Effect of histamine-receptor antagonism on the circulating inflammatory cell and cytokine response to exercise: A pilot study.

The purpose of this study was to gain insight into histamine's role in the exercise inflammatory response and recovery from exercise. To explore this, young healthy participants (n = 12) performed 300 eccentric leg extensions under control (Placebo) versus histamine H1 and H2 receptor antagonism (Blockade) in a randomized cross-over study. Circulating leukocytes and cytokines were measured for 72 h after exercise. Circulating leukocytes were elevated at 6 and 12 h after exercise (p < 0.05) with the peak response being a 44.1 ± 11.7% increase with Blockade versus 13.7 ± 6.6% with Placebo (both p < 0.05 vs. baseline, but also p < 0.05 between Blockade and Placebo). Of the cytokines that were measured, only MCP-1 was elevated following exercise. The response at 6 h post-exercise was a 104.0 ± 72.5% increase with Blockade versus 93.1 ± 41.9% with Placebo (both p < 0.05 vs. baseline, p = 0.82 between Blockade and Placebo). The main findings of the present investigation were that taking combined histamine H1 and H2 receptor antagonists augmented the magnitude but not the duration of the increase of circulating immune cells following exercise. This suggests histamine is not only exerting a local influence within the skeletal muscle but that it may influence the systemic inflammatory patterns.

Hypohydration attenuates increases in creatinine clearance to oral protein loading and the renal hemodynamic response to exercise pressor reflex.

Insufficient hydration is prevalent among free living adults. This study investigated whether hypohydration alters 1) renal functional reserve, 2) the renal hemodynamic response to the exercise pressor reflex, and 3) urine-concentrating ability during oral protein loading. In a block-randomized crossover design, 22 healthy young adults (11 females and 11 males) underwent 24-h fluid deprivation (Hypohydrated) or 24-h normal fluid consumption (Euhydrated). Renal functional reserve was assessed by oral protein loading. Renal hemodynamics during the exercise pressor reflex were assessed via Doppler ultrasound. Urine-concentrating ability was assessed via free water clearance. Creatinine clearance did not differ at 150 min postprotein consumption between conditions [Hypohydrated: 246 mL/min, 95% confidence interval (CI): 212-280; Euhydrated: 231 mL/min, 95% CI: 196-265, P = 0.2691] despite an elevated baseline in Hypohydrated (261 mL/min, 95% CI: 218-303 vs. 143 mL/min, 95% CI: 118-168, P < 0.0001). Renal artery vascular resistance was not different at baseline (P = 0.9290), but increases were attenuated in Hypohydrated versus Euhydrated at the end of handgrip (0.5 mmHg/cm/s, 95% CI: 0.4-0.7 vs. 0.8 mmHg/cm/s 95% CI: 0.6-1.1, P = 0.0203) and end occlusion (0.2 mmHg/cm/s, 95% CI: 0.1-0.3 vs. 0.4 mmHg/cm/s 95% CI: 0.3-0.6, P = 0.0127). There were no differences between conditions in free water clearance at 150 min postprotein (P = 0.3489). These data indicate that hypohydration 1) engages renal functional reserve and attenuates the ability to further increase creatinine clearance, 2) attenuates increases in renal artery vascular resistance to the exercise pressor reflex, and 3) does not further enhance nor impair urine-concentrating ability during oral protein loading.NEW & NOTEWORTHY Insufficient hydration is prevalent among free living adults. This study found that hypohydration induced by 24-h fluid deprivation engaged renal functional reserve and that oral protein loading did not further increase creatinine clearance. Hypohydration also attenuated the ability to increase renal vascular resistance during the exercise pressor reflex. In addition, hypohydration neither enhanced nor impaired urine-concentrating ability during oral protein loading. These data support the importance of mitigating hypohydration in free living adults.

Acute kidney injury biomarkers and hydration assessments following prolonged mild hypohydration in healthy young adults.

