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

Seizures in preterm infants are highly associated with adverse neurodevelopmental outcomes. Clinical diagnosis remains a challenge because seizures in preterm infants are often clinically silent. The present study examined whether seizure-related cardiovascular changes could aid seizure detection. Chronically instrumented preterm fetal sheep at 0.7 gestation received sham hypoxia-ischaemia (HI) (n = 10) or HI induced by 25 min of complete umbilical cord occlusion (n = 10). Fetal electroencephalogram (EEG) recovery and cardiovascular physiology were assessed until 72 h post HI. HI was associated with stereotypic evolving seizure activity starting 14 ± 13 h (mean ± SD) after HI, with an average total seizure count of 42 ± 2, duration 67 ± 25 s, amplitude 187 ± 88 µV, and seizure burden of 150 ± 129 s/h. Individual seizures were associated with increased mean arterial pressure (MAP) (38.2 ± 2.7 to 40.1 ± 3.2 mmHg). The fetal heart rate (FHR) response during seizures was predominantly tachycardia, but either bradycardia or no change was seen in 21% of seizures. Using minute-to-minute variation in MAP and FHR above one standard deviation as thresholds, the presence of seizures on electroencephalogram (EEG) was predicted with a sensitivity of 75.1 ± 30.4% and 66.5 ± 26.2%, respectively. Using MAP and FHR as a composite measure detected 87.1 ± 4.2% of stereotypic seizures. These data suggest that seizure-related transient fluctuations in MAP and FHR are potentially useful biomarkers for electrographic seizure activity.NEW & NOTEWORTHY In preterm fetal sheep, seizures after hypoxia-ischaemia were associated with increased mean arterial pressure and either increased or decreased fetal heart rate. Minute-to-minute variation in mean arterial pressure and fetal heart rate measures detected 75.1 ± 30.4% and 66.5 ± 26.2% of seizures, respectively, whereas together they detected 87.1 ± 4.2%. Assessment of seizure-related cardiovascular changes may help to improve seizure detection in preterm infants.

Repeated remote ischemic preconditioning (RIPC) improves endothelial-dependent cutaneous vasodilation. However, the role of repeated RIPC on the postocclusive reactive hyperemia (PORH) response in the cutaneous microvasculature is unknown; here, we assessed whether repeated RIPC would increase PORH responses. Thirty participants (23 ± 3 yr old) performed either repeated RIPC (1 session/day for a week, n = 10 or 12 sessions over 2 wk, n = 12) or 2-wk control (n = 8). Each RIPC session comprised 4 repetitions of 5-min arm blood flow occlusion interspersed by 5-min reperfusion. PORH was elicited by brachial artery occlusion for 5 min. Cutaneous vascular conductance was determined using laser speckle contrast imaging before and after the repeated RIPC. The control group did not receive RIPC but underwent the PORH measurements 2 wk later. Area under the curve and peak of PORH were not different. Max/Time to Peak, the maximum hyperemia achieved (Max) over the rate of reperfusion following arterial occlusion (Tp), improved similarly after both 1 and 2 wk of repeated RIPC (1 wk: 0.09 ± 0.04 vs. 0.12 ± 0.07, 2 wk: 0.12 ± 0.03 vs. 0.14 ± 0.04 CVC/s, Pre vs. Post, P < 0.05). Tp improved only after 2 wk of RIPC (Tp: 16.5 ± 2.1 vs. 14.8 ± 2.4 s, Pre vs. Post, P < 0.05). The control group responses did not change after 2 wk. Repeated RIPC did not increase the magnitude of the hyperemic response but did alter temporal measures of PORH such as Max/Tp and Tp following cuff deflation.NEW & NOTEWORTHY This study investigated the extent to which 1) repeated RIPC improved PORH-induced cutaneous microvascular reactivity and 2) a longer period of RIPC further improved cutaneous microvascular reactivity. Both 1 and 2 wk of RIPC improved cutaneous microvascular reactivity similarly. However, only 2 wk of RIPC altered temporal PORH variables. These results suggest that repeated RIPC increases cutaneous microvascular reactivity following occlusion, but longer duration RIPC may be needed to alter temporal cutaneous microvascular reactivity.

