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

The ability to withstand low and fluctuating oxygen levels is important for adipose tissue function. Hypoxia in mammalian cells typically stabilizes hypoxia-inducible factor (HIF-1α) that alters downstream structural and metabolic pathways, which can have pathological consequences in humans and rodents. Gray seals (Halichoerus grypus) have extensive subcutaneous adipose as blubber, which naturally undergoes oxygen restriction acutely during diving and chronically during fattening. This study explored how blubber regulates responses to chemically induced pseudohypoxia. We obtained blubber biopsies from weaned pups (n = 6) and prepared explants that we incubated with or without cobalt chloride (CoCl₂), which stabilizes HIF-1α under normoxia. One explant per animal was immediately snap-frozen, and the remaining explants and media were collected every 2 h. HIF-1α protein accumulation occurred rapidly in both control and CoCl₂-treated explants, peaking at 4 h and 2 h, respectively. HIF-1α mRNA increased in all explants. Mitochondrial complex I abundance increased in controls. CoCl₂ drove an additional increase in complex I, II, and V proteins compared with controls at all time points. Surprisingly, Adiponectin and Ppar-γ were not downregulated. Collagen VI abundance increased 6 h after treatment. Our results suggest that blubber explants experience hypoxia in culture, which is enhanced by chemical pseudohypoxia: CoCl₂ produced an additional impact on mitochondrial complex proteins. HIF-1α elevation in response to hypoxic challenge occurred earlier, to a greater extent but was shorter lived than in other mammalian adipose. Our findings highlight potential differences in responses of seal blubber to hypoxia compared with human and rodent adipose.NEW & NOTEWORTHY The molecular response to low oxygen in blubber had not been previously documented. This study showed a faster, but sustained, increase in molecular markers of hypoxia. It documents downstream molecular responses to those hypoxia-induced changes, revealing important adaptations in mechanisms that induce and sustain the hypoxia response in blubber. The exploration of natural vs. chemically reduced oxygenation in gray seal blubber suggests they induce contrasting mechanisms in the regulation of downstream effects of hypoxia.

We hypothesize that excessive central blood flow reduction leads to failure in the mechanism that appropriately distributes cerebral blood flow (CBF), preceding the pathological drop in blood pressure. This study aims to evaluate changes in CBF and cerebrovascular resistance in response to reduced cardiac output (CO) during severe central hypovolemia and elucidate the breakdown of cerebral circulation maintenance mechanisms before presyncope. Nine healthy men underwent maximal lower body negative pressure (LBNP), with ultrasound measurements of the internal carotid artery (ICA) and vertebral artery (VA) blood flow, and CO. Hemodynamic changes, including total peripheral resistance (TPR) and fractional CBF (CBF/CO), were assessed. CO decreased from LBNP25%, while ICA and VA blood flow were preserved up to LBNP50% but declined from LBNP75%. CBF/CO increased until LBNP75%, then plateaued or slightly decreased. TPR increased from LBNP50% to LBNP75%, then plateaued. Both ICA-CVRi and VA-CVRi increased with higher LBNP loads. ICA-CVRi showed significant elevations at LBNP75% and LBNPpremax, whereas VA-CVRi reached a significantly higher value at LBNPpremax. The decrease in ICA and VA blood flow was smaller than that in CO. The maintenance of blood flow at higher LBNP loads is likely due to peripheral vascular constriction, but this compensatory mechanism failed at LBNP75%, just before presyncope.NEW & NOTEWORTHY This study examined cerebral blood flow (CBF) responses to reduced cardiac output (CO) during severe central hypovolemia. The CBF/CO ratio increased but plateaued at 75% lower body negative pressure (LBNP). Decreases in internal carotid and vertebral artery blood flow were smaller than the CO reduction. CBF was maintained at high LBNP levels, likely via peripheral vasoconstriction. However, this compensatory mechanism failed at 75% LBNP, immediately before presyncope, indicating a breakdown in cerebral circulatory regulation.

