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

Objective: To evaluate reactive oxygen species (ROS) modulation of cutaneous vasodilation during local and whole-body passive heating in young and older adults.

Methods: Cutaneous vascular conductance normalized to maximum vasodilation (%CVC_max) was assessed in young and older adults (10 per group) using laser-Doppler flowmetry at 4 dorsal forearm sites treated with 1) Ringer's solution (control), 2) 100 µM apocynin (NADPH oxidase inhibitor), 3) 10 µM allopurinol (xanthine oxidase inhibitor), or 4) 10 µM tempol (superoxide dismutase mimetic), via intradermal microdialysis during local (protocol-1) and whole-body heating (protocol-2). Protocol-1: forearm skin sites were set at 33°C during baseline and then progressively increased to 39°C and 42°C (30 min each). Protocol-2: participants were immersed in warm water (35°C, mid-sternum) with the experimental forearm above water level and local skin sites maintained at 34°C. Bath temperature was increased (~40°C) to clamp core temperature at 38.5°C for 60 min.

Results: Protocol-1: there were significant treatment site by age interactions for the 39°C (P=0.015) and 42°C (P=0.004) plateaus. Although, no significant effects were observed after post-hoc adjustment. Protocol-2: there was a significant treatment site by age interaction (P<0.001) whereby %CVC_max in older adults was 11.0% [7.4,14.6] higher for apocynin (P<0.001), 8.9% [5.3,12.5] higher for allopurinol (P<0.001) and 4.8% [1.3,8.4] higher for tempol (P=0.016) sites relative to the control site.

Conclusion: ROS derived from NADPH oxidase and xanthine oxidase attenuate cutaneous vasodilation in older adults during passive whole-body heating, but not during local skin heating, with negligible effects on their young counterparts for either heating modality.

Clinical trials of hypothermia after pediatric cardiac arrest (CA) have not seen robust improvement in functional outcome, possibly because of the long delay in achieving target temperature. Previous work in infant piglets showed that high nasal airflow, which induces evaporative cooling in the nasal mucosa, reduced regional brain temperature uniformly in half the time needed to reduce body temperature. Here, we evaluated whether initiation of hypothermia with high transnasal airflow provides neuroprotection without adverse effects in the setting of asphyxic CA. Anesthetized piglets underwent sham-operated procedures (n = 7) or asphyxic CA with normothermic recovery (38.5°C; n = 9) or hypothermia initiated by surface cooling at 10 (n = 8) or 120 (n = 7) min or transnasal cooling initiated at 10 (n = 7) or 120 (n = 7) min after resuscitation. Hypothermia was sustained at 34°C with surface cooling until 20 h followed by 6 h of rewarming. At 4 days of recovery, significant neuronal loss occurred in putamen and sensorimotor cortex. Transnasal cooling initiated at 10 min significantly rescued the number of viable neurons in putamen, whereas levels in putamen in other hypothermic groups remained less than sham levels. In sensorimotor cortex, neuronal viability in the four hypothermic groups was not significantly different from the sham group. These results demonstrate that early initiation of high transnasal airflow in a pediatric CA model is effective in protecting vulnerable brain regions. Because of its simplicity, portability, and low cost, transnasal cooling potentially could be deployed in the field or emergency room for early initiation of brain cooling after pediatric CA.NEW & NOTEWORTHY The onset of therapeutic hypothermia after cardiac resuscitation is often delayed, leading to incomplete neuroprotection. In an infant swine model of asphyxic cardiac arrest, initiation of high transnasal airflow to maximize nasal evaporative cooling produced hypothermia sufficient to provide neuroprotection that was not inferior to body surface cooling. Because of its simplicity and portability, this technique may be of use in the field or emergency room for rapid brain cooling in pediatric cardiac arrest victims.

