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

Diving marine mammals must allocate time between respiring at the surface and foraging underwater. Previous studies of optimal diving theory have attempted to predict such patterns, but the amount of time divers must spend at the surface before and after dives of varying durations remains difficult to assess. Here, we examined the surfacing and breathing patterns of short-finned pilot whales (Globicephala macrorhynchus) from biologger data to examine their use of anticipatory versus reactive strategies. We used linear mixed-effects models to examine the effect of dive characteristics on surface interval (SI) durations and breathing rate. Pilot whales increased SI duration before dives of increasing duration and after dives of increasing activity. Instantaneous breathing rates (f_Rs) of pilot whales demonstrated little anticipation but rather a strong reactive pattern seen by the modulation of f_R in response to the previous rather than upcoming dive. During typical SIs, f_R was predicted by time since previous dive, duration of the previous dive, time until upcoming dive, and activity of the previous dive. Short-finned pilot whales in our study area exhibit both benthic and pelagic foraging, which may compel anticipation when prey capture is predictable and reaction when prey capture is difficult to predict. The observed surfacing and breathing patterns therefore likely reflect a balance of the needs for blood gas homeostasis, aerobic metabolism, and the variability of foraging opportunities. An improved understanding of how animals make decisions about diving is critical for informing predictions of how they will contend with changing ocean landscapes.NEW & NOTEWORTHY A new study reveals how short-finned pilot whales balance the conflicting demands of foraging underwater with breathing at the surface. Using data from digital tags, scientists found that pilot whales rely more on surfacing strategies that react to the effort of a dive rather than anticipate. Their use of such strategies may reflect variation in the ability to predict prey capture in benthic and pelagic habitats.

Allostatic load, a maladaptive biological process wherein physiological stability ("allostasis") fails owing to chronic stress exposure, is traditionally measured by the allostatic load index (ALI). Whether ALI is associated with wearable-assessed physiological responses remains unknown. We aimed to determine the association between ALI and wearable-assessed physiological responses during a 10-wk military training course. Twenty-five participants (12 women) with ALI and suitable wearable data [84.31% complete data (range: 64.71%-97.56%)] were included. ALI (0-8) was calculated using biomarker components from neuroendocrine, autonomic, and immune systems. Device variables included total energy expenditure (TEE), energy expenditure during physical activity (PAEE), daytime heart rate (HR), sleeping HR, nonlinear HR variability (detrended fluctuation analysis, DFA-α₁), and sleep architecture. Flux was calculated as raw (Δ) or absolute difference (|Δ|) in average values between days and nights. Generalized linear mixed effect models assessed the association between high allostatic load (ALI > 4) and responses (α = 0.05). Twelve (4 women) participants experienced ALI > 4. High allostatic load was associated with TEE (β = 0.658, standard error (SE) = 0.002, odds ratio (OR) = 1.931, P < 0.001), Δ in relative PAEE (β = 0.472, SE = 0.002, OR = 1.602, P < 0.001), daytime HR (β = 0.189, SE = 0.002, OR = 1.208, P < 0.001), |Δ| in relative daytime HR (β = 0.262, SE = 0.001, OR = 1.298, P < 0.001), and |Δ| in relative sleeping HR (β = -0.048, SE = 0.001, OR = 0.953, P < 0.001). Every one-standard-deviation increase in absolute TEE, flux in relative PAEE, daytime HR, flux in daytime HR, and reduced flux in sleeping HR increased the risk of high allostatic load by 5%-90%. Chronically elevated and variable cardiometabolic activity with blunted night-to-night variation in sleeping HR may be a digital phenotype of high allostatic load in military personnel.NEW & NOTEWORTHY This investigation for the first time observed an association between the traditional measurement of allostatic load, the allostatic load index, and wearable-assessed physiological responses to strenuous military training stress. We found a novel digital phenotype of allostatic load characterized by chronically elevated and variable cardiometabolic activity with blunted variation in heart rate during sleep. This phenotype may serve as an at-risk profile of high allostatic load and prompt in-training modifications to enhance posttraining readiness.

This essay examines, in an evolutionary perspective, body systems outside the brain that use the catecholamines dopamine (DA), norepinephrine (NE), and epinephrine (EPI) as chemical messengers. Peripheral catecholamine systems represent three mechanisms by which the brain regulates the functions of body organs. DA serves as an autocrine-paracrine factor in the kidneys and splanchnic organs, NE is the neurotransmitter of the sympathetic noradrenergic system (SNS), and EPI is the main hormone secreted by adrenomedullary chromaffin cells. Comparative physiological data suggest that the DA autocrine-paracrine system emerged first, followed by noradrenergic nerve networks culminating in the SNS, with the hormonal sympathetic adrenergic system (SAS) appearing most recently. Examples are presented of the diverse ways these catecholamines have been used during evolution, although the ecological niches that conferred selective advantages remain uncertain. The discussion addresses catecholamine receptors, cotransmission, and interactions between catecholaminergic, neuroendocrine, and immune systems. In humans, the transition to bipedalism likely promoted SNS adaptations for orthostatic regulation of brain blood flow as well as for sodium homeostasis and temperature control. The roles of the SAS in organism-wide stress responses, distress, and sympathoadrenal imbalance in fainting are also considered. Concepts such as antagonistic pleiotropy, allostatic load, and autotoxicity are discussed in relation to aging-associated diseases that feature catecholaminergic neurodegeneration. Understanding the phylogeny of peripheral catecholamine systems may provide a foundation for Darwinian medicine.