Maternal stress during pregnancy causes changes in circulating glucocorticoids and inflammatory cytokines that can alter fetal development. Prior studies have shown that prenatal dexamethasone impacts fetal brain development, increases anxiety-like behavior, and dysregulates neuroendocrine and autonomic function in adult rat offspring. Resiquimod (RQ) activates toll-like receptor 7, causing immune activation. The current study investigated the impact of RQ-induced maternal immune activation during late gestation on rat offspring development and behavior. Pregnant dams were weighed daily. On gestation day 18, dams were injected with vehicle (phosphate-buffered saline) or RQ (1 mg/kg). Early maternal caregiving behavior was assessed. Offspring were tracked by day of vaginal opening and weekly body weights as maturation milestones. Open field tests were conducted in separate cohorts of male and female offspring before (3-4 wk old) and after (8-10 wk old) the onset of puberty to assess anxiety-like behavior. RQ-injected pregnant dams had attenuated weight gain. However, this exposure did not affect early maternal caregiving behavior or litter metrics. Female offspring of RQ-injected dams experienced a significant delay (∼1 day) in vaginal opening, suggesting delayed pubertal onset. There were no effects of prenatal RQ on offspring weights or open field behaviors before puberty. Adult male and female offspring of RQ-injected dams had attenuated weight gain and increased anxiety-like behavior. The emergence of behavioral changes in adulthood suggests that late-gestation prenatal RQ impacts fetal brain development, as revealed by gonadal hormones and metabolic maturation. These changes highlight puberty as critical for exposing the effects of maternal immune activation.NEW & NOTEWORTHY Maternal stress during pregnancy affects offspring development and health. Data from the project show that maternal immune stress induced by resiquimod during late gestation in rats attenuated maternal weight gain and delayed female pubertal onset, increased anxiety-like behavior after puberty, and lessened weight gain over time in offspring. These results highlight puberty as critical for exposing the effects of prenatal stress and underscore the importance of tracking outcomes across development.

Bed rest (BR) studies have demonstrated the detrimental effects of microgravity and physical inactivity on cardiovascular function, including the negative consequences on microvascular function and O₂ extraction. However, whether a short period of BR affects microvascular responsiveness and its molecular mediator, nitric oxide (NO), remain unclear. Nine male volunteers (23 ± 5 yr) completed 10-day horizontal BR. Microvascular postocclusive reactive hyperemia in the vastus lateralis (VL) and rectus femoris (RF) muscles were assessed by near-infrared spectroscopy during a vascular occlusion test. We calculated the rate of muscle deoxygenation during the first minute of occlusion (slope 1) and the half-time of the reperfusion kinetics ([Formula: see text]) during the 30 s postischemia. The inverse of [Formula: see text], K (velocity constant) was "normalized" for the intensity of the ischemic/hypoxic stimulus, as estimated by [Formula: see text], the highest [Formula: see text] value at the end of ischemia. Plasma nitrite ([Formula: see text]) and nitrate ([Formula: see text]) concentrations (NO bioavailability indexes) were determined by chemiluminescence. Slope 1 and [Formula: see text] were slower after BR in both VL (0.08 ± 0.03 vs. 0.06 ± 0.02 µM·s^-1, P = 0.016; and 12 ± 3 vs. 17 ± 2 s, P = 0.002) and RF (0.07 ± 0.02 vs. 0.05 ± 0.02 µM·s^-1, P = 0.008; and 12 ± 3 vs. 18 ± 4 s, P < 0.001). No differences were detected in K/[Formula: see text] after BR (VL: 0.15 ± 0.04 vs. 0.17 ± 0.03 µM·min^-1, P = 0.166; RF: 0.20 ± 0.06 vs. 0.21 ± 0.05 µM·min^-1, P = 0.220). Plasma [Formula: see text] concentration was reduced after BR (87 ± 37 vs. 67 ± 48 nM, P = 0.011), but not plasma [Formula: see text] concentration (43 ± 24 vs. 29 ± 11 µM, P = 0.130). In conclusion, 10-day horizontal BR does not impair microvascular postocclusive reactive hyperemia parameters, despite decreasing plasma [Formula: see text] concentration.NEW & NOTEWORTHY Short-term (10 days) horizontal bed rest does not affect skeletal muscle microvascular function when assessed via near-infrared spectroscopy and postocclusion reactive hyperemia. However, both skeletal muscle resting oxygen consumption and nitric oxide bioavailability decrease following 10-days bed rest. Future studies should investigate the time course of changes in skeletal muscle microvascular function following longer period of microgravity/inactivity.

