Acta Physiologica Research Articles

Sex related differences in neuromuscular fatiguability between prepubertal children and young adults

Introduction
 Prepubertal children compared to adults manifest neuromuscular differences in a lower voluntary activation and fatigability, as well as a potentially lesser use of larger motor units innervating fast-twitch-fibers (Dotan et al., 2012). While children tend to fatigue more on a central than peripheral level, these trends vary based on exercise modality and muscle group (Ratel et al., 2015; Souron et al., 2022). Furthermore, females incline to fatigue less than males, but research on sex differences in children remains limited (Hunter, 2014). Therefore, the aim of this study was to investigate neuromuscular age and sex differences in a sustained isometric contraction until failure.
 Methods
 16 prepubertal children (9.2 ± 0.9y) and 16 adults (23.4 ± 2.4y; m = f) performed a maximal voluntary isometric contraction (MVCpre), a failure-task at 60%MVCpre, followed by another MVCpost of knee extensors. Surface electromyography for rectus femoris (RF), vastus medialis (VM), and vastus lateralis muscles (VL) was analysed at 0, 25, 50, 75, and 100% of the individual time to failure (TTF). Linear models and Cohen’s d effect sizes were used to quantify age and sex differences of TTF, MVCpre-post, as well as root mean square (RMS) and median frequency (MDF) of each muscle throughout the fatiguing trial.
 Results
 Trivial differences were observed in TTF across age, sex, and age*sex-interaction (d ≤ 0.78). Children displayed a larger decline in MVCpre-post (d = 1.24), whereas sex and age*sex interactions were minimal (d ≤ 0.63).
 Initially (0% TTF), children had a lower activation in RF, VL and VL (d > 1.32), whereas age-differences across the failure-task were found for RMS VL, MDF RF, VL and VM (d ≥ 0.15), with no prominent sex-differences (d ≤ 0.14). Sex*age-interaction yielded detectable results only in RMS VM (d = -0.36).
 Conclusion
 The lower ability to generate an MVCpost combined with a smaller change in EMG parameters in children could be due to more central rather than peripheral fatigue. This is also supported by the lower initial activation in adults, suggesting that larger, more fatigable motor units are initially preserved, which may not be available in children.
 The small to large effects in neuromuscular fatigability between age and sex groups indicate the need for more in-depth research (tracking of motor units, change of voluntary activation and twitch properties) particularly with regard to sex-related disparities.
 References
 Dotan, R., Mitchell, C., Cohen, R., Klentrou, P., Gabriel, D., & Falk, B. (2012). Child-adult differences in muscle activation—A review. Pediatric Exercise Science, 24(1), 2–21. https://doi.org/10.1123/pes.24.1.2
 Hunter, S. K. (2014). Sex differences in human fatigability: Mechanisms and insight to physiological responses. Acta Physiologica, 210(4), 768–789. https://doi.org/10.1111/apha.12234
 Ratel, S., Kluka, V., Vicencio, S. G., Jegu, A.-G., Cardenoux, C., Morio, C., Coudeyre, E., & Martin, V. (2015). Insights into the mechanisms of neuromuscular fatigue in boys and men. Medicine & Science in Sports & Exercise, 47(11), 2319–2328. https://doi.org/10.1249/MSS.0000000000000697
 Souron, R., Carayol, M., Martin, V., Enzo, P., Duché, P., & Gruet, M. (2022). Differences in time to task failure and fatigability between children and young adults: A systematic review and meta-analysis. Frontiers in Physiology, 13, Article 1026012. https://doi.org/10.3389/fphys.2022.1026012

Electrochemistry of Selected Acetaminophen Derivatives

Acetaminophen (N-(4-hydroxyphenyl)acetamide, APAP) belongs to the most frequently used pharmaceuticals with analgesic and antipyretic effect [1]. The metabolization of APAP via oxidation pathway lead to formation of highly reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI). It immediately reacts with a nucleophile e.g. with glutathione by formation of respective conjugate. The level of such conjugates can be directly linked to the toxicity of APAP in humans.Hence, three derivatives of acetaminophen were synthesized and characterized [2]. In this contribution, we focus on the characterization of redox properties of selected acetaminophen derivatives (see scheme 1) which were studied by means of cyclic voltammetry, rotating-disk voltammetry and UV-VIS absorption spectrometry. The oxidation mechanism was studied in phosphate buffers of different pH as well as in non-aqueous environment of N,N-dimethylformamide The influence of substituents on the electron transfer mechanism was estimated and corresponding rate constants were evaluated. We found that the protonation/deprotonation of acetaminophen derivatives act as a rate determining steps in aqueous media. The obtained electrochemical results were accompanied by chemical ones using reaction of the conjugates with diphenylpicrylhydrazyl (DPPH radical assay) in order to examine their interaction with radical, hence radical scavenging ability. Acknowledgement This work was supported by the Czech Science Foundation (GA19-11867S). References L. O. Boreus, F. Sandberg, Acta physiologica Scandinavica 1953, 28, 261-265.J. Vanova, D. Malinak, R. Andrys, M. Kubat, T. Mikysek, E. Rousarova, K. Musilek, T. Rousar, P. Cesla, J. Chromatogr. A 2022, 1669, 11. Figure 1

Mitochondria – More than just batteries for cellular function

Mitochondria are complex small organelles of eukaryotic cells and build the cellular source of energy. Several morphological features of mitochondria such as the double membrane and the circular DNA structure support the thesis that they originated from a prokaryotic eubacterial ancestor that has been taken up by the eukaryotic cell very early during the eukaryotic evolution. Since this "uptake-event" mitochondria were integrated into cellular processes and regulation which was realized by the transfer of mitochondrial genes into the host cell genome. 1 The mitochondrial genome reduced to for instance 13 encoded protein subunits of the oxidative phosphorylation system in human cells. Mitochondria offer energy for the cell by producing about 95% of cellular ATP.2 Nutrients, mainly pyruvate from the glycolysis enter the tricarboxylic acid cycle and undergo iterative oxidations whereas electrons are transferred to the reduction equivalents NADH and FADH2 . These redox equivalents transport electrons to the electron transport chain located on the inner mitochondrial membrane and protons are pumped into the perimembranal room. The F1 F0 -ATP synthase generates ATP driven by protons flowing down an electrochemical gradient during a process named oxidative phosphorylation. As a byproduct reactive oxygen species are generated. Mitochondria are more than simple batteries for the cell, they are furthermore involved in numerous vital cellular processes, among them are calcium homeostasis, cell death, fatty acid oxidation, reactive oxygen species (ROS) signaling, cholesterol synthesis and nucleotide synthesis, topics that are frequently published in Acta Physiologica.

Acta Physiologica, member of the top 5% club

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Investigating the control of exercise hyperpnoea: A synergy of contributions.

