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

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.

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.

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.

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).

Older adults have both lower pulmonary function and impaired thermoregulation compared with younger adults. In addition, epidemiological evidence suggests that extreme heat exposure increases the incidence of pulmonary complications in older adults. However, the impact of extreme heat exposure on pulmonary function in healthy older and younger adults is not well described. To assess this question, spirometry was performed at baseline in a thermoneutral environment and at the end of a 3-h heat exposure in a DRY (47°C and 15% humidity) and HUMID (41°C and 40% humidity) environment. Fifteen younger (7 female; 30 ± 5 yr) and 15 older (8 female; 72 ± 5 yr) adults completed the study. In the DRY condition, the younger adults had no change in forced vital capacity (FVC) from baseline (4.34 ± 0.55 L) to end-heating (4.31 ± 0.62 L; P = 0.72). In contrast, FVC in the older adults was increased from baseline (3.17 ± 0.72 L) to end-heating (3.29 ± 0.65 L; P = 0.02) in the DRY condition. Forced expiratory volume in 1 s (FEV₁) in the younger and older adults increased similarly from baseline (3.55 ± 0.47 and 2.38 ± 0.60 L, respectively) to end-heating (3.70 ± 0.50 and 2.51 ± 0.54 L, respectively; P = 0.003) in the DRY condition. The HUMID condition resulted in similar changes in FVC and FEV₁ in both age groups. In summary, the younger adults had an increase in expiratory airflow following heat exposure, indicative of some degree of bronchodilation, whereas the older adults had improved airflow in addition to increased FVC that could be indicative of altered pulmonary system compliance.NEW & NOTEWORTHY Pulmonary function increases in younger and older adults following 3 h of extreme heat exposure to a DRY (47°C and 15% humidity) and HUMID (41°C and 40% humidity) environment. Specifically, when hydration is maintained, FEV₁ increases as a result of heat-induced bronchodilation in both younger and older adults, whereas FVC increases in only the older adults due to potential improvements in pulmonary system compliance.

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.

Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea (OSA), disrupts intestinal barrier function and alters gut microbiota composition, leading to systemic inflammation and metabolic disorders. To investigate the protective role of inulin in mitigating CIH-induced intestinal barrier dysfunction and systemic inflammation in mice, with a focus on the underlying gut microbiota-mediated mechanisms. C57BL/6J mice were exposed to CIH for 10 wk with or without inulin supplementation. Intestinal permeability, tight junction protein expression, inflammatory cytokine levels, and gut microbiota composition were assessed by FITC-Dextran assay, ELISA, RT-qPCR, Western blotting, hematoxylin-eosin staining, and 16S rRNA sequencing. The role of gut microbiota was evaluated using an antibiotic intervention. Inulin significantly reduced permeability of intestines, restored protein expression of tight junction, and alleviated histological damage. It lowered transforming growth factor-β, tumor necrosis factor-α, interleukin (IL)-23, -6, and 1β, IL-6 levels, whereas increasing IL-10. Inulin reversed CIH-induced gut dysbiosis, increased microbial diversity, and modulated the Firmicutes/Bacteroidetes ratio. Antibiotic treatment confirmed microbiota-dependent effects. Inulin mitigated dysfunction of intestinal barrier that was induced by CIH and systemic inflammation through modulation of gut microbiota, thus highlighting its potential as a dietary intervention for OSA-related complications.NEW & NOTEWORTHY Inulin alleviates intestinal barrier dysfunction caused by chronic intermittent hypoxia (CIH) in mice. By modulating gut microbiota, inulin reduces systemic inflammation, restores intestinal tight junction proteins, and improves gut health. This research highlights inulin's potential as a dietary intervention to mitigate complications related to obstructive sleep apnea and CIH-induced organ damage.

The pressure-generating capacity of the diaphragm is generally thought to be compromised at high lung volume either due to loss of curvature or loss of its membrane tension. At a state of hyperinflation during airway occlusion at total lung capacity, the diaphragmatic muscle is forced to contract from an initial shorter length, the zone of apposition narrows, insertional force on the chest wall is reduced, and abdominal compliance falls. We hypothesize that these altered mechanical conditions at high lung volume lead to a loss of the pressure-generating capacity that is mediated by excessive muscle shortening rather than loss of curvature of its muscle fibers. Using a biplane fluoroscopy, locations of radiopaque markers attached to the diaphragm muscle fibers and the lower three ribs of 10 beagle dogs weighing between 7 and 10.5 kg were determined. Such measurements were conducted during quiet spontaneous breathing and during forceful inspiratory efforts against an occluded airway at three lung volumes spanning the vital capacity from functional residual capacity (FRC) to total lung capacity (TLC). Our data show that transdiaphragmatic pressure (Pdi) at TLC was reduced by nearly 80% and surface area of the midcostal diaphragm muscle at contracted state during airway occlusion at TLC reduced by nearly 35% from its value at end of expiration. In addition, muscle fiber curvature was essentially maintained during the entire vital capacity of airway occlusion. Our data demonstrate that during airway occlusion at high lung volume, the pressure-generating capacity of the diaphragm is compromised primarily due to a mechanism that involved a combined mechanical effect of hyperinflation and excessive muscle contraction rather than a significant loss of curvature of its muscle fibers.NEW & NOTEWORTHY Data from the current study support the hypothesis that the pressure-generating capacity of the diaphragm at high lung volume is compromised primarily due to a mechanism that involves a combined mechanical effect of hyperinflation and substantial muscle contraction rather than a significant loss of its muscle fiber curvature.