Acta Physiologica最新文献

Background

The circulation of 4–6 m tall giraffes is markedly affected by gravity. To ensure cerebral perfusion, upright giraffes generate a blood pressure in excess of 200 mmHg. Before drinking, the head is lowered by 3–5 m, providing exceptional hemodynamic challenges. Here, we provide quantitative hemodynamic measures during head movement and drinking.

Methods

We measured carotid pressure, jugular pressure, heart rate, and blood flow in awake giraffes, along with circulating blood volume and cerebrospinal fluid pressure in anesthetized giraffes. We also analyzed the contractility and innervation of isolated cerebral and extracranial arteries, and the mechanical properties of jugular veins.

Results

When heads were lowered for drinking (i) blood pressure at heart level decreased but increased again during drinking, (ii) jugular pressure increased and oscillated during drinking, (iii) heart rate fell, (iv) carotid blood flow was unchanged, while cephalic hemodynamic resistance increased, and (vi) cranial cerebrospinal fluid pressure increased. Small cerebral arteries exhibited strong myogenic responses, particularly at around 100 mmHg, while extracranial arteries responded at higher pressures (200–250 mmHg). The giraffe's blood volume was small and blood pressure sensitive to minor reductions in blood volume.

Conclusions

Central blood pressure decreased when the head was lowered, but drinking per se caused a surprising rise in blood pressure to pre-drinking levels. This rise in blood pressure is likely due to the transfer of esophageal water boli acting on the jugular veins. The cephalic capillaries are protected by a strong myogenic response and sympathetic innervation.

Aim

Calcineurin inhibitors (CNIs) have revolutionized transplant medicine, improving allograft survival but posing challenges like calcineurin inhibitor-induced nephrotoxicity (CNT). Acute CNT, often dose-dependent, leads to vasoconstriction and acute kidney injury, with treatment focusing on CNI exposure reduction. Chronic CNT manifests as progressive allograft function decline, with challenges in distinguishing it from nonspecific allograft nephropathy.

Methods

This narrative review provides a concise overview of the clinical management of CNT, covering acute and chronic CNT. We reviewed original articles, landmark papers, and meta-analyses on CNT mitigation strategies, including CNI-sparing approaches.

Results

Preventive measures include co-medications, CNI exposure monitoring, and CNI sparing strategies, such as reducing target trough levels and converting to mTOR inhibitors (mTORi) or belatacept. Despite improvements in graft function, challenges persist in demonstrating significant differences in allograft survival with CNI-sparing regimens. The paradigm shift from chronic CNT as the main cause of chronic allograft nephropathy toward rather immunologic triggered injuries and/or comorbidities as relevant contributors to allograft deterioration over time must be kept in mind.

Conclusion

CNIs have significantly improved kidney transplant outcomes, but their associated nephrotoxicity necessitates mitigation strategies. The decision to implement such regimens is always an individual choice balancing against the risk of immunologic injuries. Further long-term studies are needed to optimize immunosuppressive approaches and refine CNT management.

Aim

Vascular calcification contributes to morbidity and mortality in aging and is accelerated in diabetes and in chronic kidney disease. Matrix Gla Protein is a potent inhibitor of vascular calcification, which is activated by the vitamin K-dependent gamma-glutamyl carboxylase (GGCX). However, through a currently unidentified mechanism, the activity of GGCX is reduced in experimental uremia, thereby contributing to the promotion of vascular calcifications. In this study, we aim to identify the cause of these functional alterations and to stimulate the enzyme activity by potential GGCX binding compounds as a new avenue of therapy.

Methods

Two rodent models of experimental uremia and human carotid plaques were assessed for GGCX activity and modifications, as well as calcification. In silico compound screening via BindScope identified potential binding partners of GGCX which were further validated in functional assays for enzymatic activity changes and for in vitro calcification. Mass spectrometry was applied to monitor molecular mass changes of the GGCX.

