Pflugers Archiv : European journal of physiology最新文献

{"title":"The obesity pandemic and its impact on non-communicable disease burden.","authors":"Staffan Hildebrand, Alexander Pfeifer","doi":"10.1007/s00424-025-03066-8","DOIUrl":"10.1007/s00424-025-03066-8","url":null,"abstract":"<p><p>The rising prevalence of overweight and obesity across the globe is a major threat both to public health and economic development. This is mainly due to the link of obesity with the development and outcomes of non-communicable diseases (NCDs). NCDs are a leading cause of global death and disability, and reducing the burden of NCDs on patients and healthcare systems is of critical importance to improve public health. Obesity is projected to be the number one preventable risk factor for NCDs by 2035, and there is an urgent need to tackle the growing obesity rates in order to reduce NCD incidence and severity. Here, we review the current understanding of the impact of obesity on NCD burden in general, as well as the epidemiological and mechanistic relationship between obesity and some of the most common classes of NCDs. By literature review, we found that over 70% of NCDs have a documented association with obesity, highlighting the importance of a better understanding of the pathophysiologies underlying obesity/overweight as well as the interaction between obesity and NCDs in order to reduce global disease burden.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"657-668"},"PeriodicalIF":2.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intrinsic responses to hypoxia and hypercapnia of neurons in the cardiorespiratory center of the ventral medulla of newborn rats.","authors":"Hiroshi Onimaru, Yui Koyanagi, Kamon Iigaya, Keiko Ikeda, Masahiko Izumizaki","doi":"10.1007/s00424-025-03077-5","DOIUrl":"10.1007/s00424-025-03077-5","url":null,"abstract":"<p><p>The rostral ventrolateral medulla (RVLM) includes a variety of neurons essential for cardiorespiratory control. Although some of these neurons are thought to be intrinsically sensitive to hypercapnia and/or hypoxia, relationships between types of neurons and responses to hypoxia and/or hypercapnia are not well understood. Tyrosine hydroxylase (TH) is one of the cell-type markers of the RVLM neurons. Here, we report effects of hypoxia and hypercapnia on TH-positive or -negative neurons in the RVLM of newborn rats. Brainstem-spinal cord preparations were isolated from 0-3-day-old Wistar rats and superfused with artificial cerebrospinal fluid equilibrated with 95% O₂ and 5% CO₂, pH 7.4 at 25-26 °C. Membrane potential responses to hypoxia (95% → 0% O₂) and/or hypercapnia (2% → 8% CO₂) were examined in the presence of tetrodotoxin (TTX) after identification of the firing pattern. We found that TH-positive C1 neurons in the RVLM were sensitive to hypoxia with membrane depolarization but less sensitive to hypercapnia. TH-negative neurons in the C1 area showed responses similar to those of C1 neurons. Moreover, C1 area neurons remained depolarized by hypoxia in the presence of TTX plus gliotransmitter blockers. In contrast, Phox2b-positive and TH-negative neurons in the parafacial respiratory group were intrinsically sensitive to CO₂ but not sensitive to hypoxia. Respiratory-related neurons (Phox2b and TH negative) showed a variable response to hypoxia: unchanging, depolarizing, or hyperpolarizing. Our findings suggest that C1 area neurons in the RVLM are intrinsically sensitive to hypoxia and belong to one of the elements constituting central hypoxic sensors.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"685-705"},"PeriodicalIF":2.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronal subtype-dependent kinetics of EPSCs induced by thalamocortical projections from the ventroposteromedial thalamic nucleus to the insular cortex in rats.","authors":"Yuko Koyanagi, Kiyofumi Yamamoto, Kouhei Kitano, Mie Kajiwara, Masayuki Kobayashi","doi":"10.1007/s00424-025-03074-8","DOIUrl":"10.1007/s00424-025-03074-8","url":null,"abstract":"<p><p>Cerebrocortical neurons receive glutamatergic inputs via thalamocortical projections, and their activities are simultaneously controlled by GABAergic interneurons. Few studies have demonstrated the difference in the amplitude of evoked excitatory postsynaptic currents (EPSCs) via thalamocortical projections onto