Pflugers Archiv : European journal of physiology最新文献

Histamine H3 receptors (H3Rs) are known to modulate neurotransmitter release in the nervous system, but their role in cardiac injury remains unclear. The present study aimed to investigate the cardioprotective role of H3Rs in a mouse model of myocardial injury. Forty BALB/c male mice were divided into four groups: Control (SF), Isoproterenol (ISO), Imetit (IMT), and IMT + ISO. The IMT and IMT + ISO groups were pretreated orally with 10 mg/kg imetit-dihydrobromide(imetit) for 7 days. In the last 2 days, the ISO and IMT + ISO groups received a subcutaneous injection of 85 mg/kg isoproterenol to induce myocardial ischemia. Electrocardiogram (ECG) recordings were obtained, and heart tissues were analyzed histopathologically. The results demonstrated that the administration of imetit resulted in the prolongation of the PR interval in the IMT group. QRS and QT intervals were prolonged in the ISO group. The J-wave area in the ISO group was significantly larger than in the other groups. Histopathological analyses revealed the presence of small vacuoles, inflammatory cell infiltration, and collagen aggregates in cardiomyocytes in the ISO group. No significant cellular changes were observed in the IMT group, in contrast. The IMT + ISO group exhibited fewer ischemic findings than the ISO group. Immunohistochemical analyses revealed positive H3R immunoreactivity in all groups. Imetit pretreatment increased the immunoreactivity of H3Rs in both the IMT and IMT + ISO groups. The findings of this study suggest that H3Rs may be present on the postsynaptic side in cardiac myocytes, in addition to adrenergic presynaptic nerve endings. Furthermore, imetit has been found to significantly reduce the effects of myocardial ischemia by activating H3Rs. The better characterization of the postsynaptic role of H3Rs offers potential for the development of new therapeutic strategies.

In odontoblasts, intracellular Ca²⁺ signaling plays key roles in reactionary dentin formation and generation of dentinal pain. Odontoblasts also express several G_s protein-coupled receptors that promote production of cyclic AMP (cAMP). However, the crosstalk between intracellular cAMP and Ca²⁺ signaling, as well as the role of cAMP in the cellular functions of odontoblasts, remains unclear. In this study, we measured intracellular cAMP levels and intracellular free Ca²⁺ concentration ([Ca²⁺]_i). We also investigated the effect of intracellular cAMP on mineralization by the odontoblasts. In the presence of extracellular Ca²⁺, the application of forskolin (adenylyl cyclase activator) or isoproterenol (G_s protein-coupled beta-2 adrenergic receptor agonist) increased intracellular cAMP levels and [Ca²⁺]_i in odontoblasts. The [Ca²⁺]_i increases could not be observed by removing extracellular Ca²⁺, indicating that cAMP is capable to activate Ca²⁺ entry. Forskolin-induced [Ca²⁺]_i increase was inhibited by a protein kinase A inhibitor in odontoblasts. The [Ca²⁺]_i increase was sensitive to Gd³⁺, 2APB, or Zn²⁺ but not verapamil, ML218, or La³⁺. In immunofluorescence analyses, odontoblasts were immunopositive for calcium homeostasis modulator 1 (CALHM1), which was found close to ionotropic ATP receptor subtype, P2X₃ receptors. When CALHM1 was knocked down, forskolin-induced [Ca²⁺]_i increase was suppressed. Alizarin red and von Kossa staining showed that forskolin decreased mineralization. These findings suggest that activation of adenylyl cyclase elicited increases in the intracellular cAMP level and Ca²⁺ influx via protein kinase A activation in odontoblasts. Subsequent cAMP-dependent Ca²⁺ influx was mediated by CALHM1 in odontoblasts. In addition, the intracellular cAMP signaling pathway in odontoblasts negatively mediated dentinogenesis.

The glucagon-like peptide 1 receptor (GLP-1R) agonist semaglutide has revolutionized the treatment of obesity, with other gut hormone-based drugs lined up that show even greater weight-lowering ability in obese patients. Nevertheless, bariatric surgery remains the mainstay treatment for severe obesity and achieves unparalleled weight loss that generally stands the test of time. While their underlying mechanisms of action remain incompletely understood, it is clear that the common denominator between GLP-1R agonists and bariatric surgery is that they suppress food intake by targeting the brain. In this Review, we highlight recent preclinical studies using contemporary neuroscientific techniques that provide novel concepts in the neural control of food intake and body weight with reference to endogenous GLP-1, GLP-1R agonists, and bariatric surgery. We start in the periphery with vagal, intestinofugal, and spinal sensory nerves and then progress through the brainstem up to the hypothalamus and finish at non-canonical brain feeding centers such as the zona incerta and lateral septum. Further defining the commonalities and differences between GLP-1R agonists and bariatric surgery in terms of how they target the brain may not only help bridge the gap between pharmacological and surgical interventions for weight loss but also provide a neural basis for their combined use when each individually fails.