Results

Mass spectrometry analysis revealed post-translational modifications of the GGCX in uremic rats and mice, as well as in calcified human carotid plaques. Functional assays showed that the post-translational carbamylation of GGCX reduced the enzyme activity, which was prevented by vitamin K2. Chrysin, identified by compound screening, stimulated GGCX activity, reduced calcium deposition in VSMCs, and oxidized GGCX at lysine 517.

Conclusion

In conclusion, this study clearly demonstrates that the vitamin K-dependent enzyme GGCX plays a significant role in uremic calcification and may be modulated to help prevent pathological changes.

Aim

The molecular mechanisms of chronic stress-induced psychiatric disorders, including depression, remain unknown. The current study aimed to assess the role of Cav3.1 T-type calcium channels as a gateway for the chronic stress-induced activation of parvalbumin (PV)-positive gamma-aminobutyric acidergic (GABAergic) neurons in the medial prefrontal cortex (mPFC) of mice.

Methods

The function of the Cav3.1 T-type calcium channel in the mouse mPFC following chronic stress was investigated using behavioral tests, electrophysiological analyses, transcriptome analyses, and optogenetic approaches.

Results

Cav3.1-knockout (Cav3.1^−/−) mice were resistant to chronic stress-induced depressive-like behaviors induced by repeated forced-swimming test or tail-suspension test. Immunohistochemical analysis revealed that Cav3.1 was predominantly localized in PV-positive GABAergic neurons in the mPFC. Based on transcriptomic and electrophysiological analyses, the excitatory–inhibitory (E–I) balance was disrupted by the chronic stress-induced activation of PV-positive GABAergic neurons in the mPFC of wild-type (WT) mice, but not in that of Cav3.1^−/− mice. Optogenetic control of PV-positive GABAergic neurons in the mPFC revealed that they played a pivotal role in depressive-like behaviors. The administration of TTA-A2, a selective T-type calcium channel antagonist, reduced chronic stress-induced depressive-like behaviors.

Conclusion

The Cav3.1 T-type calcium channel acts as a gateway for the activation of GABAergic neurons in the mPFC of mice, thereby eliciting chronic psychobiological stress responses.

Improper gastric emptying is implicated in several gastrointestinal disorders and may result from disrupted electromechanical coupling of the gastroduodenal junction (GDJ). Rhythmic “slow waves” and myogenic “spikes” are bioelectrical mechanisms that, alongside neural and hormonal co-factors, control GDJ motility.

Aim

To characterize the electromechanical effects of prokinetic (erythromycin) infusion and truncal vagotomy on pre-clinical in vivo porcine models.

Methods

Following ethical approval, the GDJ was exposed in anesthetized crossbreed weaner pigs (N = 10), and custom high-resolution electrodes were applied to the serosal surface. An EndoFLIP catheter (Medtronic, USA) was inserted orally and positioned across the pylorus to measure luminal diameter. In all subjects, control periods preceded intravenous infusion of erythromycin. In five of those subjects, truncal vagotomy was performed approximately an hour post-infusion, before recording was resumed.

Results

Compared to control recordings, erythromycin increased contractile amplitude ([2.9 ± 1.1] mm vs. [2.2 ± 0.9] mm; p = 0.002) and was associated with more consistent gastric slow-wave rhythms and increased amplitude of slow waves and spikes. Surgical vagotomy immediately decreased contractile amplitude ([2.90 ± 1.1] mm vs. [1.2 ± 0.6] mm; p = 0.049) and was associated with reduced slow-wave amplitude, increased gastric and duodenal slow-wave frequencies, and decreased spike patch coverage.

Conclusions

In conclusion, prokinetics and vagotomy produced opposing effects on GDJ electromechanical coupling and could inform diagnostic and interventional practices for patients with pathophysiological complications of this region.

Aim

Intestinal glucose transport involves SGLT1 in the apical membrane of enterocytes and GLUT2 in the basolateral membrane. In vivo studies have shown that absorption rates appear to exceed the theoretical capacity of these transporters, suggesting that glucose transport may occur via additional pathways, which could include passive mechanisms. The aim of the study was to investigate glucose absorption in an in vitro model, which has proven useful for endocrine studies.