Multidrug resistance proteins type 4 (MRP4) and 5 (MRP5) play pivotal roles in the transport of cyclic nucleotides in various tissues. However, their specific functions within the lower urinary tract remain relatively unexplored. This study aimed to investigate the effect of pharmacological inhibition of MRPs on cyclic nucleotide signaling in isolated pig bladder. The relaxation responses of the bladder were assessed in the presence of the MRP inhibitor, MK571. The temporal changes in intra- and extracellular levels of cAMP and cGMP in stimulated tissues were determined by mass spectrometry. The gene (ABCC4) and protein (MRP4) expression were also determined. MK571 administration resulted in a modest relaxation effect of approximately 26% in carbachol-precontracted bladders. The relaxation induced by phosphodiesterase inhibitors such as cilostazol, tadalafil, and sildenafil was significantly potentiated in the presence of MK571. In contrast, no significant potentiation was observed in the relaxation induced by substances elevating cAMP levels or stimulators of soluble guanylate cyclase. Following forskolin stimulation, both intracellular and extracellular cAMP concentrations increased by approximately 15.8-fold and 12-fold, respectively. Similarly, stimulation with tadalafil + BAY 41-2272 resulted in roughly 8.2-fold and 3.4-fold increases in intracellular and extracellular cGMP concentrations, respectively. The presence of MK571 reduced only the extracellular levels of cGMP. This study reveals the presence and function of MRP4 transporters within the porcine bladder and paves the way for future research exploring the role of this transporter in both underactive and overactive bladder disorders.NEW & NOTEWORTHY This study investigates the impact of pharmacological inhibition of MRP4 and MRP5 transporters on cyclic nucleotide signaling in isolated pig bladders. MK571 administration led to modest relaxation, with enhanced effects observed in the presence of phosphodiesterase inhibitors. However, substances elevating cAMP levels remained unaffected. MK571 selectively reduced extracellular cGMP levels. These findings shed light on the role of MRP4 transporters in the porcine bladder, opening avenues for further research into bladder disorders.

Individuals over the age of 65 yr are the most vulnerable population during severe environmental heat events, experiencing worse health outcomes than any other age cohort. The risk is greater in older women than in age-matched men; however, whether that reflects a greater susceptibility to heat in women, or simply population sex proportionality, is unclear. Seventy-two participants (29 M/43 F) aged 40-92 yr were exposed to progressive heat stress at a metabolic rate designed to reflect activities of daily living. Experiments were conducted in both hot-dry (HD; up to 53°C; ≤25% rh) and warm-humid (WH; ∼35°C; ≥50% rh) environments. After critical limits were determined for each condition, forward stepwise multiple linear regression analyses were conducted with net metabolic rate (M_net) and age entered into the model first, followed by sex, body mass (m_b), maximal oxygen consumption (V̇o_2max), body surface area, and LDL cholesterol. After accounting for M_net and age, sex further improved the regression model in the HD environment ([Formula: see text] = 0.34, P < 0.001) and the WH environment ([Formula: see text] = 0.36, P < 0.005). Sex explained ∼15% of the variance in critical environmental limits in HD conditions and 12% in WH conditions. Heat compensability curves were shifted leftward for older women, indicating age- and sex-dependent heat vulnerability compared with middle-aged women and older men in WH (P = 0.007, P = 0.03) and HD (P = 0.001, P = 0.01) environments. This reflects the heterogeneity of thermal-balance thresholds associated with aging relative to those seen in young adults and suggests that older females are more vulnerable than their age-matched male counterparts.NEW & NOTEWORTHY In contrast to young adults, there are sex differences in critical environmental limits in middle-aged and older adults. Older women exhibit lower critical environmental limits in both humid and dry extreme environments demonstrated by a leftward shift in heat compensability curves. These data confirm a true sex difference in heat vulnerability of older adults and support the epidemiological mortality data from environmental heat waves.

In recent years, there has been a burgeoning interest in exploring the nuances of animal stress physiology, particularly in relation to parameters such as sex and behavioral phenotype-dependent variations, which is crucial for understanding phenotypic variation and its role in evolutionary selection. However, a significant dearth remains in how chronic stressors affect organismal stress physiology concerning the aforesaid parameters. This void is even wider pertaining to the response of peripheral tissues, such as the skin, the organ with the highest surface contact area with the environment. Hence, we behaviorally grouped the zebrafishes based on their boldness and the body condition, whole body cortisol response, along with examining the transcriptional response, global DNA methylome, and oxidative DNA damage in the skin upon chronic crowding. Upon baseline conditions, clear distinction between bold and shy phenotypes was found, particularly in males. The boldness index score distribution exhibited greater uniformity in males than in females. Regarding the body condition response to chronic crowding, shy males showed a significant relative decline compared with their bold counterparts, while this trend did not hold true for females. qPCR data revealed distinctive expression patterns in key genes that play critical roles in cellular processes such as stress-mediated gene regulation, immune response, oxidative stress protection, and maintenance of genomic integrity through epigenetic modifications across behavioral phenotypes and sexes under both with and without chronic crowding stress. Global DNA methylation levels significantly declined only in chronically crowded shy males, and sex/behavioral phenotype-dependent trends in oxidative DNA damage were identified.NEW & NOTEWORTHY This paper analyzes the response of zebrafish to crowding stress through a new approach focused on the peripheral response dynamics of the skin, the main mucosal tissue, and involving sex and behavioral phenotype influences. Shy males showed significant distress as observed by body condition, physiological and transcriptional response, and global DNA methylation. Nuances in stress response across behavioral phenotypes and sex indicate a genetic and behavioral specificity and further inherent epigenetic regulatory dimension.