glutamatergic excitatory (ENs) and GABAergic inhibitory neurons (INs); the strength of excitation among neural subtypes varies among sensory cortices. The present study aimed to reveal the profile of thalamocortical inputs to ENs and inhibitory neurons in the insular cortex (IC) by evaluating the amplitude and latency of EPSCs evoked in the connection from the ventroposteromedial (VPM) thalamic nucleus to the IC. Whole-cell patch-clamp recordings were prepared from ENs, fast-spiking neurons (FSNs), and non-fast-spiking neurons (NFSNs) in the middle layers (layer 4 and adjacent layers) of the IC. Photostimulation-induced EPSCs (pEPSCs) were evoked via the selective activation of thalamocortical axons via optogenetics. All the neuronal subtypes received direct excitatory inputs from the VPM, and pEPSCs recorded from FSNs had the greatest amplitude and shortest latency compared with those recorded from ENs and NFSNs. Under current-clamp conditions, FSNs almost invariably exhibited action potentials responding to photostimulation, whereas ENs and NFSNs often showed the failure of action potential induction. In addition to excitatory inputs, some neurons exhibited pEPSCs followed by outward GABA_A receptor-mediated currents, which curtailed the pEPSC peak and aligned the timing of the action potential to photostimulation. These results suggested that FSNs play a role in the feedforward inhibition of EN activity in the upper layer of the IC. (244 words).</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"707-717"},"PeriodicalIF":2.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intracellular pH regulates the strength of the intrinsic inward rectification of Kir4.1/Kir5.1 channels.","authors":"Iván A Aréchiga-Figueroa, Leticia G Marmolejo-Murillo, Mayra Delgado-Ramírez, Rodrigo Zamora-Cárdenas, Eloy G Moreno-Galindo, Tania Ferrer, Ricardo A Navarro-Polanco, José A Sánchez-Chapula, Aldo A Rodríguez-Menchaca","doi":"10.1007/s00424-025-03079-3","DOIUrl":"10.1007/s00424-025-03079-3","url":null,"abstract":"<p><p>Kir4.1/Kir5.1 channels play a crucial role in important physiological functions, notably in the kidneys and brain. A hallmark of these channels is the coexistence of two mechanisms of inward rectification: the classical \"extrinsic\" inward rectification induced by polyamines and Mg²⁺ blocking the pore, and a novel \"intrinsic\" voltage-dependent mechanism driven by K⁺ flux. Previous studies have shown that Kir4.1/Kir5.1 channels are modulated by the intracellular pH in the physiological range. Here, we investigated the influence of the intracellular pH on the extent of the intrinsic inward rectification of Kir4.1/Kir5.1 channels expressed in HEK-293 cells and recorded using the inside-out configuration of the patch-clamp technique. We found that mutations that are known to modulate the pH sensitivity of Kir4.1/Kir5.1 channels attenuated inward rectification. The combination of these mutations in the triple mutant channel Kir4.1(K67M)/Kir5.1(N161E-R230E) virtually abolished inward rectification at pH 7.4; however, this property was re-established at acidic pH values. Consistently, the strong inward rectification of wild-type Kir4.1/Kir5.1 channels was reduced by intracellular alkalinization and further enhanced by acidification. Altogether, these experiments indicate that the intracellular pH strongly regulates the strength of the intrinsic inward rectification. Furthermore, triple mutant channels retained the extrinsic mechanism of inward rectification at pH 7.4, as can be blocked by spermine, but lost the ability to respond to elevated levels of PIP_2, unlike wild-type channels. Interestingly, whole-cell recordings of wild-type and triple mutant channels imply that the mechanism of intrinsic inward rectification is an important contributor to the overall rectification of Kir4.1/Kir5.1 channels in basal conditions.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"741-752"},"PeriodicalIF":2.