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

Several forebrain and brainstem neurochemical circuitries interact with peripheral, neural, and humoral signals to collaboratively maintain both the volume and osmolality of extracellular fluids. Over the past decades, much progress has been made in understanding the complex mechanisms underlying the neuroendocrine control of hydromineral homeostasis. Classical experiments performed by Dr. Antunes-Rodrigues in the early 1960s, such as lesions of hypothalamic and extrahypothalamic areas and drug microinfusions, associated with behavioral analysis and electrolytes/hormones measurements, were crucial to elucidate several aspects of the regulation of hydromineral balance. Fifty years after this pioneering research, the use of immunohistochemistry shifted methodological efforts to the central nervous system, in an attempt to elucidate how neurons (and lately, also glial cells) receive and interpret sensory signals originating from the periphery. This report focuses on the main findings obtained by Dr. Antunes-Rodrigues and colleagues using immunohistochemistry as an important tool in the first two decades of this century to elucidate the brain-specific neurochemical circuits underlying functional mechanisms by which osmotic and volume challenges could impact hormonal and behavioral responses.

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.