Angiotensin II (ANG II) is known to play an important role in regulating renal hemodynamics. We sought to quantify this effect in an in vivo rat model with high-resolution renal arterial (RA) impedance. This study examines the effects of ANG II and its type 1 receptor blocker telmisartan (TELM) on RA impedance. In baroreflex-deactivated rats, we measured RA pressure (P_r) and blood flow (F_r) during random ventricular pacing to induce pressure fluctuation at three different mean P_r (60, 80, and 100 mmHg). We then estimated RA impedance as the transfer function from F_r to P_r. The RA impedance was found to align with a three-element Windkessel model consisting of proximal (R_p) and distal (R_d) resistance and compliance (C). Our study showed R_d reflected the composite characteristics of afferent and efferent arterioles. R_d increased with increasing P_r under the baseline condition with a slope of 1.03 ± 0.21 (× 10^-1) min·mL^-1. ANG II significantly increased the slope by 0.72 ± 0.29 (× 10^-1) min·mL^-1 (P < 0.05) without affecting the intercept. TELM significantly reduced the intercept by 34.49 ± 4.86 (× 10^-1) mmHg·min·mL^-1 (P < 0.001) from the baseline value of 37.93 ± 13.36 (× 10^-1) mmHg·min·mL^-1, whereas it did not affect the slope. In contrast, R_p was less sensitive than R_d to ANG II or TELM, suggesting R_p may represent the characteristics of elastic large arteries. Our findings provide valuable insights into the influence of ANG II on the dynamics of the renal vasculature.NEW & NOTEWORTHY This present method of quantifying high-resolution renal arterial impedance could contribute to elucidating the characteristics of renal vasculature influenced by physiological mechanisms, renal diseases, or pharmacological effects. The present findings help construct a lumped-parameter renal hemodynamic model that reflects the influence of angiotensin II.

It is commonly thought that steady-state thermoregulatory responses are achieved within 30-90 min of compensable heat stress. However, this assumption is based on measurements of whole body heat exchange during exercise, which stabilize (equilibrate) more rapidly than deep body temperatures, especially under resting conditions. To support the design of ecologically relevant heat exposure studies, we quantified equilibrium times for deep body temperature, as indexed by rectal temperature, in young and older adults resting in the heat. We also evaluated the lag in rectal temperature equilibrium relative to whole body heat storage (direct calorimetry). Equilibrium times were estimated with data from two laboratory-based trials (NCT04353076 and NCT04348630) in which 83 adults aged 19-80 yr (34 female) were exposed to simulated heat-wave conditions for 8-9 h. When assessed at the group level, it took rectal temperature 3.3 [bootstrap 95% confidence interval: 2.9-3.9] h to reach thermal equilibrium (<0.05°C/h rate of change) in young adults exposed to 40°C, 9% relative humidity (RH). In older adults, who were exposed to a greater range of conditions (31°C-40°C, 9-45% RH), equilibrium times were longer, ranging from 4.4 [3.8-5.3] to 5.2 [4.9-5.4] h. Furthermore, rectal temperature equilibrium was delayed 0.9 [0.5-1.4] and 1.8 [0.9-2.7] h compared with whole body heat storage in young and older adults, respectively (only assessed in 40°C, 9% RH). Individual-level equilibrium times ranged from 1 to 8 h. These findings highlight the importance of ecologically relevant exposure durations in translational research assessing the physiological impacts of hot weather.NEW & NOTEWORTHY Deep body (rectal) temperature took 3-5 h on average and up to 6-8 h at the individual level to reach thermal equilibrium in young and older adults resting in the heat. Furthermore, stable rectal temperatures were delayed by up to 2 h relative to the achievement of heat balance (0 kJ/min rate of heat storage). We provide the first quantification of the temporal profiles of thermal strain during extended rest in conditions simulating hot weather.