A rapid change in arterial CO₂ tension causes changes in ventilation, referred to as peripheral hypercapnic chemosensitivity (PHC). The PHC increases from rest to low-intensity exercise yet is not further augmented at higher exercise intensities, where additional ventilatory stimulants are present. During supra-respiratory compensation point (RCP) exercise, as arterial CO₂ tension falls, so does PHC, which may mask the effect of other ventilatory stimuli. Twenty healthy subjects (n = 10 females) completed a maximal exercise test and on subsequent days (days 2 and 3) had PHC measured at rest, 40% of maximal work rate (Wmax), and supra-RCP exercise intensities. On one experimental day, participants were kept isocapnic, and on the other, end-tidal carbon dioxide ([Formula: see text]) declined naturally during supra-RCP exercise (poikilocapnia). PHC was measured as the quotient between the change in ventilation and [Formula: see text] after two breaths of hypercapnic (10% CO₂) gas delivered 3-5 times during each condition. There was a significant increase in PHC during supra-RCP intensities with isocapnia, compared with poikilocapnic exercise (+11.2 ± 6%) (P = 0.0015). Yet during the isocapnia day, there was still no significant increase in PHC from 40% intensity to supra-RCP (P = 0.96). A repeated-measures correlation demonstrated a significant relationship between PHC and [Formula: see text] during poikilocapnia (r = 0.49, P < 0.001), with no significant relationship during isocapnia (r = 0.06, P = 0.57). We conclude that the metabolic milieu associated with supra-RCP exercise does not impact PHC and there is a CO₂-dependent relationship in which [Formula: see text] influences PHC independent of the initial exercise sensitization.NEW & NOTEWORTHY Maintaining end-tidal carbon dioxide ([Formula: see text]) at isocapnic levels during supra-respiratory compensation point (RCP) exercise significantly increased the peripheral hypercapnic chemoresponse (PHC) compared with poikilocapnic conditions. However, neither the isocapnic nor poikilocapnic exercise above RCP resulted in a significant increase in PHC compared with lower intensity exercise. Thus, although prestimulus [Formula: see text] impacts the PHC, supra-RCP exercise does not further augment the PHC beyond low intensity exercise.

Defective postprandial glucagon suppression contributes to chronic hyperglycemia in type 2 diabetes. Although insulin action and secretion have been extensively and quantitatively studied in the literature, less effort has been made to quantify the glucagon stimulatory effect on endogenous glucose production (EGP). This study aims to model the glucagon effect on EGP in healthy humans, capturing the decline of its action following sustained hyperglucagonemia. We analyzed data from 54 nondiabetic individuals studied on two occasions, where they received a glucose, labeled with [3-³H]-glucose, and an insulin infusion, mimicking systemic appearance after an oral glucose challenge, whereas endogenous hormone secretion was suppressed by somatostatin. Glucagon was infused at a rate of 0.65 ng/kg/min starting at 0 min (nonsuppressed occasion) or 120 min to mimic postprandial glucagon suppression (suppressed occasion). Plasma glucose, insulin, and glucagon concentrations were frequently measured for 300 min, and model-independent estimates of EGP were obtained from tracer specific activity. Several physiological models describing the EGP time course as a function of plasma glucose, insulin, and glucagon concentrations were developed and compared, each implementing a different hypothesis for the evanescence of glucagon effect. The best model successfully described EGP using the glucagon-to-insulin ratio and over-basal glucose to account for the waning glucagon effect. The model precisely estimated hepatic glucagon and insulin sensitivities. However, the glucose effect was excessively delayed, likely reflecting a cascade of other biological signals rather than the direct effect of hyperglycemia on the liver.NEW & NOTEWORTHY The model can be used to quantify hepatic glucagon and insulin sensitivity, accounting also for glucagon evanescence over time. The ability to quantify glucagon effects on postprandial glucose metabolism will further our understanding of its role in the onset and progression of type 2 diabetes. These findings can also be used in the design of novel glucagon-based therapies where accurate modeling of glucagon action is required to meet efficacy and safety standards.