Cardiac cachexia, characterized by adipose tissue atrophy, has the most unfavorable outcome in heart failure (HF). Adipose dysfunction might worsen HF as adipose tissue has been found to have cardioprotective effects mediated through its metabolic and endocrine functions, and therefore, could serve as a novel therapy target. In the context of adipose tissue homeostasis, adipocyte progenitor cells (APCs) play critical roles in maintaining the number and function of mature adipocytes, including lipid metabolism and hormone secretion. However, the mechanism by which HF affects APCs has not been elucidated. In this study, we aimed to evaluate the number and functions of Lin^-CD24⁺ APCs in the subcutaneous adipose tissue of mice subjected to transverse aortic constriction-induced HF. This HF model greatly reduced the number of APCs and increased their apoptosis, resulting in lipodystrophy. In vitro assays revealed that HF limited APC proliferation and senescence. With respect to the mechanism of impaired APC function in HF, we identified that augmented sympathetic nerve activity partially mediated the decrease in APC counts via unilateral adipose tissue denervation (ATD). Furthermore, ATD mitigated HF-induced APC senescence. We elucidated that HF and excess sympathetic nerve activity impaired the adipogenic differentiation capacity of APCs. In conclusion, HF induced APC loss and senescence by augmenting sympathetic nerve activity. The impaired adipogenic capacity of APCs results in reduced healthy adipose tissue mass, suggesting that this phenomenon could be responsible for the worsening of HF.NEW & NOTEWORTHY Our work elucidated the negative feedback between heart failure (HF) and the number and function of adipocyte progenitor cells (APCs). HF drastically decreases CD24⁺ APC number and proliferative capacity. Furthermore, we discovered that HF impaired the capacity of APCs to differentiate into mature adipocytes. In conclusion, impaired APC function in HF would be a new research target to ameliorate severe HF outcomes in patients with cachexia.

Skeletal muscle dysfunction contributes to exercise intolerance in patients with pulmonary arterial hypertension (PAH). Reduced blood flow to skeletal muscle has been demonstrated in a rat model of the disease. We investigated the effect of acute nitrate ([Formula: see text]) ingestion via beetroot juice (BRJ) on exercising muscle blood flow, and on plasma and muscle nitrate ([Formula: see text]), nitrite ([Formula: see text]), and cyclic GMP (cGMP) in male Sprague Dawley rats (∼200 g, n = 24) with monocrotaline-induced (60 mg/kg) pulmonary hypertension (PH). Muscle blood flow was assessed at rest and during treadmill running using fluorescent microspheres. Despite higher plasma [Formula: see text] (756 ± 118 vs. 63 ± 22 µmol/L, P ≤ 0.001) and [Formula: see text] (0.63 ± 0.10 vs. 0.24 ± 0.04 µmol/L, P = 0.003), no difference between BRJ and PL was observed in either resting (P = 0.88) or exercising (P = 0.42) blood flow. Only [Formula: see text] was higher in BRJ vs. PL for both the soleus (sol: 261 ± 20 vs. 123 ± 18 vs. µmol/kg, P ≤ 0.0005) and vastus lateralis (VL: 176 ± 34 vs. 86 ± 14 µmol/kg, P = 0.02), with no differences for [Formula: see text] (sol: 1.9 ± 0.2 vs. 1.7 ± 0.3 µmol/kg, P = 0.49; VL: 1.04 ± 0.2 vs. 1.03 ± 0.2 µmol/kg, P = 0.97) or cGMP (sol: 4.8 ± 2.1 vs. 3.9 ± 1.5 vs. nmol/kg, P = 0.22; VL 6.0 ± 3.8 vs. 5.8 ± 3.2 nmol/kg, P = 0.91). In a rat model of severe PH, acute BRJ dosing increases circulating and muscle [Formula: see text] but does not alter muscle blood flow. Absence of change in muscle [Formula: see text] and cGMP suggest insufficiently altered downstream NO signaling with BRJ supplementation.NEW & NOTEWORTHY Muscle dysfunction in pulmonary hypertension (PH) includes impairment in blood flow. The use of dietary nitrate to increase blood flow and potentially improve exercise tolerance has not been studied in this population. We show that acute dietary nitrate supplementation does not increase directly measured muscle blood flow in a PH rat, despite increases in plasma nitrate and nitrite. Muscle nitrate is elevated, but other markers of nitric oxide signaling (nitrite and cyclic GMP) are unaltered.