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reproducibility of smooth muscle mechanical properties in consecutive stretch and activation protocols.","authors":"Simon Kiem, Stefan Papenkort, Mischa Borsdorf, Markus Böl, Tobias Siebert","doi":"10.1007/s00424-025-03075-7","DOIUrl":"10.1007/s00424-025-03075-7","url":null,"abstract":"<p><p>Mechanical organ models are crucial for understanding organ function and clinical applications. These models rely on input data regarding smooth muscle properties, typically gathered from experiments involving stimulations at different muscle lengths. However, reproducibility of these experimental results is a major challenge due to rapid changes in active and passive smooth muscle properties during the measurement period. Usually, preconditioning of the tissue is employed to ensure reproducible behavior in subsequent experiments, but this process itself alters the tissue's mechanical properties. To address this issue, three protocols (P1, P2, P3) without preconditioning were developed and compared to preserve the initial mechanical properties of smooth muscle tissue. Each protocol included five repetitive experimental cycles with stimulations at a long muscle length, varying in the number of stimulations at a short muscle length (P1: 0, P2: 1, P3: 2 stimulations). Results showed that P2 and P3 successfully reproduced the initial active force at a long length over five cycles, but failed to maintain the initial passive forces. Conversely, P1 was most effective in maintaining constant passive forces over the cycles. These findings are supported by existing adaptation models. Active force changes are primarily due to the addition or removal of contractile units in the contractile apparatus, while passive force changes mainly result from actin polymerization induced by contractions, leading to cytoskeletal stiffening. This study introduces a new method for obtaining reproducible smooth muscle parameters, offering a foundation for future research to replicate the mechanical properties of smooth muscle tissue without preconditioning.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"729-739"},"PeriodicalIF":2.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probiotic Bactolac alleviates depression-like behaviors by modulating BDNF, NLRP3 and MC4R levels, reducing neuroinflammation and promoting neural repair in rat model.","authors":"Musab Işık, Fadime Köse, Özcan Budak, Cansu Özbayer, Rumeysa Keleş Kaya, Sevda Aydın, Aleyna Ceren Küçük, Mehmet Arif Demirci, Songül Doğanay, Cahit Bağcı","doi":"10.1007/s00424-025-03084-6","DOIUrl":"https://doi.org/10.1007/s00424-025-03084-6","url":null,"abstract":"<p><p>Depression, a prevalent psychiatric disorder, exerts severe and debilitating impacts on an individual's mental and physical well-being, and it is considered a chronic mental illness. Chronic stress plays an important role in the pathophysiology of depression. Lactobacillus plantarum and Streptococcus thermophilus are psychobiotic bacteria and synthesize some neurotransmitters that play a role in the pathogenesis of depression. In this study, we aimed to investigate the therapeutic effects of Bactolac (Lactobacillus plantarum NBIMCC 8767  + Streptococcus thermophilus NBIMCC 8258) on chronic stress-induced depression in rats. Behavioral tests, including the sucrose preference test, elevated plus maze test, forced swim test, and three-chamber sociability test, were employed to assess depressive and anxiety-like behaviors. The expression level of the 5-HT1A, DRD1, ADRA-2A, GABA-A α1, CNR1, NR3C2, NOD1, NLRP3 and MC4R; BDNF levels, glial activity and intestinal permeability were determined in chronic stress-induced depression in rats. In conclusions, chronic stress decreased the expression levels of 5-HT1A, DRD1, ADRA-2A, GABA-A α1, CNR1, NR3C2, NOD1 and BDNF level; increased the expression levels of NLRP3 and MC4R, caused neurodegeneration and glial activity, ultimately led to depressive effects. Bactolac was effective in reducing depressive-like behaviors according to the results of behavioral tests. Bactolac treatment provided high neuronal survival rate increasing BDNF level, prevented the excessive release of pro-inflammatory cytokines by reducing the expression levels of NLRP3 and MC4R, therefore, prevented the excessive activation of the hypothalamus-pituitary-adrenal (HPA) axis and accordingly, reduced neurodegeneration and glial cell activation in depressed rats. We can suggest that Bactolac supplementation may be beneficial in coping with stress, alleviate the effects of chronic stress and help to protect mental health.