Connections link a sequence of three related research papers. The central article which links the other two papers has been published in Experimental Physiology. In a Connections article, an author (or authors) of the central article outlines its principal novel findings, tracing how they were influenced by the first article and how the central article has contributed to the developments made in the third article. The author(s) may also speculate on the direction of future research in the field. Connections articles aim to set the research in a wide context. Muscular exercise imparts considerable and varying challenges on the human body. We have evolved several rapidly acting control mechanisms that regulate the physiological responses to exercise, with the overall aim of maintaining homeostasis. The characteristic cardiorespiratory response permits an increase in oxygen delivery and carbon dioxide removal from working muscles in proportion to the metabolic demands of the exercise. The control mechanisms that underlie the cardiovascular responses (both central and peripheral haemodynamic) are relatively well understood thanks to an impressive volume of research over the past century and more. In contrast, it has proved a considerable challenge for researchers to unmask the control of the respiratory system (specifically, the hyperpnoea) in exercise. One difficulty for researchers is that ventilation can be regulated voluntarily; hence, the obtrusive and unnatural act of its scientific measurement in a conscious participant, often requiring a mouthpiece and nose clip, can very easily impact the variable of interest. But perhaps the greatest challenge lies in the probable complex nature of its underlying physiological control. Either way, the seeming difficulty in its study might be one reason why the study of exercise ventilatory control has been, in my opinion, less popular than its cardiovascular counterpart; that is, until an apparent resurgence of interest in the 21st century, when research studies (such as recent work from my laboratory, e.g., Lam et al., 2019), have continued to try to shine a light on that mysterious physiological question: how is exercise hyperpnoea controlled? The ventilatory responses associated with exercise occur rapidly and in proportion to metabolic rate, and thereby help to ensure the maintenance of the arterial pH and partial pressures of O2 and CO2. This is a remarkable achievement of the respiratory system considering that its most closely regulated variable (arterial partial pressure of CO2/pH) appears to offer no error signal for arterial or central chemoreceptors to drive reflex hyperpnoea. With this in mind, researchers have focused their attention on other potential blood-borne mechanisms, such as exercise-induced changes in chemoreceptor sensitivity or the effects of other circulating factors (e.g., adrenaline or potassium), and on possible neural mechanisms, such as feedforward control from central command and reflex feedback from thin-fibre skeletal muscle afferents (Bruce et al., 2019). Group III and IV muscle afferent fibres contain metabosensitive and mechanosensitive receptors on their free nerve endings and can provide the CNS with information on the metabolic conditions within working muscle. As a possible control mechanism for the exercise hyperpnoea, this is an attractive theory, because these neural signals might be proportionate to metabolic rate and might account for the immediate elevation in ventilation at exercise onset. Like many others before us, in our recent work (Lam et al., 2019) we used a technique of postexercise circulatory occlusion (PECO) after cycling exercise to isolate the role of muscle metaboreceptive afferents. Here, ischaemia will trap metabolic byproducts in the previously exercised leg muscles and will continue to stimulate muscle metabosensitive receptors (a ‘metaboreflex’). But the cessation of muscle contractions should silence muscle mechanoreceptive afferent feedback and central command mechanisms. In agreement with many other groups, we demonstrated, in young healthy volunteers, that ventilation returns to resting levels during PECO, whereas blood pressure remains elevated until free-flowing conditions return (a ‘pressor reflex’). These findings are consistent with the concept that muscle metaboreceptive afferents are unimportant in exercise ventilatory control but contribute to the normal blood pressure responses associated with exercise (known to be driven via powerful sympathoexcitation). However, in our study we also devised and used a new experimental protocol involving PECO, which took some inspiration from the work of Asmussen and Nielsen (1964). Their study was one of the first attempts to examine the role of skeletal muscle afferent feedback in ventilatory control. These two great scientists used circulatory occlusion of leg muscles during cycling exercise and observed higher elevations of ventilation, heart rate and blood pressure versus free-flowing conditions. These were very encouraging findings, because the authors uncovered a method for trapping the metabolic byproducts of exercise in muscle that amplifies the ventilatory response. However, a limitation of their design was that it was impossible to distinguish whether the elevated cardiorespiratory responses were attributable to: (1) enhanced feedback from muscle metaboreceptors; (2) enhanced feedback from populations of muscle mechanoreceptors whose sensitivity can be enhanced by metabolic stimuli; (3) enhanced central command compensating for the diminished capacity of the ischaemic muscle; or (4) some complex combination. Lam et al. (2019) built upon this concept by designing a procedure to isolate the effects of enhanced metaboreflex activity during exercise. Here, the cardiorespiratory responses to single-legged cycling exercise were recorded with (and without) PECO of the inactive contralateral leg, thereby removing the possible confounding influences of augmented mechanoreceptor feedback or central command. An enhanced exercise hyperpnoea was observed during contralateral leg PECO versus free-flowing conditions, suggesting that muscle metaboreceptive inputs can drive ventilatory responses. These data were consistent with another recent study, in which muscle afferent neurotransmission was inhibited during exercise and resulted in suppression of the cardiorespiratory responses (Amann et al., 2010). Why can opposite conclusions be drawn from experimental procedures that examine the role of muscle afferent feedback during exercise versus after exercise? That is yet to be determined. We do not understand fully how neural projections from muscle afferents are integrated centrally, but it is possible that they require some type of synergistic interaction with other inputs active in exercise, such as central command or feedback from muscle mechanoreceptors or arterial chemoreceptors. This might explain why isolated stimulation (via PECO) results in no ventilatory effect, but enhanced stimulation during normal exercise elevates ventilation. If this were true, and also true of other respiratory control mechanisms, then it might explain why researchers have found it challenging to pinpoint the specific mechanisms underlying exercise hyperpnoea (for further discussion, see Bruce et al., 2019). Asmussen, E., & Nielsen, M. (1964). Experiments on nervous factors controlling respiration and circulation during exercise employing blocking of the blood flow. Acta Physiologica Scandinavica, 60, 103–111. Lam, E., Greenhough, E., Nazari, P., White, M. J., & Bruce, R. M. (2019). Muscle metaboreflex activation increases ventilation and heart rate during dynamic exercise in humans. Experimental Physiology, 104, 1472–1481. Wan, H.-Y., Weavil, J. C., Thurston, T. S., Georgescu, V. P., Hureau, T. J., Bledsoe, A. D., Buys, M. J., Jessop, J. E., Richardson, R. S., & Amann, M. (2020). The exercise pressor reflex and chemoreflex interaction: cardiovascular implications for the exercising human The Journal of Physiology, 598, 2311–2321. Interestingly, in some chronic clinical conditions, such as heart failure, muscle metaboreflex activation alone (e.g., via PECO) can generate ventilatory responses not observed in health and therefore contribute to the hyperventilation and breathlessness associated with the pathology. These findings might suggest some type of abnormality/sensitization in the muscle afferent reflex pathway. However, if synergistic interactions exist between respiratory control inputs, we should not examine the mechanisms in isolation; abnormalities might be reflected in their central integration, and this understanding might lead to new therapies. For example, Machado et al. (2020) assessed the interaction between muscle metaboreflex activation (PECO after cycling exercise) and the carotid chemoreflex in heart failure. They demonstrated a suppressed ventilatory response to PECO during conditions of hyperoxia-induced chemoreceptor inhibition in comparison to conditions of normoxia and tonic chemoreceptor activity. This implies the existence of an interaction between the chemoreflex and metaboreflex that might contribute to the hyperventilation during exercise, and any method of reducing the interaction could, theoretically, lead to tangible benefit for patients. This interesting study (Machado et al., 2020) has continued the recent resurgence of interest in ventilatory control during exercise by examining the possible synergistic interactions between different control pathways. In my opinion, this is a very exciting area of research for both physiologists and clinical scientists. Examination of these types of interactions is no easy task; it will require further novel study designs to isolate carefully and combine different mechanisms and to collect precise measurements; something made ever harder by the inherent variability (noise) in human cardiorespiratory measurement. However, given the wide-ranging implications of the research, I hope that more researchers will contribute and combine ideas (synergistically, no doubt) in this fascinating field.

A further increase in Acta Physiologica’s impact factor

Another good year for Acta Physiologica. Our current impact factor increased to 6.3. Of course, the impact factor is not very useful to measure science performance and flawed in many ways.1, 2 Keeping this in mind, we are proud that, as for the past recent years,3, 4 Acta Physiologica is in the top 10% of the physiology journals. Acta Physiologica is the leading physiology journal to publish original articles covering all physiology disciplines and funding agencies recognize this.5.