Methods

We studied both transcellular and paracellular glucose absorption in the isolated vascularly perfused rat small intestine. Glucose absorbed from the lumen was traced with ¹⁴C-d-glucose, allowing sensitive and accurate quantification. SGLT1 and GLUT2 activities were blocked with phlorizin and phloretin. ¹⁴C-d-mannitol was used as an indicator of paracellular absorption.

Results

Our results indicate that glucose absorption in this model involves two transport mechanisms: transport mediated by SGLT1/GLUT2 and a paracellular transport mechanism. Glucose absorption was reduced by 60% when SGLT1 transport was blocked and by 80% when GLUT2 was blocked. After combined luminal SGLT1 and GLUT2 blockade, ~30% of glucose absorption remained. d-mannitol absorption was greater in the proximal small intestine compared to the distal small intestine. Unexpectedly, mannitol absorption increased markedly when SGLT1 transport was blocked.

Conclusion

In this model, glucose absorption occurs via both active transcellular and passive paracellular transport, particularly in the proximal intestine, which is important for the understanding of, for example, hormone secretion related to glucose absorption. Interference with SGLT1 activity may lead to enhanced paracellular transport, pointing to a role in the regulation of the latter.

Aim

Leucine-rich repeat transmembrane proteins (LRRTMs) are synaptic adhesion proteins that regulate synapse development and function. They interact transsynaptically with presynaptic binding partners to promote presynaptic differentiation. Polymorphisms of LRRTM4, one of the four members of this protein family, have been linked to multiple neuropsychiatric disorders and childhood aggression, but the underlying mechanisms and physiological function of LRRTM4 during behavior are currently unclear.

Methods

To characterize the role of this gene for brain function, we combined a battery of behavioral assays with transcriptomic and metabolomic analyses, using zebrafish as a model system.

Results

Our findings revealed that lrrtm4l1, a brain-specific zebrafish orthologue of human LRRTM4, exhibits a brain region-specific expression pattern similar to humans, with strong expression in the dorsal telencephalon, a brain area critical for regulating emotional-affective and social behavior. lrrtm4l1^−/− zebrafish displayed heightened anxiety and reduced aggression, while locomotion and social behavior remained unaffected by the gene knockout. Transcriptomic analysis of the telencephalon identified over 100 differentially expressed genes between wild-type and mutant zebrafish and an enrichment of pathways related to synaptic plasticity and neuronal signaling. The brain metabolome of lrrtm4l1^−/− zebrafish showed multiple alterations, particularly in the dopaminergic and adenosinergic neurotransmitter systems.

Conclusion

These findings suggest that LRRTMs may have functions beyond their established role in excitatory synapse development, such as the regulation of neurotransmission and behavior. Targeting LRRTM4 therapeutically may thus be an interesting novel approach to alleviate excessive aggression or anxiety associated with a number of neuropsychiatric conditions.

Aims

To evaluate the molecular mechanisms involved in intermittent fasting 16/8 (16/8 IF), a widespread dietary practice adopted worldwide that consists of 16 h of fasting and 8 h of feeding.

Methods

Obese mice were fasted daily from 6 am to 10 pm. Food intake, body weight, and energy expenditure were measured. Molecular mechanisms were investigated using ELISA, western blot, and qPCR of white and brown adipose tissues. Glucose homeostasis was also evaluated. Ucp1 knockout and ob/ob mice were utilized.

Results

The 16/8 IF regimen improved glucose homeostasis and reduced body weight, food intake, and overall adiposity. Postprandial VO₂, heat production, brown adipose tissue (BAT) temperature, and ketone bodies increased with 16/8 IF. Postprandial thermogenesis induced by 16/8 IF was abolished in mice after BAT denervation or Ucp1 deletion. Serum leptin levels were elevated, and most metabolic effects of 16/8 IF were absent in leptin-deficient ob/ob mice. Additionally, leptin sensitivity increased in mice exposed to 16/8 IF.

Conclusion

The 16/8 IF regimen can improve metabolism, with findings underscoring the role of enhanced leptin action in inhibiting food intake and promoting postprandial thermogenesis during 16/8 IF.