A footbath may be an accessible form of passive heat therapy (PHT) to improve cardiovascular health. As a localized PHT stimulus, it is unclear whether longer durations are superior for promoting adaptive hemodynamic and vascular adjustments. Fourteen older adults (7 females; means ± SD; age: 68 ± 6 yr) performed 30-, 45-, and 60-min lower-leg hot-water (42°C) immersions and a 60-min thermoneutral (36°C) sham immersion on 4 separate days. Superficial femoral artery blood flow and flow-mediated dilation (FMD) were assessed pre- and postimmersion, and the time course of recovery was characterized over the 60 min following immersion. Twenty-four-hour ambulatory blood pressure was monitored over each experimental day. Femoral artery blood flow increased following immersion in all PHT conditions (mean of all PHT conditions: +345 ± 211%; P < 0.001) but was unchanged in sham. The 30- and 45-min PHT conditions sustained a higher leg blood flow than sham for the full hour following immersion (all post hoc comparisons: P < 0.01), whereas the 60-min condition was not different from sham by 30 min into recovery. FMD was greater following 45-min PHT than sham over the hour of recovery (mean of recovery time points: 2.5 ± 0.9% FMD vs. 1.7 ± 1.0%; P = 0.002). Twenty-four hour mean arterial pressure was lower with 45-min and 60-min PHT compared with sham (both -4 ± 4 mmHg; P < 0.05). A 45-min footbath results in comparable hemodynamic adjustments as 60 min of immersion and leads to the largest acute improvement in vascular function. As such, a 45-min footbath may be the preferred dose of PHT to use in future interventions seeking to improve vascular health and blood pressure.NEW & NOTEWORTHY A longer duration footbath may not be better for cardiovascular benefits in older adults. Leg blood flow increases, and ambulatory blood pressure is reduced similarly with 30, 45, and 60 min of lower-leg hot-water immersion. However, only a 45-min footbath improves endothelial function compared with a thermoneutral sham immersion. Forty-five minutes is the most favorable acute dose of lower-leg hot-water immersion and may be the most suitable for chronic interventions seeking to improve cardiovascular health.

This study tested the hypothesis that during localized facial cooling the human trigeminal reflex regulates sympathetic neuronal communication strategies. In 15 healthy individuals, we measured action potential (AP) discharge in muscle sympathetic nerve activity (MSNA; peroneal microneurography and continuous wavelet transform) during baseline (BSL) and 3 min of trigeminal nerve stimulation (TGS; cold pack on face). Face temperature and discomfort were measured. TGS increased total integrated MSNA via differential regulation of sympathetic AP discharge vs. AP recruitment. TGS increased sympathetic AP discharge frequency (BSL: 216 ± 150, TGS-1: 511 ± 335, TGS-2: 476 ± 323, TGS-3: 340 ± 160 APs/min, all P < 0.01). By contrast, TGS recruited previously silent larger sympathetic APs during TGS-1 and TGS-2, but not TGS-3 (BSL: 13 ± 3, TGS-1: 18 ± 4, TGS-2: 17 ± 4 clusters, both P < 0.01, TGS-3: 15 ± 4 clusters, P = 0.17). Compared with BSL, the sympathetic AP latency-size relationship was reset downward to faster latencies during TGS-1 (Δ -63 ± 6 ms, P < 0.01) and TGS-2 (Δ -31 ± 13 ms, P = 0.02) but not TGS-3 (Δ -8 ± 1 ms, P = 0.32). Across BSL and TGS, sympathetic AP recruitment (r = 0.58; P < 0.01) and latency (r = -0.52; P < 0.01) were related to perceptual discomfort but not face temperature. Thus, during localized facial cooling, trigeminal reflex activation and perceptual discomfort increase the discharge of previously active sympathetic neurons, recruit previously silent larger neurons, and reduce neuronal discharge latency.NEW & NOTEWORTHY Trigeminal reflex activation with localized facial cooling augmented human muscle sympathetic nerve activity by increasing the discharge of previously active action potentials (AP) and recruiting a subpopulation of larger previously silent APs. Also, trigeminal reflex activation reduced the latency of all active APs. Sympathetic AP recruitment and latency changes were associated with perceptual discomfort but not face temperature. These data advance our understanding regarding the trigeminal and perceptual mechanisms governing human sympathetic neural communication strategies.