Hypertension due to loss of water

In the current issue of Acta Physiologica, two papers are published investigating the development of arterial hypertension under conditions of pathological loss of free water in two disease models. Kovarik et al1 studied rats with chronic renal failure, shedding excessive free water via their remnant kidney due to a hypostenuric concentrating defect. Wild et al2 investigated a transgenic mouse model for psoriasis, losing free water via the psoriatic skin lesions. In both cases the animals displayed hypertension, cutaneous vasoconstriction and metabolic adaptations towards enhanced production of urea and organic osmolytes typical for a phylogenetically ancient water conservation response termed aestivation.3 The international consortia of investigators spearheaded by Titze, Karbach and Kitada therefore conclude that in both cases the hypertension was due to cutaneous vasoconstriction in an attempt to limit epidermal water loss. Because in either case the hypertension was associated with loss of water, and thus with hypovolaemia rather than hypervolaemia, the authors argue that this concept of pathogenesis of hypertension is antipodal to the classic view that relies on hypervolaemia due to sodium retention. Arterial hypertension is a widespread disease affecting more than a billion people worldwide. A thorough understanding of its aetiology would be crucial for developing more efficient and more personalized treatment. However, despite extensive research and debate, the aetiology remains obscure in the vast majority of cases.4 Many concepts for the pathogenesis of hypertension have been formulated, but none so far provides a satisfactory answer.4 The most prominent of these concepts is the one proposed by Borst5 and developed into an elaborate mathematical model by Guyton and Coleman.6 It is based on the interdependency between blood volume and arterial pressure via the augmentation of stroke volume and thus cardiac output with enlarged blood volume (“Frank–Starling relationship”) on the one hand and pressure-induced stimulation of urinary sodium and volume excretion (“pressure natriuresis”) on the other. Due to the accumulating effect of urine production on blood volume and pressure over time, this negative feedback loop is postulated to provide virtually infinite regulatory strength, thus overriding any other nonaccumulating regulatory system.5, 6 Accordingly, hypertension is thought to derive from volume accumulation due to insufficient pressure natriuresis, whether due to intrinsic abnormalities within the kidney or due to erroneous hormonal or sympathetic systemic signals. In this simple form, hypertension should necessarily be associated with hypervolaemia, which, however, is rarely the case. This conundrum is explained by “total body autoregulation”.5-7 This refers to global increase in vascular resistance in response to chronic elevation of arterial pressure. This would cause further elevation of pressure, which would lead to further pressure natriuresis to reduce volume. If total body autoregulation would be perfect, that is, completely restore flow despite elevated pressure, volume excretion will also be complete towards normovolaemia. There is evidence for total body autoregulation, but underlying mechanisms and time course for completion remain unclear.7 Aestivation refers to an adaptive response to arid conditions with restricted availability of food and water.3 Similar mechanisms for hypometabolism found in sponges and nematodes and fossil evidence for protective burrows and chambers give indication for an ancient phylogenetic origin.3 Apart from hypometabolism, a major component of aestivation includes mechanisms for the conservation of water, relying foremost on elevation of body fluid osmolality via urea and organic osmolytes. Urea provides the advantage of moving more freely between intracellular and extracellular compartments than electrolytes. Organic osmolytes, in the form of methylated glycine, such as sarcosine, dimethylglycine and betain, help preserve protein structures and functions despite elevated osmotic pressure. Chronic kidney disease (CKD) is typically associated with hypertension. This is generally assumed to result from impaired pressure natriuresis in the diseased kidneys. However, CKD is also associated with impaired ability for urinary concentration and dilution. If more solute than water compared to plasma osmolality is being ingested, then a commensurate urinary concentration will be required to reach balance of solute and water and maintain isotonicity of body fluids. If this cannot be achieved, then free water will be lost with the urine. Kovarik et al1 studied rats with CKD induced by surgical removal of 5/6 of total kidney tissue 3 weeks prior to analysis. They employed a comprehensive approach investigating fluid and electrolyte homeostasis, total weight, dry weight and water content separately for whole body, skin and skinned carcass, extensive metabolomics of muscle and liver, as well as cutaneous blood flow, blood congestion and transepithelial water loss at different body temperatures. CKD rats indeed developed hypostenuria with reduced urine osmolality, enhanced urine volume, but unaltered rate of solute excretion and unaltered relative contribution of Na+, K+ and urea to total urinary solutes. Plasma osmolality rose by 7 mOsmol/kg, which was due predominantly to urea (78%) with little increase in K+-solutes and unaltered Na+, indicating an active, primarily urea-driven increase in internal osmolality. Even though total body weight was unaltered in CKD rats, total dry weight was smaller than in controls. Absolute total body water was not different between CKD and controls, but due to the reduced dry weight, relative water content was slightly augmented, corresponding to fractional water content in relation to total weight of 68% in CKD versus 66% in controls. The same pattern of loss in solid mass, maintained water mass, but elevated relative water content was found in the skinned carcass, whilst in the skin compartment neither wet nor dry weight nor water content was affected by CKD. The careful analysis is compatible with accumulation of water in the skinned carcass, but not in the skin, although only in relation to the smaller dry weight, not in terms of absolute amount. Interestingly, Na+ and K+ content in relation to dry weight was enhanced in total body and in skin, but not in the skinned carcass, thus suggesting Na+and K+ accumulation in the skin in the CKD animals. The comprehensive metabolomics detected an elevated urea content in the liver, along with augmented activities for malate dehydrogenase 1 (MDH1), aspartate aminotransferase (ASAT) and arginase in the liver. As carefully annotated in the manuscript, MDH1 provides oxaloacetate as the carbonic acid backbone in the transamination catalysed by ASAT to form aspartate. The latter constitutes an essential substrate for the urea cycle for the formation of argininosuccinate and arginine, from which urea is cleaved off by arginase. The constellation of elevated hepatic urea with enhanced activities of MDH1, ASAT and arginase therefore indicates enhanced urea production. Further findings indicated catabolism of the muscular dipeptides anserine and carnosine, thought to serve as storage forms for energy and nitrogen. In contrast, production of methylated glycins sarcosine, dimethylglycine and betaine was found to be enhanced. These compounds constitute organic osmolytes with stabilizing effects on protein structures. Production rates of uric acid and of creatin were diminished, which might save nitrogen for the production of urea. Arterial hypertension was confirmed by state-of-the-art measurements via telemetry in conscious unrestrained animals. Several abnormalities were detected that could lead to elevated vascular resistance: Metabolomics in liver and muscle showed enhanced levels of methylated forms of arginine, that is, symmetric and asymmetric dimethyl-arginine (SDMA and ADMA), which are known inhibitors of nitric oxide synthase (NOS). Increased levels of γ-glutamyl-aminoacids, cysteine-glutathione-disulfide and α-hydroxy-butyrate in CKD rats suggest oxidative stress with endothelial dysfunction. Elevated levels of plasma copeptin indicated increased of vasopressin secretion. Elevated levels of urinary norepinephrine excretion indicated increased sympathetic tone. In a separate protocol, arterial pressure, cutaneous water loss and perfusion were studied in response to increasing body temperature from 35°C to 37°C. Arterial pressure was elevated in CKD rats at 35°C and 36°C but fell to the control level at 37°C. Skin blood congestion and transepithelial water loss tended to be lower in CKD at 35°C and showed a stronger increase with temperature than controls, thereby reaching the control level at 37°C. From these results the authors derived their intriguing concept that hypertension in CKD is caused by cutaneous vasoconstriction in an attempt to limit transepithelial water loss across the skin and that this conservation strategy is reprioritized in favour of cutaneous vasodilation at higher temperatures to improve thermoregulation at the expense of more transepithelial evaporation. Although 37°C is not quite hyperthermic, it is well possible that thermoregulation was slightly shifted under the employed anesthesia. The hypertension measured by telemetry in the conscious state, presumably at 37°C, gives credence to this interpretation. It is also noteworthy that estimated cutaneous blood flow was not different from controls in CKD. Nonetheless, since AP was elevated, unaltered blood flow does indicate vasoconstriction, and alteration of blood congestion alone would still be sufficient to modulate heat dissipation and transepithelial water loss. Overall, this comprehensive analysis provides intriguing and consistent indication for an aestivation-like response in CKD due to hypostenuric water loss, with metabolic adaptation towards enhanced urea production, with muscle catabolism and with cutaneous vasoconstriction for water conservation and subsequent hypertension. This provides a unifying explanation for the hypertension as well as for the muscle wasting phenotype in CKD. It might also impact on blood urea nitrogen (BUN) as compared to creatinine as a clinical marker for CKD. However, the findings do not exclude the concept of Borst and Guyton as pathogenetic cause. The absence of overt hypervolaemia at the end of the experiment does not exclude that in addition to hypostenuric loss of water, the CKD animals might initially have retained sodium and isotonic fluid in terms of hypertonic hyperhydration, which might subsequently have transformed via total body autoregulation into the final hypertonic normo- or hyperhydration. Both aestivation and pressure natriuresis might well coexist in CKD. The amount of water lost from hypostenuria will increase the greater the amount of ingested solutes versus water. The contribution of a tentative aestivation versus natriuresis component to CKD-induced hypertension might therefore increase with higher ratio of salt to water intake and minimize for isotonic intake. Wild et al2 studied a mouse model of psoriasis from transgenic overexpression of interleukin 17A in keratinocytes. As expected, transepithelial water loss was markedly enhanced in psoriatic skin patches, whilst in unaffected areas water loss was even lower than in healthy skin of control animals, but overall, psoriatic animals suffered from severe cutaneous water loss. Accordingly, water intake was augmented, urine output reduced and urine osmolality enhanced. In the kidney, expression of urea transporter UTA1, aquaporin 2 and TonEBP increased, which is typical for any kind of water conservation. Interestingly, a very similar expression pattern occurred in the skin with increased levels of UTA1, aquaporin 3 and TonEBP. This indicates that similar urea- and aquaporine-driven water conservation regimes might be at work the skin as in the renal medulla, both of which comprise countercurrent arrangement of blood vessels. Although several points remain open regarding the skin, such as the exact arrangement of the countercurrent system, the nature of the active driving force for concentration and the localization of sodium gradients in the avascular epidermis or in the dermis with countercurrent vasculature, the similarity of the expression patterns during water conservation is intriguing. Weight analysis showed substantially smaller body weight and gastrocnemius muscle mass in psoriatic mice, which was more pronounced in dry weight than in water content, so that relative water content per body weight was 70% in psoriatic versus 66% in wildtype mice. Metabolomics indicated adaptation towards urea production with increased activities for MDH1, ASAT, and Arginase. In addition, relative liver mass was substantially larger by 50% in psoriatic mice. Skin blood flow of hind-paws was lower than in controls at 36°C but increased more extensively with elevation of body temperature, so that blood flows reached the same level in both genotypes at 40°C. At the same time, arterial pressure was higher in psoriatic mice at 36°C but fell with rising temperature, so that it reached the wildtype level at 40°C. Transepithelial water loss of unaffected skin patches was similar to wildtypes at 36°C but increased more steeply to reach significantly higher values at 40°C. These data are well in line with the concept that the loss of free water leads to hypertension due to an aestivation response that included cutaneous vasoconstriction. Because in the case of psoriasis, the disturbance affects extrarenal loss of water, with no apparent reason for a shift in pressure natriuresis, hypertensive pathogenesis is indeed more easily explained by an aestivation response with cutaneous vasoconstriction than by the concept of Borst and Guyton. Taken together, the two manuscripts provide comprehensive evidence for an intriguing new pathogenetic model for hypertension induced by loss of free water mediated by an aestivation response with cutaneous vasoconstriction. Although neither of the experimental setups are suitable to reject the pressure natriuresis concept of hypertension, the aestivation concept provides a more simple explanation in these two examples, particularly in the case of psoriasis. Aestivation-like responses have also been reported by the same authors in response to high salt intake8 and will probably be found under more circumstances in the future. The author declares no conflict of interest.

Non‐enzymatic function of prostasin and sodium balance

Prostasin is a serine protease with a simple structure: a serine protease domain attached to the cell surface via a C-terminal glycosylphosphatidylinositol (GPI) anchor. Several physiological processes require membrane-attached prostasin, but, surprisingly, without its protease activity. In the current issue of Acta Physiologica, Essigke and colleagues 1 suggest that this is also the case for prostasin's activation of the epithelial Na+ channel ENaC in the kidney.