Sodium appetite is a motivated behavior that occurs in response to sodium deprivation. Various neurotransmitters, including serotonin, are thought to regulate sodium intake. In the present study, we used genetic deletion to test whether serotonergic neurons are necessary for regulating sodium appetite. First, we confirmed that Pet1-Cre;Lmx1b^flox/flox (Lmx1b^f/f/p) mice have nearly complete deletion of serotonergic neurons, with only sporadic cells remaining. Next, we measured baseline intake of water and 3% NaCl and found that Lmx1b^f/f/p mice consume more salt than Cre-negative littermate-control mice (Lmx1b^f/f). Finally, we tested the necessity of serotonergic neurons for thirst and sodium appetite inhibition. After 24-h water deprivation, mice lacking serotonergic neurons exhibited an intact thirst response by increasing water intake just like Cre-negative littermates. After furosemide diuresis followed by 24-h sodium deprivation, mice lacking serotonergic neurons exhibited an intact sodium appetite response by increasing salt and water intake like Cre-negative littermates. Interestingly, the baseline daily salt intake of Lmx1b^f/f/p mice increased between tests relative to their initial baseline. Together, these findings indicate that although serotonergic neurons are not the primary mechanism controlling sodium appetite, they act as a "brake," limiting sodium consumption. This tonic inhibitory role may protect against excess sodium intake and suggests the possibility that serotonergic medications may influence dietary sodium consumption.NEW & NOTEWORTHY This study demonstrates a fundamental role for serotonergic neurons in limiting sodium intake. Mice with genetic deletion of serotonin-producing neurons consume more salt, indicating that serotonergic neurons act like a brake to restrain sodium appetite. These findings advance our understanding of how the brain controls salt-seeking behavior.

Estrogen plays a critical role in the regulation of physiological functions, including metabolism, and its involvement in the regulation of insulin sensitivity and glucose homeostasis has major clinical relevance. Despite the importance of the brain-liver pathway in the regulation of glucose metabolism and that postmenopausal women have an increased risk of developing metabolic disorders, the effect of hormone therapy on hypothalamic neurons involved in the regulation of liver metabolism is not known. Here, we tested the hypothesis that in middle-aged, high-fat diet (HFD)-fed female mice, the excitability of liver-related neurons in the paraventricular nucleus (PVN) of the hypothalamus is increased, whereas estradiol treatment attenuates this increase. Mice fed with phytoestrogen-free control (low-fat diet) or HFD were ovariectomized, received a silastic capsule implant containing either estradiol or vehicle, and stayed on their respective diets. Estradiol treatment resulted in less fat mass and lower body weight. Liver-related neurons were identified with a retrograde, transsynaptic viral tracer, and patch-clamp recordings were conducted from identified neurons in the PVN. Our data show that the excitability of liver-related PVN neurons was increased in ovariectomized HFD mice compared with LFD-fed mice. In estradiol-treated HFD mice, the firing of liver-related PVN neurons was significantly reduced compared with vehicle-treated HFD mice, whereas in LFD mice, estradiol treatment did not alter the activity of liver-related PVN neurons. Our findings suggest that midlife estradiol treatment has beneficial effects on liver-related PVN neurons and thus may contribute to the improved metabolic status observed in estradiol-treated HFD mice.NEW & NOTEWORTHY Menopause increases the risk of metabolic disorders, and despite the importance of the brain-liver pathway in the regulation of glucose homeostasis, the effect of estradiol treatment on liver-related neurons is not known. Our data show that in middle-aged, high-fat diet-fed, ovariectomized female mice, the excitability of liver-related neurons in the paraventricular nucleus is increased, whereas estradiol treatment attenuates this increase. These data suggest that midlife estradiol treatment is beneficial for the brain-liver pathway.

Some beneficial adaptations to exercise training appear to be blunted in females with polycystic ovary syndrome (PCOS) relative to controls. Impaired hyperemic responses to exercise may contribute to this phenomenon. Therefore, we compared the active limb hyperemic response with acute dynamic single-leg exercise to exhaustion between lean females with PCOS [n = 14, age: 23 ± 5 yr, body mass index (BMI): 23 ± 2 kg/m²] and age- and BMI-matched females without PCOS (CTRL; n = 14). Femoral artery blood flow (FBF; duplex vascular ultrasound) and finger photoplethysmography-derived mean arterial blood pressure (MAP) were recorded at baseline and throughout graded concentric knee extensions to exhaustion (Biodex Pro 4 dynamometer). Resting FBF was not different between PCOS and CTRL (416 ± 238 vs. 360 ± 163 mL/min, respectively; P = 0.43). FBF and leg vascular conductance responses to exercise were blunted in PCOS relative to CTRL (effects of group: P = 0.03 and 0.02, respectively). Resting MAP was higher in PCOS than CTRL (91 ± 6 vs. 86 ± 7 mmHg; P = 0.04), although MAP responses to exercise were not different between PCOS and CTRL overall (effect of group: P = 0.31). In sum, we observed blunted hyperemic responses throughout exercise in this cohort of relatively healthy females with PCOS.NEW & NOTEWORTHY We studied a young and lean cohort of females with PCOS to determine whether acute hyperemic responses to exercise would be adversely impacted by PCOS, even in a relatively healthy cohort. Despite similar blood pressure responses to exercise, acute hyperemic responses to single-leg exercise to exhaustion were smaller in PCOS than controls. This provides novel information in an attempt to understand the cardiovascular dysfunction characteristic of females with PCOS.