This study aims to investigate the effect of estrogen hindrance, i.e., menopause in women for instance with rheumatoid arthritis on the brain hippocampal region by using collagen-induced arthritis (CIA) female rat model (RA). CIA was induced in female rats by injecting bovine type II collagen and incomplete Freund's adjuvant. Estrogen receptor antagonist, fulvestrant (Ful), was given to RA rats to create estrogen hindrance. Control (C) and RA rats were injected with saline and DMSO, respectively, while RA + Ful rats received a 7-day fulvestrant injection. Following experiment completion, rats were sacrificed, and brains were harvested. Brains were stained with H&E and cresyl violet staining and morphological changes in the hippocampus were identified. Additionally, oxidative stress, inflammatory, and apoptosis markers' levels in the hippocampus were analyzed by qPCR, ELISA, and immunohistochemistry techniques. RA + Ful rats showed neuronal atrophy and reduced neurogenesis in the hippocampal regions. NOX4, NF-κB, IL-1β, IL-6, TNF-α, IKK-β, and Bax protein expression levels in the hippocampus were increased, whereas hippocampal Bcl-2, caspase-3, caspase-9, and IGF-1R protein expression levels were decreased. Furthermore, RA + Ful rats had lower levels of antioxidants PON-1 and catalase in the hippocampal regions. The changes in these molecular markers were statistically significant when compared to RA rats without Ful treatment (p < 0.05). Estrogen hindrance exaggerated oxidative stress, inflammation, and apoptosis which resulted in neuronal degeneration in the hippocampal regions in rheumatoid arthritis.

The Na⁺-K⁺-ATPase is a critical regulator of ion homeostasis during contraction, buffering interstitial K⁺ accumulation, which is linked to muscle fatigue during intense exercise. Within this context, we adopted a recently reported methodology to examine exercise-induced alterations in maximal Na⁺-K⁺-ATPase activity. Eighteen trained healthy young males completed a repeated high-intensity cycling protocol consisting of three periods (EX1-EX3) of intermittent exercise. Each period comprised 10 × 45-s cycling at ~ 105% W_max and a repeated sprint test. Muscle biopsies were sampled at baseline and after EX3 for determination of maximal in vitro Na⁺-K⁺-ATPase activity. Blood was drawn after each period and in association with a 2-min cycling test at a standardized high intensity (~ 90% W_max) performed before and after the session to assess plasma K⁺ accumulation. Further, a 5-h recovery period with the ingestion of carbohydrate or placebo supplementation was implemented to explore potential effects of carbohydrate availability before sampling a final biopsy and repeating all tests. A ~ 12% reduction in maximal Na⁺-K⁺-ATPase activity was demonstrated following EX3 compared to baseline (25.2 ± 3.9 vs. 22.4 ± 4.8 μmol·min^-1·g^-1 protein, P = 0.039), which was sustained at the recovery time point (~ 15% decrease compared to baseline to 21.6 ± 5.9 μmol·min^-1·g^-1 protein, P = 0.008). No significant effect of carbohydrate supplementation was observed on maximal Na⁺-K⁺-ATPase activity after recovery (P = 0.078). In conclusion, we demonstrate an exercise-induced depression of maximal Na⁺-K⁺-ATPase activity following high-intensity intermittent exercise, which was sustained during a 5-h recovery period and unrelated to carbohydrate availability under the present experimental conditions. This was shown using a novel NADH coupled assay and confirms previous findings using other methodological approaches.

