American journal of physiology. Regulatory, integrative and comparative physiology最新文献

Diet-induced dilated cardiomyopathy (DCM) in dogs has been linked to grain-free, pea-containing diets, possibly due to increased oligosaccharides. Since cross-sectional human studies indicate that heart failure is associated with decreased cerebral blood flow and cognitive decline, we explored whether a similar association could be detected in dogs. This study tested whether diet-induced cardiac impairment coincides with a lower index of cerebral blood flow and cognitive decline in dogs. Eight adult Beagles were fed four diets for 5 weeks each. A commercial dental diet was fed pre-study as a husbandry diet, followed by three test diets fed in a randomized crossover design: a grain-based diet formulated with rice flour (GB), grain-based diet with rice flour and 1% of the oligosaccharide raffinose (GB O), and a grain-free diet containing pea flour (GF). Cardiac function and brain blood flow were assessed using ultrasound, and cognitive function using a sand maze test. Ejection fraction was lower and left ventricular end-systolic volume was greater in dogs fed the GF and husbandry diets compared to the GB and GB O diets. End-diastolic velocity and conductance index were greater in basilar cerebral arteries, while resistive index was lower in dogs fed GF and husbandry diets. Sand maze retrieval times were slower for GF and husbandry diet fed dogs compared to the GB O diet. Thus, reduced ejection fraction was associated with lower cerebral vascular tone and cognitive function in dogs fed GF and husbandry diets. This study is suggestive of a novel link between diet, cardiac function and cognition in dogs.

Alcohol is the most widely abused psychoactive substance globally, with thirst and xerostomia (dry mouth) being common adverse effects following consumption. This review summarizes the potential mechanisms underlying thirst and dry mouth after alcohol intake, as well as the pharmacological and non-pharmacological interventions for alleviating these symptoms. Based on relevant literature, the specific mechanisms of post-alcohol thirst and dry mouth require further investigation; the efficacy of alleviating measures varies among individuals, and additional studies are needed to identify effective strategies for relieving these discomforts.

Brain oxygen levels fluctuate with changes in neural activity and systemic physiology, yet it remains unclear whether oxygen responses to salient stimuli are structure-specific or reflect generalized brain activation. Using oxygen sensors coupled with high-speed amperometry in freely moving rats, we compared oxygen dynamics in three structures with markedly different neuronal firing properties: nucleus accumbens, medial thalamus, and substantia nigra pars reticulata, along with simultaneous measurements in the subcutaneous space. Natural arousing stimuli produced rapid oxygen increases in all brain sites coupled with robust subcutaneous oxygen decreases, though there are minor differences in magnitude. In contrast, intravenous fentanyl (30 µg/kg) induced uniform hypoxic responses in all brain sites, consisting of a rapid and strong decrease followed by a weaker post-hypoxic rebound, with low between-site variability. These findings show that physiological oxygen increases during arousal are largely generalized and likely dominated by systemic mechanisms such as peripheral vasoconstriction, cerebral vasodilation, and global increases in cerebral blood flow, whereas fentanyl-induced hypoxia reflects purely systemic effect induced by respiratory depression. Overall, these results indicate that brain oxygen dynamics are shaped predominantly by systemic physiology rather than local neuronal firing properties, highlighting important constraints on interpreting oxygen-based signals as markers of neuronal activity.