Cold-induced peripheral vasoconstriction reduces skin blood flow, skin temperatures, and manual dexterity. This study proposed the use of single and repeated ischemic preconditioning (IPC) prior to cold exposure to 1) improve peripheral skin temperatures, blood flow and manual dexterity during 90 minutes of 0°C cold air exposure with exposed hands (CA), 2) enhance the cold induced vasodilation (CIVD) response to 30 minutes of 8°C dual hand water immersion and rewarming (CWI), and 3) improve thermal perceptions during both exposures. Seventeen volunteers (16 males, 1 female) completed a repeated trial design: 1) CON, no IPC, 2) IPC1_A, one 40-min IPC procedure, 3) IPC5, five consecutive days of IPC, and 4) IPC1_B, one IPC procedure. Single IPC consisted of 4 x 5 minutes occlusion/5 minutes of reperfusion on the dominant arm. No dose of IPC, performed prior to cold tests, improved hand or finger skin temperatures, skin blood flow, manual dexterity, or thermal perceptions across 90 minutes spent in 0°C CA. No change in any CIVD or immediate rewarming parameter was demonstrated with IPC versus control. IPC5 improved non-dominant hand thermal sensations compared to CON immediately upon immersion in 8°C water (median (min-max; IPC5: -2 (-3 to -1) au, CON: -3 (-4 to -1) au, p= 0.045), with a similar trend in the dominant hand. Overall, neither one cycle of 4 x 5 min IPC nor 5 consecutive days of 4 x 5 min IPC appears capable of improving manual dexterity performance in 0°C cold air or indices of cold induced vasodilation.

Background: Although chemosensitivity plays a role in exercise-induced hyperventilation in cardiopulmonary disorders, the integration of the underlying reflexes with cardiac hemodynamics is not fully understood. We aimed to explore the interplay between right- and left-heart pressure overload, right ventricular-pulmonary arterial (RV-PA) coupling, cardiovascular autonomic modulation, and ventilatory response in patients with cardiopulmonary disorders. Methods: Forty patients underwent echocardiography, cardiopulmonary exercise testing, and right heart catheterization. Spectral analysis of heart rate variability (HRV) was used to assess cardiovascular autonomic modulation of low- (LF) and high-frequency (HF) components, with LF/HF ratio as an index of sympatho-vagal interaction. Heart rate recovery (HRR) quantified vagal reactivation. RV-PA coupling was calculated through the TAPSE/PAPs ratio, and VE/VCO₂ slope defined ventilatory inefficiency. Results: Patients were classified as NoPH (no pulmonary hypertension, n=13), PCPH (pre-capillary pulmonary hypertension, n=15), and LVDD (left ventricular diastolic dysfunction, n=12). VE/VCO₂ slope was higher in PCPH than LVDD and NoPH (53.9 vs 43.7 vs 42.2, p<0.01). The LF/HF ratio was similar in PCPH and LVDD, but higher in NoPH (p<0.01), while HRR was significantly blunted in PCPH compared to LVDD and NoPH (p<0.01). TAPSE/PAPs was significantly reduced in PCPH and LVDD vs NoPH and was significantly correlated with all HRV parameters. Conclusion: Our findings support a tight interconnection between left- and right-heart hemodynamics, pulmonary circulation, sympatho-vagal control, and ventilatory response during exercise. Although additional mechanisms are involved, cardiopulmonary efficiency, captured by RV-PA coupling, emerges as a key determinant linking cardiopulmonary hemodynamic to autonomic modulation and ventilatory inefficiency.