Ribosomal DNA (rDNA) copies exist across multiple chromosomes, and interindividual variation in copy number is speculated to influence the hypertrophic response to resistance training. Thus, we examined if rDNA copy number was associated with resistance training-induced skeletal muscle hypertrophy. Participants (n = 53 male, 21 ± 1 yr old; n = 29 female, 21 ± 2 yr old) performed 10-12 wk of full-body resistance training. Hypertrophy outcomes were determined, as was relative rDNA copy number from preintervention vastus lateralis (VL) biopsies. Pre- and postintervention VL biopsy total RNA was assayed in all participants, and mRNA/rRNA markers of ribosome content and biogenesis were also assayed in the 29 female participants before training, 24 h following training bout 1, and in the basal state after 10 wk of training. Across all participants, no significant associations were evident between relative rDNA copy number and training-induced changes in whole body lean mass (r = -0.034, P = 0.764), vastus lateralis thickness (r = 0.093, P = 0.408), mean myofiber cross-sectional area (r = -0.128, P = 0.259), or changes in muscle RNA concentrations (r = 0.026, P = 0.818), and these trends were similar when examining each gender. However, all Pol-I regulon mRNAs as well as 45S pre-rRNA, 28S rRNA, and 18S rRNA increased 24 h following the first training bout in female participants. Follow-up studies using LHCN-M2 myotubes demonstrated that a reduction in relative rDNA copy number induced by bisphenol A did not significantly affect insulin-like-growth factor-induced myotube hypertrophy. These findings suggest that relative rDNA copy number is not associated with myofiber hypertrophy.NEW & NOTEWORTHY We examined ribosomal DNA (rDNA) copy numbers in men and women who resistance trained for 10-12 wk and found no significant associations with skeletal muscle hypertrophy outcomes. These data, along with in vitro data in immortalized human myotubes whereby rDNA copy number was reduced, provide strong evidence that relative rDNA copy number is not associated with anabolism.

Near-infrared spectroscopy combined with vascular occlusion test (NIRS-VOT) is a reactive hyperemia technique for in vivo evaluation of skeletal muscle microvascular reactivity. Previous studies using NIRS-VOT have been shown to be able to detect impairments in microvascular function in high-risk cardiovascular disease populations, such as older individuals. It has been demonstrated that older individuals have slower reactive hyperemia compared with young individuals. Importantly, older individuals also show less desaturation during ischemia compared with young individuals. Based on these findings, it has been suggested that the slower reactive hyperemia observed in older individuals is explained by the lower desaturation during blood flow occlusion (reduced ischemic stimulus). This retrospective analysis compared reactive hyperemia in 36 young and 47 older tissue desaturation-matched individuals that underwent 5-min blood flow occlusion. Overall, we showed that older individuals have impaired reactive hyperemia compared with young when matching for the degree of desaturation and blood flow occlusion time. These findings provide evidence that lower tissue desaturation during ischemia is not a major determinant of impaired reactive hyperemia in older individuals.NEW & NOTEWORTHY Previous findings have suggested that aging-related impairment in skeletal muscle reactive hyperemia is majorly influenced by a lower degree of tissue desaturation during ischemia in older individuals compared with young individuals. In a retrospective analysis including 83 tissue desaturation-matched individuals, we show that the degree of tissue desaturation is not a major determinant of aging-related impairments in reactive hyperemia.

Aging is associated with inspiratory muscle dysfunction; however, the impact of aging on diaphragm blood flow (BF) regulation, and whether sex differences exist, is unknown. We tested the hypotheses in young animals that diaphragm BF and vascular conductance (VC) would be greater in females and that aging would decrease the diaphragm's ability to increase BF with contractions. Young (4-6 mo) and old (22-24 mo) Fischer 344 rats were divided into four groups: young female (YF, n = 7), young male (YM, n = 8), old female (OF, n = 9), and old male (OM, n = 9). Diaphragm BF (mL/min/100 g) and VC (mL/mmHg/min/100 g) were determined, via fluorescent microspheres, at rest and during 1 Hz contractions. In YF versus OF, aging blunted the increase in medial costal diaphragm BF (44 ± 5% vs. 16 ± 12%; P < 0.05) and VC (43 ± 7% vs. 21 ± 12%; P < 0.05). Similarly, in YM versus OM, aging blunted the increase in medial costal diaphragm BF (43 ± 6% vs. 24 ± 12%; P < 0.05) and VC (50 ± 6% vs. 34 ± 10%; P < 0.05). In female rats, age increased dorsal costal diaphragm BF, whereas in male rats, age increased crural diaphragm BF (P < 0.05). Compared with age-matched females, dorsal costal diaphragm BF was lower in YM and OM (P < 0.05). In conclusion, aging results in an inability to augment medial costal diaphragm BF and alters regional diaphragm BF distribution in response to muscular contractions. Furthermore, sex differences in regional diaphragm BF are present in young and old animals.NEW & NOTEWORTHY This is the first study, to our knowledge, to demonstrate that old age impairs the hyperemic response and alters blood flow distribution in the diaphragm of both female and male rats. In addition, this investigation provides novel evidence of sex differences in regional diaphragm blood flow distribution with contractions. The data presented herein suggest that aging compromises diaphragm vascular function and provides a potential mechanism for the diaphragm contractile dysfunction associated with old age.