The use of peripheral blood mononuclear cells (PBMCs) in cardiovascular research is increasingly common. However, little is known regarding potential age-related changes in mitochondrial bioenergetics and oxidative stress in PBMCs, or whether such changes relate to endothelial function. We assessed mitochondrial bioenergetics and antioxidant buffering capacity (AoxBC) capacity in PBMCs from young (n = 18; 21 ± 2 yr) and older (n = 17, 66 ± 4 yr) adults. High-resolution respirometry and fluorometry measured mitochondrial respiration rate (JO₂) and membrane potential (Δψm), respectively, in response to substrate provision (pyruvate, glutamate, malate, and succinate; PGMS) and a bioenergetic creatine kinase (CK) clamp at physiological ATP:ADP ratios (PCr1, PCr2, and PCr3). MtROS emission was measured as hydrogen peroxide (H₂O₂) emission, and H₂O₂ production was quantified using inhibitors of glutathione reductase and thioredoxin/peroxiredoxin. AoxBC was calculated as the percentage of H₂O₂ produced but not emitted. Endothelial function was assessed through flow-mediated dilation (FMD). JO₂ was similar between groups at baseline (P = 0.08) and lower energetic states (PCr2, PCr3; P ≥ 0.09), but was lower in older adults at higher energetic states (PCr1: 14.05 ± 2.11 vs. 12.03 ± 2.98 pmol·s^-1·10⁶ cells^-1, P = 0.03; PGMS: 20.61 ± 2.11 vs. 16.58 ± 3.56 pmol·s^-1·10⁶ cells^-1; P = 0.0009). Δψm was hypopolarized in older compared with young adults at all energetic states (P ≤ 0.003). Although there were no statistical differences in H₂O₂ emission (P = 0.43) or production (P = 0.18), AoxBC was lower in older adults (52.59 ± 15.44% vs. 63.49 ± 10.30%; P = 0.03). Age-related changes in JO₂ (PGMS, P = 0.02) and Δψm (PGMS, P = 0.0008; PCr2, P = 0.04; PCr3, P = 0.02) were related to FMD. These data demonstrate associations between altered PBMC mitochondrial bioenergetics and age-related vascular endothelial dysfunction.NEW & NOTEWORTHY The use of peripheral blood mononuclear cells (PBMCs) is increasingly common in cardiovascular research. However, relatively little is known regarding potential age-related changes in PBMC mitochondrial bioenergetics and oxidative stress, or whether age-related changes are related to endothelial (dys)function. We demonstrate altered mitochondrial bioenergetics (oxygen consumption rates and membrane potential) and antioxidant buffering capacity in PBMCs from older compared with young adults. We additionally demonstrate associations between mitochondrial bioenergetics and endothelial function (brachial-artery flow-mediated dilation).

We recently reported that countdown (CD) before voluntary exercise induced cerebral activation and pressor responses, resulting in muscle vasodilation (Manabe et al. J Appl Physiol 128: 1196-1206, 2020). We examined whether responses were enhanced as peak aerobic capacity (V̇o_2peak) increased. We studied 27 young men with V̇o_2peak from 25.2 to 61.4 mL·kg^-1·min^-1. We evaluated CD responses before initiating voluntary cycling at 50% of V̇o_2peak for 1 min in a semirecumbent position while measuring middle cerebral artery blood flow velocity (V_MCA; Doppler ultrasonography), heart rate, mean arterial pressure (MAP; finger photoplethysmography), oxygen consumption rate (V̇o₂), cardiac output (Q_c; ModelFlow), total peripheral resistance (MAP/Q_c), and oxygen saturation in thigh muscle (near-infrared spectrometry). All subjects performed eight trials, intermitted by ≥5-min rest, and were either given a 30-s countdown (CD+) or immediately signaled to begin exercise (CD-), with the order randomized and counterbalanced. We classified subjects with both V_MCA and MAP increases by CD as "responders" (Resp, n = 11) and those with either V_MCA or MAP increase, or an increase of neither, as "minimal responders" (MinResp, n = 16). We found that cerebro-cardiovascular and V̇o₂ responses to CD before starting exercise were all significantly greater in Resp than in MinResp (all P < 0.017), and cerebro-cardiovascular responses were significantly correlated with individual V̇o_2peak in data pooled from both groups (all P < 0.034). The increase in V̇o₂ by CD in Resp continued for a few seconds after starting exercise. Thus, cerebro-cardiovascular responses to CD before starting voluntary exercise were enhanced, as individual V̇o_2peak increased in young men, which might accelerate V̇o₂ response at starting exercise.NEW & NOTEWORTHY The delay of oxygen transport to muscle at the onset of exercise by the cardio-respiratory system increases anaerobic energy production and oxygen deficit, which can disturb a smooth start of exercise. We found that the anticipatory cerebro-cardiovascular responses evoked by a countdown before starting voluntary exercise were enhanced as peak aerobic capacity increased, suggesting that the central as well as peripheral mechanisms contribute to increasing aerobic energy production at the onset of exercise.

