Pflugers Archiv : European journal of physiology最新文献

The activation of cannabinoid receptor type II (CB2r) has been demonstrated to provide cardioprotective benefits against heart diseases. Nevertheless, the physiological effects of CB2r activation in healthy myocardial tissue remain poorly understood. Given the current gap in knowledge, particularly relevant in light of the growing therapeutic use of cannabinoids, this study aimed to investigate the effects of a single intraperitoneal injection of the selective synthetic CB2r agonist HU-308 on ventricular contractility, the expression of Ca²⁺-handling proteins, cyclic adenosine monophosphate (cAMP) levels, and redox biomarkers in male Wistar rats. Isolated left ventricular strips from HU-308-treated animals exhibited significant improvements in force of contraction (Fc), cardiac pumping capacity (CPC), and the rates of contraction (+ dF/dt) and relaxation (-dF/dt). Treatment with the CB2r agonist increased myocardial cAMP levels and upregulated the expression of sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA2a), phospholamban (PLB), and Na⁺/Ca²⁺ exchanger (NCX1). Additionally, HU-308 administration increased the glutathione (GSH)/oxidized glutathione (GSSG) ratio and the activity of antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR). Enhancement of the antioxidant defense system contributed to the maintenance of redox balance, as evidenced by decreased levels of lipid peroxidation (LPO), protein carbonyl (PC), and DNA strand breaks (DNA-sb). This study provides the first evidence that CB2r activation exerts antioxidative effects while enhancing both inotropy and lusitropy in the healthy rat myocardium, highlighting CB2r as a potential therapeutic target for preserving cardiac function.

Diet is a key physiological factor shaping brain function and gut microbiota, which together form the dynamic gut-brain axis. This bidirectional communication system plays a pivotal role in regulating behavioural outcomes. Therefore, it is worth investigating various behavioural aspects and connecting them with gut microbial dynamics shaped by differential dietary composition. Using zebrafish, we examined the effects of monotypic and combined diets of live feed and commercial feed on behavioural outcomes, morphometry, and gut microbiota. After chronic dietary intervention, fish receiving a mixed diet (Artemia, pellet, and spirulina) showed behavioural profile with enhanced exploration, reduced anxiety-like behaviour, and moderate aggression, alongside a balanced gut microbial composition. In contrast, monotypic diets produced distinct effects: Artemia-only fish displayed reduced boldness, heightened anxiety, and pathogenic microbial enrichment, while pellet-only fish showed greater growth but increased aggression. These findings highlight the importance of mixed feeding regimens for maintaining healthy gut-brain-behaviour interactions and support zebrafish as a model for studying diet-microbiota-behaviour relationships.

Recent kinetic studies show that the interstitial space contains two functional fluid compartments. This study explores the prerequisites for accumulation of infused crystalloid fluid in the remote slow-exchange space ("third fluid space¨, V_t2). Volume kinetic analysis based on log likelihood mathematics was applied to retrospective data from 132 intravenous infusions in 85 healthy volunteers who received 0.6-2.5 L of crystalloid fluid over 30 min. Frequent measurements of the blood hemoglobin concentration during and after these infusions, together with the measured urine output, served as calculation inputs. Three substudies were set up to illustrate key issues regarding V_t2 filling. In the first of them, infusions were preceded by blood withdrawal, which is known to decrease the interstitial pressure (P_if). Blood withdrawal resulted in smaller volumes entering V_t2, confirming that V_t2 filling is dependent on P_if. In the second substudy, modeled and measured urine outputs were compared after varying the inclusion of V_t2 in kinetic analyses in which the infused volume was gradually increased. Consideration of V_t2 was deemed appropriate when > 1.2 L of fluid was administered. In the third substudy, assessment of V_t2 filling during 7 time periods just before and after the 30 min infusions confirmed that uptake of fluid to V_t2 was initiated between 30 and 35 min. In conclusion, accumulation of fluid in V_t2 is dependent on P_if and occurs following infusion of > 1.2 L of crystalloid fluid. Uptake is not gradual but is initiated at a specific point in time.

Prolonged bed rest or microgravity exposure, as experienced during spaceflight, profoundly impacts cardiac health. Yet, the molecular mechanisms driving these detrimental changes remain largely elusive. Hindlimb unloading (HLU), a model of simulated microgravity, induces endoplasmic-reticulum (ER) stress, and its role in maladaptive cardiac remodeling remains unknown. To investigate the impact of HLU, its underlying molecular mechanisms and the therapeutic potential of ER stress suppression, C57BL6 mice were assigned to grounded control (GC) or HLU group. HLU mice received daily vehicle or 4-phenylbutyrate (4-PBA), an ER stress inhibitor, for 21 days. Additionally, HL-1 cardiomyocytes were treated with the ER stress inducer thapsigargin, with or without 4-PBA, to explore the cross-communication between ER stress and mitochondrial and metabolic dysfunction in vitro. Cardiac transcriptomic analysis revealed significant gene dysregulation in HLU compared to GC hearts. In HLU hearts, downregulated genes were mainly enriched for mitochondrial function and metabolic pathways, while upregulated genes were linked to extracellular matrix (ECM) pathways. Conversely, HLU mice treated with 4-PBA showed upregulation of mitochondrial function-related genes and downregulation of ECM-related genes. The oxidative phosphorylation (OXPHOS), which was downregulated in HLU hearts, became one of the most upregulated pathways following 4-PBA treatment. Consistent with the in vivo findings, thapsigargin-induced ER stress significantly compromised mitochondrial function, whereas co-treatment with 4PBA significantly preserved mitochondrial function. Together, our findings strongly suggest that prolonged bed rest or microgravity exposure triggers ER stress-induced mitochondrial and metabolic dysfunction in the heart, and pharmacological suppression of ER stress limits these detrimental cellular effects.