This study investigates the role of renal nerve afferents in sympathetic vasomotor responses during acute low-dose furosemide administration intravenously or directly in the renal pelvis. We hypothesized that furosemide activates renal nerve afferents, modulating sympathetic vasomotor activity. To test this hypothesis, we conducted simultaneous recordings of renal sympathetic nerve activity (rSNA) and splanchnic sympathetic nerve activity (sSNA) in Wistar rats. The effects of intravenous furosemide infusion (1 mg/kg/h) on mean arterial pressure, heart rate, rSNA, and sSNA in control (CTRL, n = 5) and afferent renal denervated rats (ARD, n = 5) were investigated. In addition, we infused furosemide (from 10 to 100 µg/mL; 200 µL) directly in the renal pelvis (n = 8), with simultaneous recordings of hemodynamic parameters and sympathetic nerve activity. Furosemide induced a significant reduction in rSNA (spikes/s) but not in sSNA in the ARD compared with the CTRL group (rSNA maximal decrease of 21 ± 7 in ARD vs. a maximal increase of 27 ± 13 spikes/s in CTRL at 120 min, *P < 0.05), as well as in the amplitude of bursts (rSNA -0.21 ± 0.072 vs. 0.062 ± 0.16 mVs at 120 min, *P < 0.05). Moreover, intrapelvic furosemide infusion in CTRL rats preferentially increased rSNA (69% of the maximal response induced by capsaicin); as for sSNA, there was no significant difference. These findings suggest that transient receptor potential vanilloid type-1-expressing C-fiber afferents, located in the renal pelvis, are activated by furosemide, leading to a preferential change in the pattern of sympathetic activity to the kidneys, independently of blood volume depletion.NEW & NOTEWORTHY Afferent nerves from the renal pelvis contribute to the modulation of renal sympathetic nerve activity (rSNA) in response to low-dose furosemide intravenous administration. Capsaicin-sensitive C-fiber afferents, located in the renal pelvis, selectively alter the pattern of sympathetic outflow to the kidneys. Intrapelvic low-dose furosemide increases rSNA without affecting splanchnic sympathetic nerve activity (sSNA).

Recent advances and foundational knowledge are integrated to provide a comprehensive description of brain-gut signaling relevant to colorectal motility, with an emphasis on defecation. We discuss molecular targets of therapeutic potential. We identify four levels of neural control: 1) cortical and hypothalamic centers; 2) pontomedullary cell groups; 3) the lumbosacral defecation centers; and 4) the enteric nervous system (ENS). The critical role of central nervous system (CNS) input is evidenced by the constipation that follows spinal cord injury or during Parkinson's disease. The constipation of spinal cord injury suggests that propulsive reflexes generated by the ENS require augmentation from the CNS. Conversely, the crucial role of the ENS is revealed by the failed defecation in Hirschsprung and Chagas diseases. Spinal descending pathways receive inputs from the cortex and hypothalamus, and converge on a common efferent neuronal link between the CNS and the ENS: parasympathetic preganglionic neurons (PPG neurons) that connect with ENS directly or via pelvic ganglia. CNS pathways respond to the urge to defecate, to stress or alarm, and to signals from the large intestine. The ENS responds to signals from its lumen, commonly mediated through the release of local hormones, and to signals from the CNS. PPG neurons, the CNS to ENS link, express a wide range of amine and peptide receptors that are potential targets for the treatment of constipation. Important among targets are ghrelin, dopamine, and serotonin receptors. The receptors within the colon that connect luminal signals with propulsive contractile activity also represent potential therapeutic targets.

Preeclampsia is the leading cause of maternal and fetal morbidity and mortality in the United States. Maternal hypertension occurs to increase blood perfusion but it is inadequate, resulting in growth-restriction. Improving placental perfusion could alleviate maternal hypertension and improve fetal outcomes. An imbalance between vasodilators and vasoconstrictors mediates the pathophysiology of preeclampsia shifting the balance toward vasodilation would be beneficial for maternal and fetal outcomes. Our hypothesis is that increasing the VEGFR2 receptors in the uterine tissue will improve the pathophysiology of preeclampsia. To test our hypothesis, we used the reduced uterine perfusion pressure rat model (RUPP) and treatment with non-viral l-tyrosine polyphosphate (LTP) nanoparticles containing the plasmid DNA for VEGFR2. The LTP nanoparticles are administered in one dose at gestational day 14 (same day as surgery). Maternal blood pressure, measured at gestational day 21 in anesthetized rats, mean arterial pressure was decreased in the RUPP rats treated with LTP-VEGFR2 nanoparticles (72.8 ± 3.6 mmHg) compared with control RUPP (100 ± 6 mmHg, P = 0.01). In addition, myogenic reactivity of uterine arteries isolated from RUPP treated with LTP-VEGFR2 demonstrated decreased myogenic reactivity compared with RUPP. At the 120 mmHg pressure step, arteries from RUPP treated with LTP-VEGFR2 nanoparticles increased in diameter by 42 ± 12% compared with a decrease of 22 ± 5% in untreated RUPP (P = 0.003). The role for the VEGF myogenic studies was confirmed with VEGF neutralizing antibodies. In addition, treatment with LTP-VEGFR2 nanoparticle treatments increased fetal and placental weights in RUPP rats. This study demonstrates that overexpression of VEGFR2 by LTP nanoparticles may provide a novel therapeutic agent for the treatment of preeclampsia.NEW & NOTEWORTHY This study demonstrates that overexpression of VEGFR2 by LTP nanoparticles may provide a novel therapeutic agent in the treatment of preeclampsia, which would improve maternal and fetal outcomes. The VEGFR2 nanoparticles successfully decreased MAP, while also normalizing the myogenic response of uterine arteries and improving fetal and placental weights.