Physiological Societies Across the Globe Unite in an Effort to Handle the COVID-19 Pandemic

EditorialPhysiological Societies Across the Globe Unite in an Effort to Handle the COVID-19 PandemicSusan M. Barman, László Csernoch, and Jayasree SenguptaSusan M. BarmanMichigan State University, East Lansing, MichiganSearch for more papers by this authorVice Chair, Board of the General Assembly, László CsernochUniversity of Debrecen, Debrecen, HungarySearch for more papers by this authorMember, Board of the General Assembly, and Jayasree SenguptaRetired, All India Institute of Medical Sciences, New Delhi, IndiaSearch for more papers by this authorChair, Board of the General AssemblyPublished Online:17 Feb 2021https://doi.org/10.1152/physiol.00001.2021MoreSectionsPDF (86 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat The year 2020 will forever be cast in a negative light because of the coronavirus infectious disease (COVID-19) pandemic that changed everyday life globally, with nearly 220 countries and territories experiencing its devastating impact. As 2020 came to an end, based on the data supplied by the World Health Organization, the novel coronavirus had infected over 81 million people worldwide and nearly 1.8 million people had died because of complications of COVID-19 (1). These numbers continue to grow at alarming rates. Whole countries or states across the globe have enacted rules designed to limit the spread of the virus by requiring inhabitants to stay home and adhere to social distancing; nonessential businesses have closed their doors, including restaurants, theaters, performing arts centers, barber shops, health clubs, and even churches. In many cases, schools have changed to online learning or at least markedly limited face-to-face activities; many youth, college, and professional sporting events have been canceled; and national and international travel has been curtailed. In many places, science laboratories were shuttered for months. The changes in life precipitated by COVID-19 have the potential to change human behavior forever and have certainly changed the everyday life of biomedical researchers and educators (2).Despite the global anxiety posed by the novel coronavirus, a bright spot is how it brought together teams of scientists across the globe who cooperated to develop treatments that hopefully will help to bring an end to fatalities linked to the pandemic (3). Remarkably, by the time 2020 came to an end, several manufacturers (Pfizer-BioNTech, Moderna) had begun to release vaccines in multiple countries with high efficacy to control the devastating actions of the virus that causes COVID-19 (4). In fact, there are over 50 candidate vaccines under development globally, allowing us to see at least a glimpse of that proverbial “light at the end of the tunnel.”In late summer 2020, the Board of the General Assembly of the International Union of Physiological Sciences (BGA/IUPS) reached out to member societies to gather information on the impact of the COVID-19 pandemic on their society operations and the activities of their members. Feedback was received from 25 physiological societies representing Africa, the Americas, Asia, Europe/European Union, the Mideast, and Oceania. Table 1 and Table 2 capture the responses received to two pointed questions, respectively:Table 1. How has COVID-19 impacted the functioning of your Society?Member OrganizationResponseAmerican Physiological SocietyThe most obvious functional impact was the almost complete shutdown of our main headquarters in Rockville, MD for several months. The entire operation was transformed into a virtual effort; this is ongoing. We anticipate that a large part of the operation will continue in virtual mode into 2021. Some of our colleagues will continue working remotely for the foreseeable future. A survey revealed that a large percentage of staff find they can work efficiently from home, and our significant achievements during the pandemic have confirmed that this is the case. The absence of major commuting time for many staff residing in the Washington DC area has played a major role in this increase in efficiency, a positive impact of the pandemic.From a member point of view, we have achieved, and in many cases exceeded, the goals laid out in our last strategic plan, despite the pandemic. Interactions with member leaders on APS council, committees, in the sections, and in publications areas have continued with little disruption.The pandemic has also pushed APS more quickly than anticipated into the virtual meetings arena. In the past few months, we have hosted highly successful scientific and education meetings, webinars, town halls, and career development programs in which thousands of members have participated—many more, in fact, than for the equivalent live sessions at face-to-face meetings. The cancellation of our major meeting of the year at Experimental Biology (EB) was a difficult decision made in the early stages of the pandemic, in January, but turned out to be wise and necessary in retrospect. While the time frame of this decision did not allow us to replace EB fully in April 2020, we did organize a limited number of sessions online that were very well attended and received by our members. The 2021 EB meeting is also virtual, but the long lead-up time has allowed us to organize a more complete virtual meeting, using a professional online platform, with the other contributing societies that normally participate in EB.One positive effect of the new virtual life of APS is that we can serve our international members more effectively. Since our leadership meetings are virtual, it is now possible to envisage increasing the international representation in these efforts by, among other considerations, carefully taking account of geographic diversity and international time zones during the organization process.Another positive effect of the pandemic is that potential budget shortfalls (e.g., reduced journal subscription revenue, reduced meeting registration income) have been to some extent balanced by a large reduction in travel and associated costs normally expended to assemble committee members and leaders for a variety of meetings. It is likely that reduced travel expenses will be a permanent feature of our budgeting even when we move out of pandemic mode.Australian Physiological SocietyThe major impact has been the cancellation of our major events such as the 2020 Annual Scientific Meeting and our PhD research training award (a 2-day onsite research training event). This has deprived all our members of valuable opportunities to present their research and to network.Council has continued to function mostly unhindered, with twice-yearly Council meetings being moved from in-person to online.Our Annual General Meeting of all members is this year planned to be held online.Bangladesh Society of PhysiologistsLike other organizations, in this pandemic-induced lockdown, the Society activities are affected. Seminars and the meeting of the Society have been postponed.Very limited conversation regarding society activities has been made over the telephone as all the senior members are forced to stay home for health risk.By arranging Zoom meetings, efforts for regular meetings of the Society have been made to maintain the activity in a very limited scale.Despite this adverse situation, the Society successfully published its journal within the stipulated time.Bulgarian Society for Physiological SciencesSociety members write and publish articles how to fight the still ongoing COVID-19 pandemic such as the recently published review, “Emerging Neurological and Psychobiological Aspects of COVID-19 Infection” in Brain Sciences 2020, vol. 10, issue 11, 852, doi:10.3390/brainsci10110852.For the 3rd Conference “Neurosciences—from Theory to Experiment and Practice,” held in the University Campus Bachinovo of South-West University in Blagoevgrad, Bulgaria 23–25 October 2020, all participating physiologists dedicated a special meeting discussing the challenges of COVID-19 pandemic and how to counteract it.Canadian Physiological SocietyWe held our first official Society symposium in May 2019 after 7–8 yr without having a meeting. We hoped to continue with this by hosting another symposium in May 2020, but this had to be cancelled due to lockdowns in Canada.Overall, the main objective of the Society has been to work towards re-energizing a national community for physiology, with a focus on sponsoring trainee activities.Our primary planning activities have been to look ahead towards late 2021, when we hope we can continue with symposium organization and other trainee activities.Chilean Society of Physiological SciencesThe Society’s annual meeting was cancelled, but we managed to run the 2020 annual meeting in a virtual form. This activity has been very well valued.To open our region to Latin America researchers in physiology, we decided to have our 2020 annual meeting as a joint meeting with the Latin American Association of Physiological Sciences. We had more than 650 registered scientists for the meeting. This collaborative activity was a perfect platform for young researchers to show their data and establish new contacts with not only physiologists from LA but from all continents.Since March, the monthly meetings of the directory board of the Society have been virtual meetings, and the Society operations were unaltered. Our general feeling is that it was helpful to meet without the typical problems finding a suitable place and time to meet.The Society organizes regular selected seminars that have been cancelled since March. Mainly because we, as researchers and teachers, were involved in a new way to conduct these two activities virtually. This is a major weakness since there was not an option for interacting and establishing networks by meeting, talking, and discussing with the speaker.Chinese Association for Physiological SciencesThe COVID-19 had quite a negative impact on the routine operation of our Society in the beginning. Luckily, we transformed and advanced the management in terms of the operation. For instance, we have adopted the online application system for the review and approval of all the documents.The Zoom Cloud Meetings system has been used for our online meetings weekly so that all our directors and colleagues could easily communicate with each other, especially during the COVID-19 period.Chinese Physiological Society in TaipeiThe election of new Society council members was conducted through voting by post instead of our usual vote in-person due to the cancellation of our annual joint conference with other societies in March.Our council meeting was also conducted through web meeting to avoid gathering.Although the large-scale joint conference in Taipei was cancelled in March, another scientific meeting and teaching workshop hosted by the Society took place for our members in August 2020.We are watching closely with strict precautions to adjust the schedule for our council meetings in 2020/2021.Overall, the Society has functioned regularly with minimal obstacles due to COVID-19.Cuban Society of Biomedical Basic Sciences (formerly Cuban Society of Physiological Sciences)The Society had to respond and adapt to the COVID-19 pandemic and its impact on academic and clinical instruction. Most of the preclinical conferences and scientific meetings were substituted by “online” activities.Revista Cubana de Investigaciones Biomédicas continues its work as usual. The editorial staff works at home to produce the journal that is now first among the Cuban scientific journals according to the last Scimago Journal Rank and is third among the Cuban journals in Google Scholar because of the number of received citations.Finnish Physiological SocietyIn Finland, emergency conditions were declared due to the COVID-19 pandemic in March 2020. This meant the closure of the Society, travel bans, and isolation.The Society had to hold its annual meeting on short notice as a remote meeting. To guarantee its legitimacy, the Governmental umbrella organizations of the scientific societies quickly made the necessary changes to the rules.The Society changed its scholarship policy so that instead of congress trips, scholarships were also awarded for other purposes.Grants to be used in 2020 were transferred for use in 2021 without a separate application. The Society moved to continuous application policy instead of fixed dates.French Society of PhysiologyCOVID-19 impacted our Society at the organizational level. However, we have overcome this unprecedented situation. We have organized the meetings of Scientific and Administrative Councils via Zoom.We are going to organize, via internet call system, the annual General meeting. As is the case for most of the national and international Congresses, we postponed the annual Congress of the Society that was scheduled for June 2020.German Physiological SocietyAll meetings in 2020 (i.e., Europhysiology2020 and the annual meeting of the young physiologists) were cancelled.All society board meetings were transformed to online meetings.We plan online meetings for young physiologists, the general assembly of our society, as well as “a day of physiology” covering research aspects for October 2020.Iranian Society of Physiology and PharmacologySince starting the COVID-19 pandemic, we increased our communications with the members in virtual space through websites, channels, e-mails, etc. to share information and new findings.The Society has encouraged physiologists and pharmacologists to design research projects about COVID-19, especially on the virus deleterious effects on the body physiology and potential treatments.We have also published a weekly newsletter to provide an overview of the COVID-19 situation in Iran and the world with the latest scientific news.Israel Society of Physiology and PharmacologyWe had to cancel a big meeting, and we are unsure if we can conduct our annual meeting.Life Science Switzerland (LS2)-PhysiologyWe had to adapt quickly to the pandemic situation and to cope with the COVID-19 crisis.We could not have our annual meeting on-site as planned, but we updated the program to offer an online version and to include extra short talks to increase the knowledge exchange among participants: https://meetings.ls2.ch/physiology2020.Physiological Society of IndiaThe Society organized the following five national webinar-based awareness programs against the ongoing COVID-19 pandemic:Dept. of Sports Science, University of Calcutta; 21 August 2020 via Stream Yard and YouTube; Effect of Yoga in Sports Performance during COVID-19Dept. of Physiology, Midnapur College (Autonomous), Midnapore, West Bengal organized 1-day program; 29 August 2020; Development & Maintenance of Physical & Mental Wellness during COVID-19 PandemicDept. of Sports Science, University of Calcutta; Application of Biomechanics in Sports Performance—A COVID-19 