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The formation and function of calciprotein particles.","authors":"Edward R Smith, Stephen G Holt","doi":"10.1007/s00424-025-03083-7","DOIUrl":"https://doi.org/10.1007/s00424-025-03083-7","url":null,"abstract":"<p><p>Vertebrate extracellular fluids lie below the threshold for spontaneous calcium phosphate (Ca-P_i) precipitation; yet, they remain supersaturated enough to foster crystal growth if unchecked. Calciprotein particles (CPP) and their smaller precursor calciprotein monomers (CPM) have emerged as fast-acting \"mineral buffers\" that mitigate abrupt local oversaturation. Although these complexes typically contain only trace amounts of Ca-P_i relative to total plasma levels, they exhibit remarkably high turnover kinetics, with clearance from the circulation within minutes, far outpacing hormonal loops that operate on timescales of hours to days. By forming ephemeral colloidal assemblies, CPM/CPP help maintain fluid-phase stability and avert uncontrolled crystallization \"accidents\" in microenvironments such as the intestine or bone-remodeling sites. However, under chronic mineral stress, such as in chronic kidney disease, multiple inhibitory factors (e.g., fetuin-A, pyrophosphate) can become deficient, enabling persistent generation of more advanced, crystalline CPP species. These \"modified\" CPP can adsorb additional ligands (e.g., apolipoproteins, microbial remnants, growth factors) and have been linked to inflammatory and pro-calcific changes in vascular and immune cells. Despite their minor quantitative contribution, these rapidly mobilized colloids may exert outsized influence on vascular and skeletal homeostasis, underscoring the need to clarify their origins, biological roles, and potential therapeutic targeting in disorders of mineral metabolism.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The crucial decade that ion channels were proven to exist : The vision of Bertil Hille and Clay Armstrong and how it came through.","authors":"Luigi Catacuzzeno, Antonio Michelucci, Fabio Franciolini","doi":"10.1007/s00424-025-03085-5","DOIUrl":"https://doi.org/10.1007/s00424-025-03085-5","url":null,"abstract":"<p><p>This retrospective begins with the first recording of the Na⁺ and K⁺ currents underlying the action potential in the giant squid axon reported by Hodgkin and Huxley in 1952, which made the question of where ions pass through the membrane more compelling. The notion of channels in the membrane had been around for quite some time but was so vague and contested that even the recording of Na⁺ and K⁺ currents through the membrane was not considered sufficient proof of their existence. In fact, Hodgkin and Huxley never referred to ion channels in their papers, only currents and conductances. The word \"channel\" remained somewhat left out from the scientific debate for almost another two decades, even though its idea was slowly making its way into the minds of discerning scientists. It is precisely this period that the present retrospective focuses on to understand the evolution of the ion channel concept from a speculative functional entity to a physical transmembrane object that serves the efficient and selective passage of ions. In this regard, the fundamental contribution of Bertil Hille and Clay Armstrong in promoting this idea, in the cold attitude, when not open aversion, of much of the scientific community, is fully acknowledged. Mention should also be made of Erwin Neher and Bert Sakmann's patch-clamp technique, which made it possible to directly measure ion currents through individual channels, thus conclusively demonstrating their presence in cell membranes. The retrospective goes on to briefly show how the cloning of ion channels in the 1980s and the first X-ray crystallographic structures at the turn of the century fully confirmed the initial suggestions, and closes by illustrating the relevance of ion channels in biology and medicine.