The vagal nerves in mice run ventrally and dorsally below their diaphragm. They form four branches (common hepatic, R1; ventral gastric, R2; dorsal gastric, L1; celiac, L2) that project into the abdominal organs, such as the stomach, small intestine, and liver. To identify the vagal afferents that receive inputs from these organs, we examined the neural responses to the gastrointestinal and portal injection of capsaicin, a known stimulant of vagal afferents. The afferent fibers of the three branches (R1, R2, and L1) were activated following the intragastric (IG) injection of capsaicin in anesthetized mice. Moreover, the injection of a wheat germ agglutinin tracer into the stomach enabled the detection of positive cells in the nodose ganglion of intact mice, but not in vagotomized (VG) mice with transected R1, R2, and L1 branches. Capsaicin administered into the duodenum or portal vein activated the afferent neural activities of the R1 and L2 or R1, R2, and L1 branches, respectively. Moreover, IG injection of capsaicin increased the efferent sympathetic outflows to the brown adipose tissue and the kidney. The sympathetic response of the brown adipose tissue, but not the kidney, was abolished in the VG mice. In addition, an anorexigenic response to capsaicin was also abolished in the VG mice. Finally, increased vagal afferents were observed in diet-induced obese mice, which were comparable with the responses observed with capsaicin treatment of control mice. Thus, vagal afferents activated by capsaicin may contribute to the suppression of diet-induced obesity through efferent sympathoexcitation and appetite reduction.NEW & NOTEWORTHY In a mouse study, we identified input patterns from the gastrointestinal organs and liver to vagal afferents, with physiological evidence that there is no one-to-one correspondence between nerve branches and organs; multiple nerve branches receive inputs from a single organ. This new discovery is important as it contributes to elucidating the mechanisms of physiological function based on the vagal afferent pathway affected by nutrition, osmotic pressure, and hormones.

In preclinical models, the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO) sense changes in serum sodium chloride (NaCl) concentration and mediate NaCl-induced changes in sympathetic nerve activity, vasopressin (AVP), thirst, and blood pressure (BP). In humans, brain imaging studies have shown that acute hypernatremia alters the activity or functional connectivity of the SFO and OVLT. However, no studies have investigated whether there are sex differences in central NaCl sensing in humans, which could underlie sex differences in neurohumoral responses to hypernatremia. Therefore, the purpose of this study was to test the hypothesis that acute relative hypernatremia would increase resting-state functional connectivity between NaCl-sensing brain regions and that these responses would be greater in men. Thirty-two young adults (17 men/15 women) underwent resting-state functional magnetic resonance imaging (fMRI) at baseline and during a 30-min intravenous hypertonic saline infusion. We performed a seed-to-seed functional connectivity analysis. Despite similar increases in serum sodium, thirst, systolic BP, and plasma AVP between the sexes, there was a time × sex interaction (P < 0.001) on SFO-OVLT functional connectivity, as SFO-OVLT functional connectivity increased in men during the late phase (15-30 min) of the hypertonic saline infusion (z-scores: baseline = 0.21 ± 0.20, late phase = 0.29 ± 0.21; P = 0.04), but decreased in women (z-scores: baseline = 0.27 ± 0.17, late phase = 0.15 ± 0.18; P = 0.004). Collectively, these results suggest that the functional coupling of the SFO and OVLT, which regulate sympathoexcitation and BP during acute hypernatremia, may be modulated by sex.NEW & NOTEWORTHY We used resting-state fMRI to assess whether there are sex differences in the functional connectivity of salt sensing brain regions during acute hypernatremia in young healthy adults. Despite having similar increases in serum sodium, thirst, systolic BP, and plasma AVP, functional connectivity between the SFO and OVLT increased with acute hypernatremia in men but decreased in women. This suggests there may be sex differences in salt sensing in brain regions that regulate sympathoexcitation and BP.