PerspectiveDept. of Sports Science, University of Calcutta; 20 September 2020; Exercise Program and Nutritional Supplement to prevent COVID-19 and other viral infectionsDept. of Physiology, Berhampur Girls’ College, Berhampur, Murshidabad, West Bengal; 25–27 September 2020; Three-Day National Webinar on COVID-19: Fighting Together and Moving ForwardPhysiological Society of JapanThe 97th Society Annual Meeting was Mar 17–19, 2020; the outbreak of COVID-19 occurred at the final stage of the meeting preparation. The meeting presidents made a courageous decision at the last minute to give up the on-site meeting, and to hold only in the presentation abstract issue of the official society journal, The Journal of Physiological Sciences. The council meeting and the general assembly were held in a hybrid style of on-site and online.The 98th Annual Meeting is scheduled for Mar 28–30, 2021. In Oct 2020, the meeting presidents decided to hold the meeting online.Physiological Society of NepalThe biggest impact of the COVID-19 on the Society and our members is the financial aspect. All our members are employed as physiology teachers in various medical colleges in the country. With the closure, the colleges adopted a “no work no pay” policy for the first few months. However, lately, most colleges have started to give salaries, but heavily reduced.The theory classes of the undergraduate courses are being conducted online. Some brief orientation and training were conducted to familiarize teachers to such methods.Because travel and movements are restricted, our members have been mostly confined to home. Research labs and works have stopped altogether.Our Society’s regular meetings are on hold, and previously planned symposia, conference have been postponed indefinitely.Physiological Society of NigeriaOrdinarily, the Society Annual Scientific Conference and Annual General Meeting occur between the months of August and September. Due to the COVID-19 pandemic, we had to postpone the conference to next year, when it is hoped the situation will be better. The Society is considering the possibility of hosting the AGM through an online mode.In the last 6 mo, higher institutions have been closed. Members of the Society have had to work from home, and this has affected negatively teaching and research.Physiological Society of New ZealandOur major activity is to run our annual meeting, which is part of a larger professional society meeting called MedSciNZ. This year’s meeting was cancelled, but we held a virtual meeting which was transformed into an awards symposium that was held over 2 half days. This symposium was formatted to allow us to present our student, emerging researcher, and early career researcher awards, plus our triannual medal for excellence in physiological research that is awarded to an established physiologist.We have resorted to running the Society via virtual Council meetings and have a virtual Annual General Meeting scheduled for mid-October.Slovak Physiological SocietyFortunately, we just managed to organize the annual meeting of the Society in February 2020 before the pandemic strike.Other smaller events with participation of our Society had to be cancelled.Committee meetings and correspondence (e.g., evaluation of the best posters at the annual meeting and the best publication 2019 of the Society members) are done electronically.Slovenian Physiological SocietyDespite the COVID-19 crises, the Society is active. We have organized in September a general assembly meeting via the videoconference Cisco Webex platform.On 10 December 2020 we are organizing the annual society meeting.The Day of Physiology 2020, which takes place each year on the day the Nobel Prize in Physiology or Medicine is awarded. We will have lectures and workshops for the general public, biology teachers, students, members of the Society, etc. on physiology of inflammation, with the focus on hepatitis C and SARS-CoV-2 virus physiology and the COVID-19 pandemic. The meeting will take place via videoconference using the Zoom platform.Spanish Society of Physiological SciencesDue to COVID-19 the biannual meeting of our Society, planned to be held at Badajoz in October 2020, had to be suspended, and has been postponed until 2022.Payment for 2020 memberships was suspended this year.The Physiological SocietyWe established a COVID-19 Advisory Panel to provide an evolving understanding of the physiological and pathophysiological mechanisms underpinning this disease with the aim of enhancing patient outcomes. They addressed questions from clinicians during the summer.Through social media, video, and our media work, we have a page hosting our coronavirus-related content including explainer videos, blogs, and our in-house podcast. We highlighted the work of our members in tackling the COVID-19 pandemic to the government and organizations such as Public Health England. (Information can be found at https://www.physoc.org/covid19/)Online training courses (using videos and e-learning platforms) and guidance on providing a supportive environment for the management of stressWe have provided financial aid to members in the most difficult of financial situations—including those resulting from COVID-19.We have run two professional development webinar series for members, bringing together expertise from across the physiological sciences, from both an academic and career perspective, to give advice and tips on areas such as publishing, social media engagement and improving resilience.The Journal of Physiology Virtual Journal Club is a platform for physiologists to meet on a regular basis to discuss papers that have been published in the journal.The Journal of Physiology and Experimental Physiology are committed to making all potentially relevant research papers free to access.We launched a report recommending that the Government initiate a “National Covid-19 Resilience Programme” to bring together a package of measures to support older people through the lockdown and beyond, keeping them healthy and resilient over the winter. (Information can be found at https://www.physoc.org/policy/covid19resilience/)Turkish Association of Physiological SciencesWe were thoroughly affected by COVID-19. We could not organize the National Physiology Congress and other meetings.The Society managed to publish a Human Physiology Textbook; members of the Society broadly contributed to writing the chapters.Table 2. How has your Society assisted its members to deal with the impact of COVID-19 on their teaching and research?Member OrganizationResponseAmerican Physiological SocietyAs part of our information blitz, the September issue of The Physiologist was dedicated to the COVID-19 pandemic. We published articles on maintaining a sense of community during the pandemic, an interview with a member including how the pandemic has affected her research, two articles about the physiology of the SARS-Cov-2 virus and infection, and an article about efforts being made on the prevention and treatment of COVID-19.We provided a discussion forum, inviting APS members to share their experiences via e-mail ([email protected]org) and by Twitter. We published a selection of these comments in the September issue of The Physiologist.We transformed a section of our website into a COVID-19 resource center that collects and displays relevant scientific literature, information, and news related to the pandemic. The information section contains helpful hints and tips on pandemic-induced changes in work style and career development, such as video interviewing, connecting with co-workers during the pandemic, and how to get promoted when you are working from home. It also provides information on getting involved as a volunteer to help society and science in various ways during the pandemic, up to and including being a vaccine volunteer. https://www.physiology.org/career/teaching-learning-resources/covid-19-resources?SSO=YWe have moved much of our operation to virtual, allowing members to participate in a variety of activities during the pandemic—ranging from scientific meetings and webinars to career development programs and routine operational meetings such as sectional committees, working groups, and task forces.Through the Women in Physiology committee, we introduced a “dependent care” grant program to provide financial support to those who need help while they attend virtual events online.We have an ongoing survey of our members asking how the pandemic has affected their research and educational activities. It has not yet been completed and analyzed.Australian Physiological SocietyWe have transitioned to offering online meetings for student and early career members and for physiology educators to present their research.We increased the monetary value of our PhD grant scheme to assist some of our best student researchers to conduct their research in the COVID-19 environment.Bangladesh Society of PhysiologistsThe members of the Society are putting hard efforts to continue the academic activity and keep contributions in overcoming the deadly situation of COVID-19.The educationists took initiative to overcome the obstacles and cope with the stalemate situation by applying principles of internet communication network.Digital Bangladesh has used the digital method to improve the condition and maintain the communication. The digital platform has been used to run the undergraduate Physiology education system.Animal experiments are running without much hazard, but it is very difficult to enroll patients for study.Physiology postgrad students are involved in serving humanity. Along with their clinical colleagues they are playing an active role in COVID-19 patient management.Bulgarian Society for Physiological SciencesBulgarian physiologists participate in research projects concerning the COVID-19 pandemic such as “Agonists of Angiotensin (1-7)/Mas receptors and mesenchymal stem cells—innovative strategies for the treatment of COVID-19 in an experimental model of pulmonary fibrosis in vivo” and “Development of therapeutics for treatment of coronavirus infection and vaccines for prevention of SARS-CoV2 infection, proven in in vivo models”An awareness campaign from Bulgarian physiologists on what a COVID-19 pandemic is and how to prevent it is going on. Special thanks to Professor Radostina Alexandrova, a member of the Society, for her devoted and frequent interviews on TV and radio stations about the COVID-19 pandemic and how to curb it.Chilean Society of Physiological SciencesWe encourage ourselves to run the annual meeting anyway in a virtual mode. This is something that helped our members to show their data.The Society asked for contributions to all members with informative capsules (i.e., shot videos or abstracts) addressing several aspects of the pandemic. We had a good collaboration from members and released seven informative capsules in text and other several lectures regarding this aspect on the web.Several members did not have the option to be in their labs for the last 9 mo. Therefore, many students (under- and postgraduates) starting their research projects were unable to get enough data to communicate at the annual meeting of the Society. We therefore opened the possibility for them to present at the meeting under the concept of “hypothesis.” This was a way for them to show their research ideas and future projects.Members organized several online activities; they asked for sponsorship from the Society. We helped by promoting it as much as possible on the web page and SM applications.Teaching has been transformed with the pandemic. The Society encourages its members to adjust to the new way to teach. The suggestion to the members has been short and informative lectures (10–12 min), discussion with students (10 min), time free between lectures (10–20 min), and, where possible, evaluation as a group of the raised questions or commentaries. This was applied in the recent 2020 annual meeting of the Society and was well received by attendees.Chinese Association for Physiological SciencesWe have been trying our best to assist our members in facing the impact of COVID-19 on their teaching, to integrate more educational resources for their learning, and to create more opportunities for their research.For promoting best standards of teaching and training for our members during the pandemic threat, we have launched a series of symposia domestically and internationally, especially for undergraduate and postgraduate education in the physiological discipline.The International Symposium for Physiological Online Teaching was organized by our Society in late April as the first conference to provide a platform for our physiological education community to share possibilities for the physiological teaching process during the spread of COVID-19.A second online International Symposium was held in early July with the topic of “Innovation and exploration of physiology teaching in the post COVID-19 era” with invited speakers giving talks and having discussions about how to better deal with the impact of COVID-19 on physiological teaching.In August, we had successfully launched our 2020 Annual Conference that not only provided the latest updates to physiological researchers but also shared practical experiences about teaching and training with our members from the physiology education family. We have encouraged the Acta Physiologica Sinica to publish more research articles focused on COVID-19 since our Society is one of the prominent sponsors of this journal.As for teaching and introducing the developing history of physiology and physiologists in China, this year our Society has also set up the science column in the popular messaging app WeChat.Chinese Physiological Society in TaipeiEven though there is some inconvenience caused by COVID-19, CPS still functions normally to maintain academic activities.The Society has launched a new International Affairs and Physiology Education Committee (IAPEC) to proactively prepare for any upcoming difficulty. The IAPEC is formed by six young investigators (mostly in their early career phase), and the committee is directed by one of the council members in CPS. The communication among IAPEC members is mostly done in e-mails and video meetings.We have interviewed our society members and asked for their opinions regarding what kind of help they need from the Society to facilitate their teaching, research, and career development during COVID-19.The one thing that cannot to be held back by COVID-19 is the education of our youngsters and knowledge in physiology which is the cornerstone that promotes medical progress.Cuban Society of Biomedical Basic Sciences (formerly Cuban Society of Physiological Sciences)There are many pandemic-related activities in process across the Cuban universities and research institutions. Faculty and students from the Medical School and other university institutes have used innovative technologies to dev

