear stress within the internal carotid artery (ICA) that peaks at ∼20 s after CO2 onset and is followed by ICA vasodilatation at ∼80 s (Hoiland et al. 2017). Since this time course is akin to that observed in other conduit vessels during the flow-mediated dilatation test, the authors discounted any direct actions of CO2 and instead hypothesized that a shear-stress-mediated release of nitric oxide (NO) was responsible for the latent ICA vasodilatation. To explore this possibility, Hoiland et al. (2022) re-evaluated the ICA response to the transient CO2 stimulus both with a saline control and i.v. infusion of the non-selective NO synthase inhibitor, NG-monomethyl-l-arginine (l-NMMA, 5 mg/kg bolus and 50 μg/kg/ min maintenance dose). Notably, l-NMMA abolished the increase in the trans-cerebral release of nitrite (index of NO production) during the transient CO2 stimulus and reduced the increase in ICA vasodilatation (by ∼37%), while shear stress was not different between conditions. Such observations were interpreted as revealing the integral role of shear-stress-mediated endothelial NO release to the cerebrovascular response to a transient CO2 stimulus. In contrast, an NO synthasemechanismwas not observed to be obligatory for the cerebrovascular response to steady-state CO2 stimulus. Indeed, the magnitude of the ICA response, along with that of the vertebral artery (VA) and middle cerebral artery blood velocity (MCAv), to steady-state hypercapnia (5 min at +4.5 and +9 mmHg PaCO2 ) was not different in the l-NMMA and salin","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1283-1284"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39912244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensorimotor integration within the primary motor cortex by selective nerve fascicle stimulation.","authors":"Federico Ranieri, Giovanni Pellegrino, Anna Lisa Ciancio, Gabriella Musumeci, Emiliano Noce, Angelo Insola, Lorenzo Alirio Diaz Balzani, Vincenzo Di Lazzaro, Giovanni Di Pino","doi":"10.1113/JP282259","DOIUrl":"10.1113/JP282259","url":null,"abstract":"<p><p>The integration of sensory inputs in the motor cortex is crucial for dexterous movement. We recently demonstrated that a closed-loop control based on the feedback provided through intraneural multichannel electrodes implanted in the median and ulnar nerves of a participant with upper limb amputation improved manipulation skills and increased prosthesis embodiment. Here we assessed, in the same participant, whether and how selective intraneural sensory stimulation also elicits a measurable cortical activation and affects sensorimotor cortical circuits. After estimating the activation of the primary somatosensory cortex evoked by intraneural stimulation, sensorimotor integration was investigated by testing the inhibition of primary motor cortex (M1) output to transcranial magnetic stimulation, after both intraneural and perineural stimulation. Selective sensory intraneural stimulation evoked a low-amplitude, 16 ms-latency, parietal response in the same area of the earliest component evoked by whole-nerve stimulation, compatible with fast-conducting afferent fibre activation. For the first time, we show that the same intraneural stimulation was also capable of decreasing M1 output, at the same time range of the short-latency afferent inhibition effect of whole-nerve superficial stimulation. The inhibition generated by the stimulation of channels activating only sensory fibres was stronger than that due to intraneural or perineural stimulation of channels activating mixed fibres. We demonstrate in a human subject that the cortical sensorimotor integration inhibiting M1 output previously described after the experimental whole-nerve stimulation is present also with a more ecological selective sensory fibre stimulation. KEY POINTS: Cortical integration of sensory inputs is crucial for dexterous movement. Short-latency somatosensory afferent inhibition of motor cortical output is typically produced by peripheral whole-nerve stimulation. We exploited intraneural multichannel electrodes used to provide sensory feedback for prosthesis control to assess whether and how selective intraneural sensory stimulation affects sensorimotor cortical circuits in humans. Activation of the primary somatosensory cortex (S1) was explored by recording scalp somatosensory evoked potentials. Sensorimotor integration was tested by measuring the inhibitory effect of the afferent stimulation on the output of the primary motor cortex (M1) generated by transcranial magnetic stimulation. We demonstrate in humans that selective intraneural sensory stimulation elicits a measurable activation of S1 and that it inhibits the output of M1 at the same time range of whole-nerve superficial stimulation.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1497-1514"},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/26/49/TJP-600-1497.PMC9305922.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39736378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}