Neurons in the nucleus of the solitary tract (NTS) are activated by inputs from the vagus nerve, including those from the gastrointestinal tract. This activation is relayed to central nervous system (CNS) regions critical for the control of food intake. Changes to NTS neuron activation, therefore, impact the transmission of vagal information to the brain. Injection of neuropeptide Y (NPY) and the Y2 receptor agonist PYY-(3-36) into the dorsal vagal complex (DVC) containing the NTS increases food intake. However, how NPY produces this effect is not known. Here, we use transgenic mice with enhanced green fluorescent protein (EGFP) expression driven by the tyrosine hydroxylase promoter (TH-EGFP) to identify NTS catecholamine neurons, as NPY terminals have been found in close proximity to NTS-TH neurons. We recorded from NTS TH-EGFP neurons in horizontal brain slices containing vagal afferents within the solitary tract (ST) using whole cell patch-clamp techniques. NPY inhibited ST-evoked excitatory postsynaptic currents (ST-EPSCs) in approximately two-thirds of TH-EGFP neurons. This effect was blocked by the Y2 receptor antagonist N-[(1S)-4-[(Aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide hydrochloride (BIIE0246) and mimicked by the Y2 agonist PYY-(3-36). In contrast, the Y1 receptor agonist LP-NPY did not inhibit ST-EPSCs. NPY also reduced both basal and vagal-evoked action potentials in CA neurons. Finally, NPY attenuated the ability of the satiety peptide cholecystokinin (CCK) to increase glutamate release onto TH-EGFP neurons, an effect mimicked by PYY-(3-36). These results indicate that NPY inhibits both vagal- and CCK-induced activation of most NTS-TH neurons and suggest a potential mechanism for its effects to increase food intake at the level of the hindbrain.NEW & NOTEWORTHY NPY administered to the NTS stimulates food intake. However, the underlying cellular mechanisms were not well understood. Here we show that NPY inhibits vagal-evoked currents in NTS TH neurons through presynaptic Y2Rs, resulting in reduced throughput of vagal-evoked action potentials. NPY and Y2R activation also inhibited both basal and CCK-induced glutamate release, corresponding with a decrease in basal action potentials. This research identifies presynaptic Y2Rs as the major site of NPY-induced inhibition of NTS neurons.

Evidence suggests that muscle activity can affect muscle carnosine, but the results are mixed. To address this question, we investigated muscle carnosine under the two extremes of the muscle activity-inactivity spectrum. Forty-five male Wistar rats were divided into 3 groups: immobilisation (n=16), SHAM control (n=14), and immobilisation+exercise (n=15). In the immobilised groups, one side was submitted to a sciatic nerve sectioning surgery, with the opposite side being submitted to a SHAM control surgery, creating 4 experimental conditions: denervated (DEN), SHAM active control (SHAM), denervated+exercise (DEN+Ex), and SHAM+exercise (SHAM+Ex). The immobilisation period was 12 weeks, and the swimming training period was 10 weeks (4 times per week, up to 30 min per session). The tibialis anterior (TA) and soleus muscles from both sides were assessed for carnosine and anserine content, total histidine-dipeptides (HCDs), cross-sectional fibre area (CSA) and fibre type distribution. Contractile function was determined ex-vivo in the extensor digitorum longus and the expression of the Carns1, Cndp2 and TauT genes was determined with real-time PCR in TA. Physical inactivity reduced drastically muscle mass, contractile function, and fibre CSA. Long-term post-denervation muscle paralysis reduced muscle carnosine and anserine content, which was not dependent on diet, age, sex or fibre-type. This demonstrates that muscle inactivity is a strong modulator of muscle HCDs content, at least under extreme conditions. Gene expression was not significantly altered in any of the experimental conditions. Exercise training, on the other hand, did not affect muscle HCDs, and may be a less potent regulator of muscle HCDs content.

The global rise in obesity has become a major health concern, in part due to the easy availability and consumption of high-calorie foods together with an increasingly sedentary lifestyle. More than a mere consequence of excess fat accumulation, obesity is now considered a complex health issue involving disrupted balance in how the body manages energy, primarily due to miscommunication between brain regions, such as the hypothalamus, and peripheral organs. One important aspect of this problem is how specific cell signaling pathways are disrupted by aberrant energy sensing and by oxidative stress-mediated damage and inflammation. Among these, AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) have gained wide attention as key players that integrate nutrient-, hormone- and inflammation-related signals. Here, we provide a comprehensive review of isoform-specific JNK functions, highlighting recent advances in the understanding of JNK1, JNK2 and JNK3 in hypothalamic circuits that govern energy balance, thermogenesis and hepatic lipid metabolism. In addition, we also highlight the evolutionary and physiological significance of these kinase isoforms. Thus, this review encompasses current knowledge and key unanswered questions regarding the role of JNK in central and peripheral metabolic regulation.