Why low concentrations of salt enhance sweet taste.

A long-standing culinary practice is to sprinkle a little salt on fruits such as watermelon, tomatoes or cantaloupe to make them taste sweeter. In the current issue of Acta Physiologica, Yasumatsu et al. 1 describe a likely mechanism for this phenomenon. They report for the first time that the sodium-glucose cotransporter 1 (SGLT1) is expressed in the apical membrane of sweet-sensitive taste cells and is an important contributor to the taste of glucose-containing sugars.

Massage during muscle unloading increases protein turnover in the massaged and non‐massaged, contralateral limb, but does not attenuate muscle atrophy

In the current issue of Acta Physiologica, Lawrence et al. [1] provide a rigorous investigation into the effects of mechanical massage therapy on skeletal muscle during normal weight bearing (WB) and unloading conditions. One week of hindlimb suspension (HS) in rats was used to determine if massage is an effective therapy to blunt disuse associated muscle loss.Massage therapy increased muscle protein turnover compared to HS control, though muscle atrophy still occurred following massage and muscle disuse. Interestingly, message therapy increased muscle protein turnover in the contralateral, non-messaged limb compared to HS control.

Another record in submissions to Acta Physiologica

Another record in submissions to Acta Physiologica

Acta Physiologica Award: outperforming original articles from 2015 to 2017

Recently we announced what maybe the highest award in scientific publishing, the Acta Physiologica Award. The Scandinavian Physiological Society, as the owner of Acta Physiologica, sponsors the prize in recognition of your efforts that have increased the journal's performance. Here is an update of some outstanding original articles from 2015 and 2017. This article is protected by copyright. All rights reserved.

Acta Physiologica's appearance and gestalt 2017

My tailor suggests I should dress for the body I have, not for the body I want. Conversely, Acta Physiologica's lean and muscular build calls for streamlining her appearance. Over the latest years, Acta Physiologica has been ranked highly among the physiology journals (Persson 2014a, 2015a). Our readers have increasingly downloaded our articles, and many more manuscripts have been submitted year by year (Persson 2014b,c, 2015b). Reflecting these changes, more persons read Acta Physiologica not only out of general interest but also to stay on top of their fields. To meet these new demands, starting last year, figures and artwork are being enhanced visually. Often, we have had the submitted artwork and schemes redrawn professionally. Now, our text flow will become more user-friendly. Starting from 2017, Acta Physiologica articles will be subdivided according to the following order: Abstract – Introduction – Results – Discussion – Methods. Placing the Methods at the end of the manuscript allows the authors to present extensive methodology without interposing the general presentation of Results and their Discussion. To further facilitate reading, in-text citations will be numerical and appear in the reference list according to sequence. As most physiology journals adhere to the classical format, all authors may still submit their work in the traditional subdivision and citing. We are looking forward to the future developments of Acta Physiologica, which may bring up more changes in presentation. None.

Announcing the $100,000 (one hundred thousand US Dollars)Acta Physiologica Award

Announcing the $100,000 (one hundred thousand US Dollars)<i>Acta Physiologica Award</i>

Acute kidney injury.