The high prevalence of inadequate hydration (e.g., hypohydration and underhydration) is concerning given that extreme heat increases excess hospitalizations for fluid/electrolyte disorders and acute kidney injury (AKI). Inadequate hydration may also be related to renal and cardiometabolic disease development. This study tested the hypothesis that prolonged mild hypohydration increases the urinary AKI biomarker product of insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 ([IGFBP7·TIMP-2]) compared with euhydration. In addition, we determined the diagnostic accuracy and optimal cutoffs of hydration assessments for discriminating positive AKI risk ([IGFBP·TIMP-2] >0.3 (ng/mL)2/1,000). In a block-randomized crossover design, 22 healthy young adults (11 females and 11 males) completed 24 h of fluid deprivation (hypohydrated group) or 24 h of normal fluid consumption (euhydrated group) separated by ≥72 h. Urinary [IGFBP7·TIMP-2] and other AKI biomarkers were measured following the 24-h protocols. Diagnostic accuracy was assessed via receiver operating characteristic curve analysis. Urinary [IGFBP7·TIMP-2] [1.9 (95% confidence interval: 1.0-2.8) vs. 0.2 (95% confidence interval: 0.1-0.3) (ng/mL)2/1,000, P = 0.0011] was markedly increased in hypohydrated versus euhydrated groups. Urine osmolality (area under the curve: 0.91, P < 0.0001) and urine specific gravity (area under the curve: 0.89, P < 0.0001) had the highest overall performance for discriminating positive AKI risk. Optimal cutoffs with a positive likelihood ratio of 11.8 for both urine osmolality and specific gravity were 952 mosmol/kgH2O and 1.025 arbitrary units. In conclusion, prolonged mild hypohydration increased urinary [IGFBP7·TIMP-2] in males and females. Urinary [IGFBP7·TIMP-2] corrected to urine concentration was elevated in males only. Urine osmolality and urine specific gravity may have clinical utility for discriminating positive AKI risk following prolonged mild hypohydration.NEW & NOTEWORTHY This study found that prolonged mild hypohydration in healthy young adults increased the Food and Drug Administration approved acute kidney injury (AKI) biomarker urinary insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 [IGFBP7·TIMP-2]. Urine osmolality and specific gravity demonstrated an excellent ability to discriminate positive AKI risk. These findings emphasize the importance of hydration in protecting renal health and lend early support for hydration assessment as an accessible tool to assess AKI risk.

Transcutaneous delivery of sodium bicarbonate increases intramuscular pH.

Introduction: Oral bicarbonate loading improves the buffering of metabolic acidosis and may improve exercise performance but can also result in gastric distress. Momentous' PR Lotion contains a novel composition intended to provide a transdermal delivery vehicle for sodium bicarbonate which could allow the same ergogenic effect without the gastric distress. The present study explored the effect of transdermal delivery of sodium bicarbonate in a resting condition. Methods: We measured the pH from intramuscular dialysate, via microdialysis, of the vastus lateralis during a 2 h application of PR Lotion (40 g of lotion per leg) in 9 subjects (3 women, 6 men). Venous blood samples were obtained for serum pH before and after application. A placebo time control was also performed in 4 subjects (2 women, 2 men). We hypothesized that PR Lotion application would increase pH of intramuscular dialysate. Results: PR Lotion resulted in a rise in pH of 0.13 ± 0.04 units (p < 0.05), which translates to a 28% reduction in [H+]. Increases in serum pH were smaller (∼9%) yet consistent (p < 0.05). In contrast, placebo time control pH tended to decrease (p = 0.08). The effect of PR Lotion on pH tended to correlate with the dose per kg body weight of each individual (r = 0.70, p = 0.08). Conclusion: These observations support the idea of transdermal bicarbonate delivery impacting pH buffering both systemically and intramuscularly. Further work investigating these potential benefits in an exercising model would be critical to establishing PR Lotion's utility as an ergogenic aid.

The effect of local passive heating on skeletal muscle histamine concentration: implications for exercise-induced histamine release.