Prior reports suggested the beneficial effects of cocoa intake on cardiovascular system. However, the effects of cocoa on cardiac baroreflex sensitivity (CBRS) remain poorly understood. In this study, we hypothesized that cocoa ingestion would increase CBRS in a dose-dependent manner. Seventeen healthy older adults (61 ± 8 yrs; 8 M, 9 F) participated in five trials using 250 ml drinks containing 0, 2, 5, 13, or 26 grams of cocoa, while the drinks had a similar appearance and taste. The trials were conducted in a randomized, double-blind design, at the same time each morning, with at least 72 hours between sessions. Two hours after ingesting the experimental drink, beat-by-beat heart rate (HR) and blood pressure (BP) were recorded in a supine position. Spontaneous CBRS was calculated from the beat-by-beat systolic BP and R-R interval data using a sequence method. There were no significant differences in BP and HR after ingesting the drink across all visits (repeated measures ANOVA; P > 0.05). Cocoa ingestion dose-dependently decreased CBRS (repeated measures ANOVA, P = 0.009). CBRS was significantly lower following 26 g of cocoa compared to 0 g (12.1 ± 5.7 vs. 18.2 ± 7.7 ms/mmHg, post-hoc test, P = 0.018). Addtionally, CBRS was significantly and negatively correlated with cocoa dose (R= -0.35, P = 0.003). The data suggest that acute cocoa ingestion dose-dependently reduces CBRS in healthy older adults. As reduced CBRS may be associated with increased cardiovascular risks, this potential effect of cocoa warrants attention despite its known cardiovascular benefits.

Heat acclimation enhances thermoregulation and cardiovascular function. While daily training protocols are typically recommended for humans, optimal training protocols for Thoroughbred horses remain unclear. Here, we compared the effects of two heat acclimation protocols, consecutive and intermittent, in Thoroughbred horses. In a randomized crossover study, eight trained Thoroughbred horses completed either a consecutive (CONS: 9 consecutive days) or an intermittent (INT: 3 days/week for 3 weeks) heat acclimation protocol, comprising 30 min of exercise in hot conditions (WBGT 30°C). Incremental exercise tests were performed before and after heat acclimation. Pulmonary artery temperature (T_PA), cardiovascular function, blood gases, plasma lactate, and HSP expression in skeletal muscle were assessed. Both protocols decreased resting T_PA (CONS, -0.24°C; INT, -0.25°C), increased the velocity at which T_PA reached 40°C (CONS, +14.4%; INT, +4.2%) and improved time to exhaustion (CONS +5.7%; INT +11.6%). Increased markers of aerobic performance were also observed, including V̇_O₂max (CONS, +7.5%; INT, +3.4%), the speed eliciting V̇_O₂max (CONS, +6.5%; INT, +10.4%) and HRmax (CONS, +10.6%; INT, +7.6%). The CONS group showed higher improvement of maximal stroke volume (CONS, +11.8%; INT, +3.9%) and body weight reduction (CONS, -1.8%; INT, -0.6%), whereas the INT group showed higher upregulation of HSP70 expression (CONS, +9.9%; INT, +21.5%). Both protocols elicited beneficial physiological adaptation, with differences in cardiovascular responses, body weight reduction, and HSP70 expression. These findings shed light on equine heat acclimation and may help to optimize training strategies for racehorses competing under heat stress.