Polymodal vagal afferent nerves terminating in the mucosa of the large conducting airways play essential roles in regulating cough. These cough receptors project bilaterally from the nodose ganglia, are activated by protons and by mechanical stimulation, and terminate centrally in the medial (SolM) solitary tract nuclei (nTS). While many vagal afferent nerves utilize non-NMDA type glutamate receptors exclusively for transmission centrally, cough receptor signalling requires NMDA receptor activation. We hypothesized that nTS nitric oxide synthase (NOS) activation and a cGMP transduction cascade would act as downstream messenger systems during the encoding of cough. We also hypothesized that NOS expression may be a defining characteristic of cough receptor relay neurons. NADPH-diaphorase staining identified NOS-expressing neurons throughout the brain stem (especially in the trigeminal and cuneate nuclei and in the dorsal motor nuclei of the vagus nerves). NOS expressing nTS neurons were rare but found in SolM. Bilateral SolM microinjections of NOS inhibitors or the NMDA receptor blocker SDZ 220581 markedly reduced coughing evoked by tracheal citric acid challenges. But citric acid evoked coughing was neither attenuated by inhibiting soluble guanylate cyclase in SolM nor potentiated by inhibiting the cGMP-selective phosphodiesterase-5. No changes in basal respiratory patterns were observed with NOS inhibitor or NO donor microinjections, but NMDA microinjection into SolM induced respiratory responses including cough that were at least partially NOS dependent. We conclude that NO is an essential downstream regulator of NMDA receptor mediated encoding of cough in nTS but does not act via soluble guanylate cyclase or cGMP.

Estradiol activates the G protein-coupled estrogen receptor 1 (GPER1), which promotes natriuresis in female rats. Extracellular adenosine triphosphate (ATP) released via connexin 30 (Cx30) hemichannels activates purinergic P2Y₂ receptor, promoting Na⁺ excretion via inhibiting epithelial Na⁺ channel (ENaC) activity. Interestingly, ovariectomy downregulates renal P2Y₂ receptor expression in Sprague Dawley (SD) rats. We hypothesized that GPER1 activation regulates renal Cx30/ATP/P2Y₂/ENaC signaling pathway in females. To test our hypothesis, female SD rats were implanted with telemetry transmitters and then ovariectomized (OVX) and simultaneously implanted with osmotic minipumps to deliver either the selective GPER1 agonist G1 or vehicle for 3 wk. Rats were fed a normal-salt (0.4% NaCl) diet from the start of the experimental protocol until day 14 after ovariectomy. Afterward, rats were shifted to a high-salt diet (4% NaCl) for 7 days. Ovariectomy increased blood pressure during normal salt intake. High salt intake elicited further increases in mean arterial pressure. These increases in blood pressure were prevented by G1. Cx30 and P2Y₂ receptor mRNA expressions were higher in the cortex of OVX SD rats with G1 treatment plus high salt intake. Genetic deletion of GPER1 in mice reduced the renal expression of Cx30 and P2Y₂ receptor. Importantly, renal medullary infusion of G1 in ovary-intact female rats increased urinary ATP and Na⁺ excretion. Furthermore, P2 receptor blockade by suramin blocked GPER1-evoked natriuresis. These findings indicate that GPER1 upregulates the natriuretic Cx30/ATP/P2Y₂ receptor signaling pathway in the kidney, which may contribute to the blood pressure-lowering response to GPER1 activation.NEW & NOTEWORTHY Systemic GPER1 activation upregulated renal Cx30 and P2Y₂ receptor mRNA expression in ovariectomized rats, whereas genetic deletion of GPER1 downregulated renal Cx30 and P2Y₂ receptor mRNA expression in ovary-intact female mice. Acute renal medullary GPER1 activation enhances natriuresis and urinary ATP excretion in ovary-intact female rats. These findings indicate that GPER1 regulates the natriuretic Cx30/ATP/P2Y₂ receptor signaling pathway in the kidney, which may contribute to the blood pressure-lowering response to GPER1 activation.