Aerobic exercise induces mast cell degranulation and increases histamine formation by histidine decarboxylase, resulting in an ∼150% increase in intramuscular histamine. The purpose of this study was to determine if the increase in skeletal muscle temperature associated with exercise is sufficient to explain this histamine response. Specifically, we hypothesized that local passive heating that mimics the magnitude and time course of changes in skeletal muscle temperature observed during exercise would result in increased intramuscular histamine concentrations comparable to exercising values. Seven subjects participated in the main study in which pulsed short-wave diathermy was used to passively raise the temperature of the vastus lateralis over 60 min. Heating increased intramuscular temperature from 32.6°C [95% confidence interval (CI) 32.0°C to 33.2°C] to 38.9°C (38.7°C to 39.2°C) (P < 0.05) and increased intramuscular histamine concentration from 2.14 ng/mL (1.92 to 2.36 ng/mL) to 2.97 ng/mL (2.57 to 3.36 ng/mL) (P < 0.05), an increase of 41%. In a follow-up in vitro experiment using human-derived cultured mast cells, heating to comparable temperatures did not activate mast cell degranulation. Therefore, it appears that exercise-associated changes in skeletal muscle temperature are sufficient to generate elevations in intramuscular histamine concentration. However, this thermal effect is most likely due to changes in de novo histamine formation via histidine decarboxylase and not due to degranulation of mast cells. In conclusion, physiologically relevant increases in skeletal muscle temperature explain part, but not all, of the histamine response to aerobic exercise. This thermal effect may be important in generating positive adaptations to exercise training.NEW & NOTEWORTHY The "exercise signal" that triggers histamine release within active skeletal muscle during aerobic exercise is unknown. By mimicking the magnitude and time course of increasing skeletal muscle temperature observed during aerobic exercise, we demonstrate that part of the exercise-induced rise in histamine is explained by a thermal effect, with in vitro experiments suggesting this is most likely via de novo histamine formation. This thermal effect may be important in generating positive adaptations to exercise training.

Heat therapy improves glucose tolerance and adipose tissue insulin signaling in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is associated with high rates of obesity and metabolic dysfunction. Repeated passive heat exposure (termed heat therapy) is a novel lifestyle intervention for improving health in obese women with PCOS. The purpose of this study was to examine changes in metabolic function in obese women with PCOS following heat therapy. Eighteen age- and BMI-matched obese women with PCOS (age: 27 ± 1 yr, BMI: 41.3 ± 1.1 kg/m-2) were assigned to heat therapy (HT) or time control (CON). HT participants underwent 30 one-hour hot tub sessions over 8-10 wk, while CON participants completed all testing but did not undergo heat therapy. Before (Pre), at the mid-point (Mid), and following (Post) 8-10 wk of heat therapy, metabolic health was assessed using a 2-h oral glucose tolerance test, a subcutaneous abdominal fat biopsy (Pre-Post only), and other blood markers relating to metabolic function. HT participants exhibited improved fasting glucose (Pre: 105 ± 3, Post: 89 ± 5mg/dl; P = 0.001), glucose area under the curve (AUC) (Pre: 18,698 ± 1,045, Post: 16,987 ± 1,017 mg·dl-1·min-1; P = 0.028) and insulin AUC (Pre: 126,924 ± 11,730, Post: 91,233 ± 14,429 IU l-1·min-1; P = 0.012). Adipocyte insulin signaling (p-AKT at Ser-473 with 1.2 nM insulin) increased in HT (Pre: 0.29 ± 0.14, Post: 0.93 ± 0.29 AU; P = 0.021). Additionally, serum testosterone declined in HT participants (Pre: 51 ± 7, Post: 34 ± 4 ng/dl; P = 0.033). No parameters changed over time in CON, and no change in BMI was observed in either group. HT substantially improved metabolic risk profile in obese women with PCOS. HT also reduced androgen excess and may improve PCOS symptomology.