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KEY POINTS Low dose ketamine is a leading medication used to provide analgesia in pre-hospital and hospital settings. Low dose ketamine is increasingly used off-label to treat conditions such as depression. In animals, ketamine stimulates the sympathetic nervous system and increases blood pressure, but these physiological consequences have not been studied in conscious humans. Our data suggest that low dose ketamine administration blunts pain perception and reduces blood pressure, but not muscle sympathetic nerve activity burst frequency, responses during a cold pressor test in healthy humans. These mechanistic, physiological results inform risk-benefit analysis for clinicians administering low dose ketamine in humans. ABSTRACT Low dose ketamine is an effective analgesic medication. However, our knowledge of the effects of ketamine on autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low dose ketamine influences autonomic cardiovascular responses during painful stimuli in humans. We tested the hypothesis that low dose ketamine blunts perceived pain, and blunts subsequent sympathetic and cardiovascular responses during an experimental noxious stimulus. Twenty-two adults (10F/12M; 27 ± 6 years; 26 ± 3 kg m-2 , mean ± SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed cold pressor tests (CPT; hand in ∼0.4°C ice bath for 2 min) pre- and 5 min post-drug administration (20 mg ketamine or saline). We compared pain perception (100 mm visual analogue scale), muscle sympathetic nerve activity (MSNA; microneurography, 12 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) during the pre- and post-drug CPTs separately using paired, two-tailed t tests. For the pre-drug CPT, perceived pain (P = 0.4378), MSNA burst frequency responses (P = 0.7375), and mean BP responses (P = 0.6457) were not different between trials. For the post-drug CPT, ketamine compared to placebo administration attenuated perceived pain (P

Older adults have reduced fluid intake and impaired body fluid and electrolyte regulation. Older female adults exhibit exaggerated exercise blood pressure (BP) responses, which is associated with an increased risk of adverse cardiovascular events. However, it is unclear if dysregulated body fluid homeostasis contributes to altered exercise BP responses in older female adults. We tested the hypothesis that short‐term water deprivation (WD) increases exercise BP responses in older female adults. Fifteen female adults (eight young [25 ± 6 years] and seven older [65 ± 6 years]) completed two experimental conditions in random crossover fashion; a euhydration control condition and a stepwise reduction in water intake over three days concluding with a 16‐hr WD period. During both trials, beat‐to‐beat BP (photoplethysmography) and heart rate (electrocardiogram) were continuously assessed during rest, handgrip exercise (30% MVC), and post‐exercise ischemia (metaboreflex isolation). At screening, older compared to young female adults had greater systolic and diastolic BP (p ≤ .02). Accelerometer‐assessed habitual physical activity was not different between groups (p = .65). Following WD, 24‐hr urine flow rate decreased, whereas thirst, urine specific gravity, and plasma osmolality increased (condition: p, The current data suggest that healthy female aging is associated with a maintained ability to preserve body water balance during short‐term reductions in water intake. These data also indicate that reduced water intake is not associated with augmented cardiovascular responses during exercise pressor reflex activation in older female adults.

Key points Overload training is required for sustained performance gain in athletes (functional overreaching). However, excess overload may result in a catabolic state which causes performance decrements for weeks (non‐functional overreaching) up to months (overtraining).Blood ketone bodies can attenuate training‐ or fasting‐induced catabolic events. Therefore, we investigated whether increasing blood ketone levels by oral ketone ester (KE) intake can protect against endurance training‐induced overreaching.We show for the first time that KE intake following exercise markedly blunts the development of physiological symptoms indicating overreaching, and at the same time significantly enhances endurance exercise performance.We provide preliminary data to indicate that growth differentiation factor 15 (GDF15) may be a relevant hormonal marker to diagnose the development of overtraining.Collectively, our data indicate that ketone ester intake is a potent nutritional strategy to prevent the development of non‐functional overreaching and to stimulate endurance exercise performance. Abstract It is well known that elevated blood ketones attenuate net muscle protein breakdown, as well as negate catabolic events, during energy deficit. Therefore, we hypothesized that oral ketones can blunt endurance training‐induced overreaching. Fit male subjects participated in two daily training sessions (3 weeks, 6 days/week) while receiving either a ketone ester (KE, n = 9) or a control drink (CON, n = 9) following each session. Sustainable training load in week 3 as well as power output in the final 30 min of a 2‐h standardized endurance session were 15% higher in KE than in CON (both P, Key points Overload training is required for sustained performance gain in athletes (functional overreaching). However, excess overload may result in a catabolic state which causes performance decrements for weeks (non‐functional overreaching) up to months (overtraining).Blood ketone bodies can attenuate training‐ or fasting‐induced catabolic events. Therefore, we investigated whether increasing blood ketone levels by oral ketone ester (KE) intake can protect against endurance training‐induced overreaching.We show for the first time that KE intake following exercise markedly blunts the development of physiological symptoms indicating overreaching, and at the same time significantly enhances endurance exercise performance.We provide preliminary data to indicate that growth differentiation factor 15 (GDF15) may be a relevant hormonal marker to diagnose the development of overtraining.Collectively, our data indicate that ketone ester intake is a potent nutritional strategy to prevent the development of non‐functional overreaching and to stimulate endurance exercise performance.