Calcium (Ca²⁺) and magnesium (Mg²⁺) are important for bone formation, muscle contraction and mass, and nerve function. Processes regulating Ca²⁺, Mg²⁺, parathyroid hormone (PTH), and vitamin D₃ are tightly coupled, ensuring proper bone metabolism and intestinal and renal absorption of Mg²⁺ and Ca²⁺. To better understand the synergy among these processes, mathematical modeling can be used in conjunction with experimental studies. Although several Ca²⁺ homeostasis models exist, computational models for studying Mg²⁺ homeostasis are much more limited. To fill this knowledge gap, we developed a model of Ca²⁺ and Mg²⁺ homeostasis in humans (more specifically, men), based on a previously published model in male rats. The model describes the exchanges of Ca²⁺, Mg²⁺, PTH, and calcitriol among five compartments: plasma, parathyroid gland, intestine, kidney, and bone. Given the increasing prevalence of dietary Mg²⁺ deficiency and its clinical importance as a risk factor for osteoporosis, we simulated severe dietary Mg²⁺ deficiency. Our model predicted a significant drop in PTH and calcitriol levels and an increase in bone resorption. In addition, we analyzed the systemic effects of diuretics, commonly used for the management of blood pressure and fluid balance. Although the pharmacological targets of diuretics typically directly mediate Na⁺ transport, they also indirectly alter renal Ca²⁺ and Mg²⁺ handling through changes in the transepithelial electrochemical gradient, thus affecting Ca²⁺ and Mg²⁺ balance. Model results suggest that acute administration of these three diuretics may not significantly perturb plasma concentrations of Ca²⁺, Mg²⁺, and the calciotropic hormones, whereas chronic administration can cause electrolyte and hormonal dyshomeostasis and affect bone mineral content.NEW & NOTEWORTHY The kidneys play an important role in maintaining the homeostasis of calcium and magnesium. Although diuretics directly affect the kidney's handling of sodium, they also indirectly affect renal calcium and magnesium reabsorption through changes in electrochemical gradients. How do diuretics affect whole body calcium and magnesium balance? To answer this question, we simulate the effect of acute and chronic administration of loop, thiazide, and K-sparing diuretics on renal transport and homeostasis of calcium and magnesium.

High-altitude (HA) exposure induces an integrated physiological response to mitigate hypoxemia. Exogenous ketosis at simulated HA was previously shown to accentuate sympathetic activation and attenuate pulse oxygen saturation ([Formula: see text]) decreases through hyperventilation. The aim of this study was to extend these findings by investigating the effects of intermittent exogenous ketosis (IEK) across 2 days at terrestrial HA (3,375 m) on baroreflex sensitivity, heart rate variability, and hypoxic/hypercapnic ventilatory responses. Thirty-four healthy active adults completed neutral, hypoxic, and hypercapnic (0.03 [Formula: see text]) exposures, each comprising 6 min of seated rest, once at sea level (SL) and once after 2 days at HA. Across the 2 days, participants intermittently ingested either ketone monoester supplements (IEK) or placebo (PLA). During each exposure, blood pressure, ventilation, [Formula: see text], and end-tidal CO₂ pressure ([Formula: see text]) were continuously recorded, and arterialized capillary blood gas content was measured in the final 30 s. Baroreflex sensitivity and time-domain metrics of heart rate variability were reduced at HA (P = 0.006-0.043) but unaffected by group (P = 0.288-0.525). However, ventilation at HA under all three conditions was significantly higher in IEK compared with PLA (all P < 0.001). In hypoxia, this induced a higher [Formula: see text] (P = 0.038) and capillary O₂ pressure (P = 0.003). In hypercapnia, this induced a lower [Formula: see text] and capillary CO₂ tension (both P < 0.001). These results extend previous findings, suggesting that IEK enhances ventilation at terrestrial HA after 2 days of exposure, with this effect being independent from baroreflex sensitivity or heart rate variability changes.NEW & NOTEWORTHY This study demonstrates that 2 days of intermittent exogenous ketosis at 3,375 m terrestrial altitude does not alter baroreflex sensitivity or heart rate variability but significantly increases pulmonary ventilation under neutral, hypoxic, and hypercapnic conditions, improving oxygenation and lowering carbon dioxide retention. These findings suggest that ketone supplementation may enhance ventilatory acclimatization to high altitude via metabolic acidosis-driven respiratory stimulation, offering a nonpharmacological alternative to typical interventions used to support acclimatization.