Both demographic trends and the current rise in the number and complexity of diagnostic and surgical procedures have let acute kidney injury (AKI) grow into an enormous medical challenge and common clinical complication among hospitalized patients. In these populations, AKI is an important cause of morbidity and mortality, with rising incidence (Zarjou et al. 2012, Rabadi & Lee 2015). AKI is characterized by a sudden reduction in renal function, ranging from a small decrease in glomerular filtration rate (GFR) to complete loss of renal function (Srisawat & Kellum 2011) and often results in chronic loss of renal function or end-stage kidney disease. There is growing evidence that AKI is associated with an increased risk for the development of chronic kidney disease (CKD), depending on AKI severity and the underlying pathophysiological mechanism (Coca 2013). In their recent meta-analysis of AKI association with CKD and end-stage renal disease, Coca et al. investigated renal and non-renal outcomes of patients who survived AKI. AKI patients not only have a higher risk of CKD, but also to develop further complications in organ systems such as the heart, lung and liver. Renal fibrosis, permanent impairment of renal function and complications in non-renal organs apparently contribute to CKD development (Coca et al. 2012). As numerous different definitions of AKI existed in parallel, the 2004 developed RIFLE (risk, injury, failure, loss and end-stage kidney disease) system was introduced to standardize AKI classification in patient care and research (Bellomo et al. 2004). This well-validated system was further modified in the year 2008 and is based on GFR and urine output (Zappitelli 2008). The closely related AKIN (Acute Kidney Injury Network) classification is based on serum creatinine (SCr) and on urinary output. SCr is, in general, only useful as a late indicator for AKI, as detectable changes in SCr require that the kidney already lost 50% of the GFR (Zarjou et al. 2012). This is in line with our knowledge from basic physiology that the (measured) GFR is better suited to detect early changes in loss of kidney function in contrast to SCr. The practical advantages of the scoring systems were and are under investigation in clinical studies. Unfortunately, none of the scoring systems is able to characterize AKI as pre-renal, post-renal or intrinsic. New sensitive and specific biomarkers are urgently needed to support the current, yet insufficient diagnostic ‘gold standard’. Urinary calprotectin and neutrophil-gelatinase-associated lipocalin (NGAL) showed promising results in a study by Seibert et al. (2013) with high sensitivity and specificity values for calprotectin. NGAL for instance is produced by injured epithelial cells and is upregulated very early in animal models of AKI (Zarjou et al. 2012). Kidney injury molecule-1 (KIM-1) is released into the urine during proximal tubular injury in different models of AKI (Vaidya et al. 2008), and interestingly so by those very cells that are commonly injured in AKI. The leading causes of AKI are ischaemia/reperfusion injury (IRI), rhabdomyolysis, hepatic malfunction, sepsis and nephrotoxic substances (Persson 2013). Strong research efforts in animal models of AKI have, during the last years, lead to a better understanding of the cellular and molecular basis of this complex disease. Ischaemia/reperfusion injury, the restriction of blood supply to an organ followed by reperfusion, leads to tubular and endothelial necrosis and apoptosis. The tissue damage is exacerbated by the initiated inflammatory response after reperfusion and re-oxygenation of the kidney. The complex serial events during IRI include the release of reactive oxygen species (ROS) and pro-inflammatory cytokines and chemokines and lead to the activation of apoptotic pathways, intracellular Ca2+ accumulation and tubular cell injury (Shokeir et al. 2014, Malek & Nematbakhsh 2015). The detoxification of ROS during oxidative stress is essential for recovery of the kidney and is, for instance, regulated by the transcription nuclear factor erythroid 2-related factor (Nrf2) that accumulates in the nucleus and activates the transcription of phase 2 enzyme genes, such as haeme-oxygenase-1, glutathione reductase and glutathione peroxidase. Shokeir et al. investigated the impact of ischaemic pre- and post-conditioning on the expression of Nrf2 and dependent genes in the kidney. Ischaemic pre-conditioning (Ipre) improved renal function as measured by SCr and blood urea nitrogen, whereas ischaemic post-conditioning (Ipost) did not lead to a significant improvement. Furthermore, Ipre caused an increase in the immediate expression of Nrf2 and dependent genes in proximal convoluted tubular cells. This supports the idea of Nrf2 as the mediator of the renoprotect-ive effect of Ipre and Ipost. In addition, caloric restriction enhances the cellular adaption to hypoxia via Sirt1 pathway, provides protection against acute tissue injury and improves survival and kidney function after acute IRI (Mitchell et al. 2010, Lempiäinen et al. 2013). The hypoxic environment of the renal medulla renders it extremely vulnerable to changes in blood flow and oxygen supply (Liu et al. 2013). Increases in medullary blood flow (MBF) wash out the cortico-medullary osmotic gradient, whereas decreases in MBF lead to hypoxia and IRI, followed by tissue necrosis and CKD (Kennedy-Lydon et al. 2013). Kennedy-Lydon et al. intensively discuss controversial data of MBF regulation from different rat models. They shed light on the role of pericytes in the context of the fact that a passive MBF regulation is the accepted mechanism. Those smooth muscle-like cells on the abluminal side of the endothelium wrap their claw-like processes around microvessels and contribute to vessel stabilization, endothelial cell regulation, angiogenesis and phagocytosis. Despite different peptide and hormonal vasoactive agents, pericytes respond to acetylcholine, ATP and noradrenaline, so it seems likely that the release of these substances by adjacent sympathetic nerve terminals contributes to the regulation of MBF. Pericytes seem to bridge tubular and endothelial cell signalling by detecting vasoactive stimuli – and responding through regulation of vasa recta diameter and MBF. Although heavily discussed, pericytes could be, by de-differentiation and migration, one source of myofibroblasts in the kidney. Myofibroblasts initiate renal fibrosis by producing large amounts of extracellular matrix components. The identification of decisive signalling molecules and pathways activated by hypoxia is the central issue of a number of excellent AKI-related studies published in Acta Physiologica. During haemorrhagic shock, when arterial pressure falls below the autoregulatory region, filtration pressure and perfusion of the kidney decrease, leading to hypoxia and kidney injury with reduced GFR. Major systems that maintain arterial pressure, worsen the hypoxic environment in the kidney by enhancing oxygen consumption in the kidney and lowering renal perfusion to protect heart and brain (Hultström 2013). Hultström describes the neuro-hormonal interactions between the sympathetic nervous system, the renin-angiotensin-aldosteron system (RAAS) and vasopressin during shock. Interventions to protect the kidney have to maintain blood pressure during inhibition of one of the mentioned systems. A careful use of RAAS inhibitors is suggested by Hultström as experimental data from several studies showed their reno-protective effects in AKI through IRI. Hypoxia-inducible transcription factor (HIF) activates the transcription of more than 100 genes and is involved in erythropoiesis, angiogenesis, regulation of vascular tone, iron metabolism, anaerobic metabolism, regulation of cell proliferation and apoptosis. Renal prolyl 4-hydroxylases (P4Hs) are the cellular oxygen sensors that regulate HIF stability. Selective pharmacological inhibition of P4Hs showed beneficial effects in different rodent models of IRI (Myllyharju 2013); nevertheless, potential unwanted side effects need to be studied further. Other promising pharmaceutical targets in AKI are transient receptor potential vanilloid-1 and 4 (TRPV1,4) with potential reno-protective role in IRI (Kassmann et al. 2013). Activation of TRPV1 by capsaicin and other agonists ameliorated IR-induced renal dysfunction. The authors discuss that catheter-based renal denervation of hypertensive patients could affect the ischaemic response of those individuals; thus, renal denervation of sensory neurones in rats exacerbates ischaemic renal injury. Nevertheless, over-activity of the sympathetic nervous system is involved in hypertension-associated kidney failure (Khan et al. 2014) and is caused by neurohormonal signalling by the kidney itself. In a model of cisplatin-induced kidney injury in rats, Kahn et al. showed a blunted high-pressure baroreflex regulation of renal sympathetic nerve activity (RSNA). Renal denervation helped to normalize the baroreflex regulation of RSNA. Due to the wide range of agents and conditions causing AKI, numerous pathways have been identified in animal models that seemed to be promising for pharmaceutical interventions, as, for instance, inhibition of inflammation. Unfortunately, none of them has so far been translated into a therapeutic option for human AKI (Zarjou et al. 2012). Studies on renal detoxification mechanisms identified haeme-oxygenase-1 as an attractive target (Haines et al. 2012). This enzyme indirectly contributes to detoxification of ROS and is for instance induced by HIF. It ameliorated renal injury in a mouse model of IRI-induced AKI. In addition, cell-based strategies such as the therapeutic application of mesenchymal stem cells (MSCs) are under intensive investigation. MSCs are a multipotent cell population found in bone marrow, where they are easily isolated from. They promote the functional repair of nephrons through paracrine and endocrine mechanisms. Intravenous administration of exogenous MSCs protected for instance from cisplatin-induced kidney dysfunction (Humphreys & Bonventre 2008), and are currently tested in clinical trials. New treatment procedures in combination with new early detection markers of AKI hopefully offer a chance to improve the outcome of AKI and ultimately contribute to the prevention of CKD. None.

Outcome of a public consultation on the Draft Scientific Opinion of the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) on Dietary Reference Values for phosphorus

EFSA Supporting PublicationsVolume 12, Issue 7 851E Technical reportOpen Access Outcome of a public consultation on the Draft Scientific Opinion of the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) on Dietary Reference Values for phosphorus European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author First published: 28 July 2015 https://doi.org/10.2903/sp.efsa.2015.EN-851 Published date: 28 July 2015 Question number: EFSA-Q-2015-00098 AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References Anderson J, 2005. Phosphorus. In: Encyclopedia of Human Nutrition. B Eds Caballero, L Allen and A. Prentice Elsevier, Oxford, UK, 486– 490. Bonjour JP, Gueguen L, Palacios C, Shearer MJ and Weaver CM, 2009. Minerals and vitamins in bone health: the potential value of dietary enhancement. British Journal of Nutrition, 101, 1581– 1596. Calvo MS and Uribarri J, 2013. Contributions to total phosphorus intake: all sources considered. Seminars in Dialysis, 26, 54– 61. Delgado-Andrade C, Seiquer I, García MM, Galdó G and Navarro MP, 2011. Increased Maillard reaction products intake reduces phosphorus digestibility in male adolescents. Nutrition, 27, 86– 91. EFSA (European Food Safety Authority), 2005. Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to the Tolerable Upper Intake Level of phosphorus. The EFSA Journal 233, 19 pp. doi:10.2903/j.efsa.2005.233 EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2015a. Scientific Opinion on Dietary Reference Values for phosphorus. EFSA Journal 2015; 13(7):4185, 54 pp. doi:10.2903/j.efsa.2015.4185 EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2015b. Scientific Opinion on Dietary Reference Values for calcium. EFSA Journal 2015; 13(5):4101, 84 pp. doi:10.2903/j.efsa.2015.4101 Finch JL, Lee DH, Liapis H, Ritter C, Zhang S, Suarez E, Ferder L and Slatopolsky E, 2013. Phosphate restriction significantly reduces mortality in uremic rats with established vascular calcification. Kidney International, 84, 1145– 1153. Gallagher JC and Wilkinson R, 1973. The effect of ethinyloestradiol on calcium and phosphorus metabolism of post-menopausal women with primary hyperparathyroidism. Clinical Science and Molecular Medicine, 45, 785– 802. Greger JL, Baligar P, Abernathy RP, Bennett OA and Peterson T, 1978. Calcium, magnesium, phosphorus, copper, and manganese balance in adolescent females. American Journal of Clinical Nutrition, 31, 117– 121. Guéguen L, 1982. Les phosphates dans l'alimentation humaine. Médecine et Nutrition, 18, 237– 245. Heaney RP and Nordin BE, 2002. Calcium effects on phosphorus absorption: implications for the prevention and co-therapy of osteoporosis. Journal of the American College of Nutrition, 21, 239– 244. Heaney RP, 2012. Phosphorus. In: Present Knowledge in Nutrition. Eds JW Erdman, IA Macdonald and SH Zeisel. John Wiley & Sons, Washington, DC, USA, 447– 458. Kemi VE, Karkkainen MU and Lamberg-Allardt CJ, 2006. High phosphorus intakes acutely and negatively affect Ca and bone metabolism in a dose-dependent manner in healthy young females. British Journal of Nutrition, 96, 545– 552. Kjerulf-Jensen K, 1941. Excretion of phosphorus by the bowel. Acta Physiologica Scandinavica, 3, 1– 27. Netherlands Food and Nutrition Council, 1992. Recommended dietary allowances 1989 in The Netherlands. The Hague, 115 pp. O'Brien KO, Kerstetter JE and Insogna KL, 2014. Phosphorus. In: Modern Nutrition in Health and Disease. Eds AC Ross, B Caballero, RJ Cousins, KL Tucker and TR Ziegler. Lippincott Williams & Wilkins, Philadelphia, PA, USA, 150– 158. Smith DA and Nordin BE, 1964. The effect of a high phosphorus intake on total and ultrafiltrable plasma calcium and on phosphate clearance. Clinical Science, 26, 479– 486. Spencer H, Menczel J, Lewin I and Samachson J, 1965. Effect of high phosphorus intake on calcium and phosphorus metabolism in man. Journal of Nutrition, 86, 125– 132. Takeda E, Yamamoto H, Yamanaka-Okumura H and Taketani Y, 2014. Increasing dietary phosphorus intake from food additives: potential for negative impact on bone health. Advances in Nutrition, 5, 92– 97. Teegarden D, Lyle RM, McCabe GP, McCabe LD, Proulx WR, Michon K, Knight AP, Johnston CC and Weaver CM, 1998. Dietary calcium, protein, and phosphorus are related to bone mineral density and content in young women. American Journal of Clinical Nutrition, 68, 749– 754. Toussaint ND, Pedagogos E, Tan SJ, Badve SV, Hawley CM, Perkovic V and Elder GJ, 2012. Phosphate in early chronic kidney disease: associations with clinical outcomes and a target to reduce cardiovascular risk. Nephrology (Carlton), 17, 433– 444. Wilkinson R, 1976. Absorption of calcium, phosphorus, and magnesium. In: Calcium, phosphate and magnesium metabolism. Ed BEC Nordin. Churchill Livingstone, Edinburgh, UK, 36– 112. Zoccali C, Ruggenenti P, Perna A, Leonardis D, Tripepi R, Tripepi G, Mallamaci F, Remuzzi G and Group RS, 2011. Phosphate may promote CKD progression and attenuate renoprotective effect of ACE inhibition. Journal of the American Society of Nephrology, 22, 1923– 1930. Volume12, Issue7July 2015851E ReferencesRelatedInformation

Waterworks.