Obesity is a leading global health issue, closely associated with a chronic low-grade inflammation termed metaflammation. Metaflammation is driven by immune cell reprogramming, particularly of macrophages. In white adipose tissue (WAT), obesity induces a shift from anti-inflammatory to pro-inflammatory macrophage phenotypes, contributing to insulin resistance and tissue fibrosis. Recent studies have also illuminated the role of macrophages in brown and beige adipose tissue (BAT and scWAT), where they influence thermogenic capacity. Beyond the adipose tissue, the liver is the other main metabolic organ impacted by obesity. Liver macrophages play a critical role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) by promoting inflammation, lipid accumulation, and fibrosis. This review highlights the role of macrophages in the development and regulation of metaflammation in metabolic organs.

Human locomotion in water involves unique forces (buoyancy, drag) influencing metabolic cost. However, a validated model integrating these forces to predict the cost of transport (COT) during shallow water walking (SWW) is lacking, and energetic optimization strategies remain unclear compared to terrestrial gaits. We measured the COT in nine healthy men during SWW across four immersion depths (knee to xiphoid) and four walking speeds (0.2-0.8 m/s). We developed and validated a physiomechanical model based on the mechanical work done against buoyancy-affected body weight and hydrodynamic drag. Using this model, we compared the energetics of SWW with swimming and dry land walking (including hypogravity conditions) and analyzed self-selected walking speeds. The minimum COT occurred at hip immersion depth (0.2 m/s), rather than at intermediate speeds, with the J-shaped relationship observed only at knee immersion depth. Metabolic power, in contrast, remained relatively constant during self-selected walking across immersion depths. An immersion depth threshold near the center of mass emerged, above which swimming becomes more economical than SWW. Our physiomechanical model accurately predicted the measured COT. The interplay between buoyancy and drag dictates SWW energetics, shifting optimization away from intermediate speeds common on dry land. From a physiological perspective, these findings quantify the energetic consequences of human locomotor adaptation to the unique mechanical challenges posed by aquatic environments. Furthermore, identifying an immersion depth threshold influencing the economical choice between walking and swimming provides new insights into human aquatic locomotor adaptations.

The ion channel TRPV2 has multiple roles in immunology, cancer, cardiovascular function and pain signaling. However, only few endogenous modulators of TRPV2 have been described. The phospholipase A2 (PLA2)-derived lipid lysophosphatidylcholine (LPC) was demonstrated to induce pain and itch by activating sensory neurons, and it seems to be a direct agonist of TRPV4 and TRPC5. Although LPC was suggested to modulate TRPV2, the molecular mechanisms for this effect remain unclear. Here we used patch clamp and calcium imaging techniques to investigate if and how TRPV2 is modulated by LPC. Rat, mouse and human TRPV2 were not directly activated by LPC. Instead, 10 µM LPC induced a TRPV2-independent calcium influx and irreversible inward currents in HEK 293T cells. However, 3 µM LPC induced a reversible potentiation of membrane currents induced by 2-APB, cannabidiol (CBD), probenecid (PBC) and weak acids, but not to heat. This sensitization of TRPV2 was robust in whole cell experiments, but not in cell-free inside-out or outside-out patches. A disruption of the actin cytoskeleton with cytochalasin D, but also the depletion of cholesterol or sphingomyelin from the cell membrane diminished the potentiating effects of LPC on TRPV2. In conclusion, we present novel data describing that the PLA2 downstream signaling lipid LPC amplifies TRPV2-mediated responses via indirect mechanisms that seem to involve a destabilization of lipid rafts and the actin cytoskeleton.

The myogenic response is an important regulatory mechanism under physiological as well as pathophysiological conditions. However, little is known about the myogenic response under pulsatile pressure conditions. Therefore, based on the known mechanisms governing the myogenic response induced by static pressure, we tested the hypothesis that a stronger myogenic response induced by pulsatile pressure is due to a larger increase of the intracellular calcium concentration and/or a higher calcium sensitivity of vessel tone. Rat small tail and gracilis arteries were studied using isobaric myography and FURA-2 fluorimetry. We found that in small tail arteries, the effect of pulsatile pressure on the myogenic response is determined by its systolic pressure, whereas in gracilis arteries, the effect of pulsatile pressure is determined by its mean pressure. Interestingly, the effect of pulsatile pressure on the intracellular calcium concentration in both vessels is determined by its systolic pressure. However, while calcium sensitivity of myogenic tone did not differ between static and pulsatile pressure conditions in small tail arteries, it was weaker under pulsatile pressure than under static pressure in gracilis arteries. In conclusion, a stronger myogenic response under pulsatile pressure conditions, i.e., the capability of a vessel to respond to systolic pressure, requires the vessel's ability to maintain and not lose the calcium sensitivity of myogenic tone compared to static pressure conditions.