The nucleus tractus solitarius (NTS) contains neurons that relay sensory swallowing commands information from the oropharyngeal cavity and swallowing premotor neurons of the dorsal swallowing group (DSG). However, the spatio-temporal dynamics of the interplay between the sensory relay and the DSG is not well understood. Here, we employed fluorescence imaging after microinjection of the calcium indicator into the NTS in an arterially perfused brainstem preparation of rat (n = 8) to investigate neuronal population activity in the NTS in response to superior laryngeal nerve (SLN) stimulation. Respiratory and swallowing motor activities were determined by simultaneous recordings of phrenic and vagal nerve activity (PNA, VNA). The analysis of SLN stimulation near the threshold triggering a swallowing allowed us to analyze Ca²⁺ signals related to the sensory relay and the DSG. We show that activation of sensory relay neurons triggers spatially confined Ca²⁺ signals exclusively unilateral to the stimulated SLN at short latencies (114.3 ± 94.4 ms). However, SLN-evoked swallowing triggered Ca²⁺ signals bilaterally at longer latencies (200 ± 145.2 ms) and engaged anatomically distributed DSG activity across the dorsal medulla oblongata. The Ca²⁺ signals originating from the DSG preceded evoked VNA swallow motor bursts, thus the swallowing premotor neurons that drive laryngeal motor pools are located outside the DSG. In conclusion, the study illuminates the spatial-temporal features of sensory-motor integration of swallowing in the NTS and further supports the hypothesis that the NTS harbors swallowing pre-motor neurons that may generate the swallowing motor activity, while first-order pre-motor pools are located outside the DSG.

The global increase of overweight and obesity in children and adults is one of the most prominent public health threats, often accompanied by insulin resistance, hypertension, and dyslipidemia. The simultaneous occurrence of these health problems is referred to as metabolic syndrome. Various criteria have been proposed to define this syndrome, but no general consensus on the specific markers and the respective cut-offs has been achieved yet. As a consequence, it is difficult to assess regional variations and temporal trends and to obtain a comprehensive picture of the global burden of this major health threat. This limitation is most striking in childhood and adolescence, when metabolic parameters change with developmental stage. Obesity and related metabolic disorders develop early in life and then track into adulthood, i.e., the metabolic syndrome seems to originate in the early life course. Thus, it would be important to monitor the trajectories of cardio-metabolic parameters from early on. We will summarize selected key studies to provide a narrative overview of the global epidemiology of the metabolic syndrome while considering the limitations that hinder us to provide a comprehensive full picture of the problem. A particular focus will be given to the situation in children and adolescents and the risk factors impacting on their cardio-metabolic health. This summary will be complemented by key findings of a pan-European children cohort and first results of a large German adult cohort.

Adequate assessment of the contribution of the different phases of atrial mechanical activity to the value of ejection volume and pressure developed by the ventricle is a complex and important experimental and clinical problem. A new method and an effective algorithm for controlling the interaction of isolated rat right atrial and right ventricular strips during the cardiac cycle were developed and tested in a physiological experiment. The presented functional model is flexible and has the ability to change many parameters (temperature, pacing rate, excitation delay, pre- and afterload levels, transfer length, and force scaling coefficients) to simulate different types of cardiac pathologies. For the first time, the contribution of the duration of the excitation delay of the right ventricular strips to the amount of work performed by the muscles during the cardiac cycle was evaluated. Changes in the onset of atrial systole and the delay in activation of ventricular contraction may lead to a reduction in cardiac stroke volume, which should be considered in the diagnosis and treatment of cardiovascular disease and in resynchronization therapy.

The ventromedial hypothalamus (VMH) plays an important role in feeding behavior and control of the sympathetic nervous system (SNS). The VMH includes a group of neurons that exhibit strong synchronized rhythmic burst firing (so-called VMH oscillation). This VMH oscillation is glucose inhibited, responsive to feeding-related peptides, and is functionally coupled to outputs of the SNS. However, the details of its rhythm generation and synchronization mechanisms are unknown. In the present study, we investigated cellular mechanisms of VMH oscillation by means of electrophysiological recordings and calcium imaging in juvenile rat slice preparations including the VMH. In the electrophysiological study, we performed membrane potential recording from neurons in the vicinity of pipettes for field potential recording. We found that the rhythmic bursts in the VMH were preserved in low Ca²⁺/high Mg²⁺ synaptic transmission blockade solution. During membrane hyperpolarization by current injection, the action potential was largely inhibited, but fluctuation of the membrane potential remained with a frequency similar to that at resting potential level. The electric VMH oscillation disappeared after application of either a gap junction blocker, carbenoxolone (100 µM), or a persistent sodium channel blocker, riluzole (20 µM). Membrane potentials and input resistances of rhythmic burst neurons in the VMH were not significantly changed during these manipulations. A calcium imaging study revealed that all VMH cells exhibiting synchronized rhythmic activity detected by intracellular calcium increases were silenced following the application of carbenoxolone. These results suggest that VMH oscillation arises from the activation of persistent sodium channels and coupling via gap junctions.