Having taught for some years in medical school, I still vividly remember the A+ student who collapsed in the library hyperventilating while studying pathological ventilation patterns, definitely a case of too much focussing all of one's attention on the physiology text in front of herself. I have always wondered what happens when they progress to the urine production chapter. Jokes aside, the human urinary tract is a fascinating, tightly regulated organ system. Understanding its function is of increasing relevance for medical caregivers, especially those dealing with ever-ageing patient populations in the Western world. Demographic change forces us to refocus our attention to diseases of the elderly with ever-increasing life expectancies, such as non-neurogenic male lower urinary tract symptoms (Gratzke et al. 2015), overactive bladder symptoms of the elderly (Wolff et al. 2015) and bladder cancer. Age and male gender are the risk factors for bladder cancer, with a median age at diagnosis of 70 years and a male-to-female ratio of 3 : 1. Incidence rates are on the rise, with approx. 380 000 new cases and approx. 150 000 deaths per year worldwide (Knowles & Hurst 2015). Traditionally, the kidney had been one of the hot topics of physiological research, which has increasingly been extending its focus from basic mechanisms and molecular kidney physiology (Svenningsen et al. 2014) to disease mechanisms underlying and/or associated with Western lifestyles and ageing populations, such as essential hypertension (Damkjaer et al. 2014), metabolic syndrome and acute and chronic kidney injury (Seibert et al. 2013, Singer et al. 2013, Svenningsen et al. 2013). Acta Physiologica has recently added to our understanding of lower urinary tract structure and function and its pathophysiology. In 2013, Nevéus & Sillén shared a closer look on the early development of bladder function and disturbances in childhood. Embryonic bladder development starts at an early gestational age. At birth, higher CNS centres control micturition, while control of urinary function develops as the child grows and matures, a process which, for many parents, resembles a rather bumpy, curvy ride. Often, however, simple measures such as parent education and non-medical bladder training help significantly. Continued incontinence or nocturnal enuresis may become major issue for an astonishingly high percentage of parents, as approx. 5–10% of 7-year-old children suffer from daytime incontinence and/or nocturnal enuresis, with some never outgrowing it (Nevéus & Sillén 2013). Bladder problems in childhood increase the risk of developing according dysfunctions in adulthood (Nevéus & Sillén 2013) such as nocturia, which is, due to its multi-factorial aetiopathogenesis, now viewed as a distinct clinical condition rather than a mere symptom (Osman et al. 2013). The excellent articles of both Griffiths & Fowler (2013) and de Groat & Wickens (2013) have shed light on recent insights into the mechanisms and circuits by which the CNS controls micturition. Urothelial signalling cascades give rise to the sensation that initiates the perception of ‘needing to go’ (Birder & Wyndaele 2013), while continence and voiding are controlled in close cooperation of the autonomous and somatic systems (Ochodnicky et al. 2013). When we take a closer look at signalling cascades and events in the lower urinary tract, purinergic signalling pathways are of major importance (Avelino et al. 2013, Birder et al. 2013, Burnstock 2013). Current research on bladder interstitial cells, several different subgroups of which have been recently identified within the bladder wall to be interacting with nerves and smooth muscle and probably critically involved in intercellular communication and key physiological functions (McCloskey 2013), is but one example of an emerging field in research on lower urinary tract structure and function. Both neurodegenerative disease (Feinstein et al. 2015) and traumatic damage to the spinal cord (Thomas et al. 2014, Gomez-Amaya et al. 2015) are often accompanied by urinary tract dysfunction. Improved overall survival of patients suffering from according pathologies are accompanied by an increasing relevance of these dysfunctions, which may severely affect the quality of life and ability to participate in day-to-day activities. Thus, a better understanding of the molecular and (patho-) physiological mechanisms will help provide novel opportunities for prognostic patient evaluation, monitoring and treatment. Time for a comfort break. None.

Acta Physiologica introduces a 48-h policy for a first editorial decision upon your submissions

Acta Physiologica introduces a 48-h policy for a first editorial decision upon your submissions

TRPs in the kidney - location, location, location

A recent study by Chen et al., featured in this issue of Acta Physiologica, may provide the molecular basis for new treatment avenues for acute kidney injury (AKI) by targeting of specific members of the vanilloid (V) transient receptor potential (TRP) subfamily of cation channels (Chen et al., 2014). Maintenance of ideal tissue hemodynamics is vital for organ homeostasis and relies in part on the finely tuned ability of small arteries and arterioles to constrict or dilate in response to changes in perfusion pressure. Pathological states can impair this intrinsic ability, leading to increases in vascular resistance and ischemic injuries. A reduction in blood flow to the kidneys, usually caused by acute hypovolemia, sepsis, surgery and major trauma, can lead to AKI, a disease characterized by rapid loss of kidney function and reduction in glomerular filtration rate (GFR), mainly due to reduction in renal blood flow. AKI is a disease with a high mortality rate, ranging from 40-75%. Impairment of endothelium-dependent dilation of the renal microcirculation, mainly through generation of nitric oxide (NO), is involved in the development of AKI and its progression to chronic kidney disease (Basile and Yoder, 2014). Currently, treatment of AKI consists of pharmacological interventions to mitigate the underlying cause and maintain blood electrolytes values within normal ranges, and dialysis. The findings of Chen and colleagues described in this issue could lead to the development of therapeutics that specifically restore blood flow to the renal pre-glomerular microvasculature during AKI. Heterogeneous tissue distribution of the members of the TRP channel superfamily is well appreciated, but the study by Chen et al. shows that there is differential activity, likely due to preferential expression, of a single TRP channel, TRPV1, within the renal vascular tree. The authors show that activation of Ca2+-permeable TRPV1 channels with capsaicin, a substance derived from hot peppers, dilated vessels in the renal preglomerular microvasculature, characterized by a blunted vascular resistance in isolated perfused kidneys. This effect was inhibited by capsazepine, a selective TRPV1 inhibitor, and was absent from TRPV1−/− mice. Interestingly, large conductance renal arteries only dilated to high concentrations of capsaicin, an effect that was still observed in TRPV1−/− mice, suggesting TRPV1-independent dilatory mechanisms (Chen et al., 2014). In addition, isolated arterioles from the medullary vasa recta were unresponsive to capsaicin stimulation, strengthening the argument that involvement of TRPV1 in endothelium-dependent dilation is indeed restricted to the pre-glomerular renal microcirculation. These novel data compellingly highlight functional heterogeneity of TRP channel activity within the renal vascular tree. Such differential responses may allow the development of tailored therapies aimed at reducing vascular resistance in the renal pre-glomerular microvasculature that will improve renal blood flow and function during AKI. A second intriguing finding of this study is that TRPV4 channels are functional in all segments of the renal circulation, and that TRPV4 vasodilatory activity seems to be coupled to the generation of NO by the enzyme NO synthase (NOS). These data add another dimension to our current understanding of TRPV4 channels in the regulation of vascular tone. Most studies report the importance of TRPV4 in dilations mediated by endothelium-derived hyperpolarization independent of NO production (Sonkusare et al., 2012, Earley et al., 2009). However, TRPV4 has recently been shown to be important for the rescue of NO production in endothelial cells after hypoxic pre-conditioning both in vitro and in vivo (Rath et al., 2012), showing its vital role in the organ protective responses facing ischemic injuries. Thus, TRPV4-mediated NO generation could emerge as a prominent drug target for the treatment of AKI. The present study raises stimulating questions that warrant further investigation. It remains to be determined what genetic factors regulate the selective expression of TRPV1 in the renal pre-glomerular microcirculation, and if this occurs during development or post-development. In addition, it would be interesting to determine if TRPV4 and NOS are located in close proximity, such as that the inflow of Ca2+ caused by TRPV4 activity in the form of TRPV4 sparklets (Sullivan et al., 2012, Sonkusare et al., 2012) generate Ca2+ microdomains with locally elevated Ca2+ concentration that directly activate NOS. It is also possible TRPV4-mediated Ca2+ influx causes a global increase in intracellular Ca2+ by Ca2+-induced Ca2+ release from intracellular stores. It should be noted that TRPV4 is present in membrane caveolae rich in the protein caveolin-1, which is a stereotactic inhibitor of the endothelial NOS (Trane et al., 2014). Unraveling the interplay between TRPV4 and NOS would provide further insight in the intracellular organization of membrane subdomains. Such data would complement recent studies that provide evidence that TRPV4 channels in smooth muscle cells are present in signaling complexes organized by A-kinase anchor protein 150 (AKAP150) allowing activation downstream of G-protein coupled receptors (Mercado et al., 2014). In contrast, the endogenous regulation of TRPV1 channels in the vasculature remains unknown. In summary, the report by Chen et al. elegantly shows through functional studies using isolated arteries and perfusion of whole kidneys differential functional consequences of TRPV1 and TRPV4 activity in different segments of the renal circulation. Pharmacological activation of TRPV1 may emerge as a promising candidate for treatment of AKI to selectively target the pre-glomerular microcirculation, possibly restoring renal blood flow, GFR and, with them, renal function.