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of Rho-kinase by fasudil contributes to the modulation of the synaptic plasticity response in the rat hippocampus.","authors":"Ercan Babur, Hatice Saray, Cem Süer, Nurcan Dursun","doi":"10.1007/s00424-025-03078-4","DOIUrl":"https://doi.org/10.1007/s00424-025-03078-4","url":null,"abstract":"<p><p>Metaplasticity refers to an activity-dependent change in the physiological or biochemical state of neurons that changes their ability to generate subsequently induced synaptic plasticity, such as long-term potentiation (LTP) or long-term depression (LTD). Rho-kinases (ROCK) are known to be important for stable changes in synaptic strength, especially LTP. In this study, we investigated whether LTP inhibition in synapses primed with 1-Hz stimulation was affected by ROCK inhibition in young adult male rats. The study also examined the pattern of tau phosphorylation that occurs during metaplastic regulation, applying into perspective the phosphorylation of tau protein by ROCK. Field potentials consisting of an excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded from the granule cell layer of the hippocampal dentate gyrus (DG). Metaplastic LTP was induced by strong tetanic stimulation (HFS) of the lateral perforant path after a low-frequency stimulation (LFS) protocol. A glass micropipette was inserted into the granule cell layer of the ipsilateral dentate gyrus to record fEPSP and drug infusion. Drug infusion (saline, n = 8; fasudil, n = 8, 10 µM) was started after the 15-min baseline recording and lasted for 60 min. Total and phosphorylated tau levels were measured in the stimulated hippocampus, which was immediately removed after the electrophysiological recording. LFS prevented the induction of LTP in response to HFS and even produced synaptic LTD in the saline-infused group (83.8 ± 2.6% of the baseline), but moderate potentiation of fEPSP (121.1 ± 7.7% of the baseline) occurred at the end of recording in the experiments where fasudil infusion was performed. LFS caused a comparable early depression, and HFS resulted in a comparable potentiation of the PS amplitude in both groups. Granular cells of the DG failed to exhibit synaptic LTP inhibition in the presence of fasudil, and levels of total and phosphorylated GSK-3β and levels of phosphorylated tau (Ser³⁹⁶ and Ser²⁰²-Thr²⁰⁵) were found to be lower than those of the control group. Based on these findings, it can be concluded that pharmacological inhibition of ROCK results in impaired ability of dentate gyrus neurons to inhibit synaptic LTP, and this result is accompanied by decreased phosphorylation of GSK-3β and tau proteins. The negative effect of fasudil on neuronal function should not be neglected when evaluating its effects as a therapeutic agent for diseases.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144037466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of aldosterone deficiency on the development of diuretic resistance in mice.","authors":"Daniel Essigke, M Zaher Kalo, Andrea Janessa, Bernhard N Bohnert, Xiaqing Li, Andreas L Birkenfeld, Ferruh Artunc","doi":"10.1007/s00424-025-03082-8","DOIUrl":"https://doi.org/10.1007/s00424-025-03082-8","url":null,"abstract":"<p><p>The effect of diuretics can be limited by stimulation of counter-regulatory mechanisms, eventually leading to diuretic resistance. It is thought that the mineralocorticoid aldosterone might contribute to the development of diuretic resistance. To test this, we challenged genetically modified mice with or without a deletion of the gene coding for the aldosterone synthase (AS) with furosemide, hydrochlorothiazide (HCT) and triamterene. Urinary excretion was studied in metabolic cages; kidneys were studied for expression of sodium transporters. In both genotypes, a 4-day treatment with HCT via drinking water (400 mg/l) induced a similar natriuresis and modest loss of body weight < 10%. In contrast, furosemide (125 mg/l) and triamterene (200 mg/l) via drinking water stimulated a significantly higher natriuresis and body weight loss in AS^-/- mice and in addition, triamterene caused massive hyperkalemia > 9 mM and acidosis (pH < 7.0). In AS^+/+ mice, plasma aldosterone concentration tended to increase under furosemide and HCT administration, while triamterene induced a robust ~ sixfold increase. In the kidney, apical targeting and proteolytic activation of the epithelial sodium channel ENaC were stimulated in AS^+/+ mice under triamterene treatment, an effect that was diminished in AS^-/- mice. In conclusion, aldosterone is essentially involved in the development of diuretic resistance to ENaC blockade by triamterene and to a lesser extent to furosemide. In contrast, resistance to HCT was independent of aldosterone.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}