Short-term cocoa bioflavanol supplementation does not improve cold-induced vasodilation in young healthy adults.

PURPOSE: Cold-induced vasodilation (CIVD) is an oscillatory rise in blood flow to glabrous skin that occurs in cold-exposed extremities. Dietary flavanols increase bioavailable nitric oxide, a proposed mediator of CIVD through active vasodilation and/or withdrawal of sympathetic vascular smooth muscle tone. However, no studies have examined the effects of flavanol intake on extremity skin perfusion during cold exposure. We tested the hypothesis that acute and 8-day flavanol supplementation would augment CIVD during single-digit cold water immersion (CWI). METHODS: Eleven healthy adults (24 ± 6 years; 10 M/1F) ingested cocoa flavanols (900 mg/day) or caffeine- and theobromine-matched placebo for 8 days in a double-blind, randomized, crossover design. On Days 1 and 8, CIVD was assessed 2 h post-treatment. Subjects immersed their 3rd finger in warm water (42 °C) for 15 min before CWI (4 °C) for 30 min, during which nail bed and finger pad skin temperature were measured. RESULTS: Flavanol ingestion had no effect on CIVD frequency (Day 1, Flavanol: 3 ± 2 vs. Placebo: 3 ± 2; Day 8, Flavanol: 3 ± 2 vs. Placebo: 3 ± 1) or amplitude (Day 1, Flavanol: 4.3 ± 1.7 vs. Placebo: 4.9 ± 2.6 °C; Day 8, Flavanol: 3.9 ± 1.9 vs. Placebo: 3.9 ± 2.0 °C) in the finger pad following acute or 8-day supplementation (P > 0.05). Furthermore, average, nadir, and apex finger pad temperatures during CWI were not different between treatments on Days 1 or 8 of supplementation (P > 0.05). Similarly, no differences in CIVD parameters were observed in the nail bed following supplementation (P > 0.05). CONCLUSION: These data suggest that cocoa flavanol ingestion does not alter finger CIVD. Clinical Trial Registration Clinicaltrials.gov Identifier: NCT04359082. April 24, 2020.

Central versus peripheral mechanisms of cold-induced vasodilation: a study in the fingers and toes of people with paraplegia.

PURPOSE: This study examined physiological and perceptual parameters related to cold-induced vasodilation (CIVD) in the fingers and toes of people with paraplegia and compared them with responses observed in able-bodied individuals. METHODS: Seven participants with paraplegia and seven able-bodied individuals participated in a randomized matched-controlled study involving left-hand and -foot immersion in cold water (8 ± 1 °C) for 40 min during exposure to cool (16 ± 1 °C), thermoneutral (23 ± 1 °C), and hot (34 ± 1 °C) ambient conditions. RESULTS: Similar CIVD occurrence was observed in the fingers in the two groups. In toes, three of the seven participants with paraplegia revealed CIVDs: one in cool, two in thermoneutral, and three in hot conditions. No able-bodied participants revealed CIVDs in cool and thermoneutral conditions, while four revealed CIVDs in hot conditions. The toe CIVDs of paraplegic participants were counterintuitive in several respects: they were more frequent in cool and thermoneutral conditions (compared to the able-bodied participants), emerged in these conditions despite lower core and skin temperatures of these participants, and were evident only in cases of thoracic level lesions (instead of lesions at lower spinal levels). CONCLUSION: Our findings demonstrated considerable inter-individual variability in CIVD responses in both the paraplegic and able-bodied groups. While we observed vasodilatory responses in the toes of participants with paraplegia that technically fulfilled the criteria for CIVD, it is unlikely that they reflect the CIVD phenomenon observed in able-bodied individuals. Taken together, our findings favor the contribution of central over peripheral factors in relation to the origin and/or control of CIVD.

Effect of 8 days of exercise-heat acclimation on aerobic exercise performance of men in hypobaric hypoxia.

Exercise-heat acclimation (EHA) induces adaptations that improve tolerance to heat exposure. Whether adaptations from EHA can also alter responses to hypobaric hypoxia (HH) conditions remains unclear. This study assessed whether EHA can alter time-trial performance and/or incidence of acute mountain sickness (AMS) during HH exposure. Thirteen sea-level (SL) resident men [SL peak oxygen consumption (V̇o2peak) 3.19 ± 0.43 L/min] completed steady-state exercise, followed by a 15-min cycle time trial and assessment of AMS before (HH1; 3,500 m) and after (HH2) an 8-day EHA protocol [120 min; 5 km/h; 2% incline; 40°C and 40% relative humidity (RH)]. EHA induced lower heart rate (HR) and core temperature and plasma volume expansion. Time-trial performance was not different between HH1 and HH2 after 2 h (106.3 ± 23.8 vs. 101.4 ± 23.0 kJ, P = 0.71) or 24 h (107.3 ± 23.4 vs. 106.3 ± 20.8 kJ, P > 0.9). From HH1 to HH2, HR and oxygen saturation, at the end of steady-state exercise and time-trial tests at 2 h and 24 h, were not different (P > 0.05). Three of 13 volunteers developed AMS during HH1 but not during HH2, whereas a fourth volunteer only developed AMS during HH2. Heat shock protein 70 was not different from HH1 to HH2 at SL [1.9 ± 0.7 vs. 1.8 ± 0.6 normalized integrated intensities (NII), P = 0.97] or after 23 h (1.8 ± 0.4 vs. 1.7 ± 0.5 NII, P = 0.78) at HH. Our results indicate that this EHA protocol had little to no effect-neither beneficial nor detrimental-on exercise performance in HH. EHA may reduce AMS in those who initially developed AMS; however, studies at higher elevations, having higher incidence rates, are needed to confirm our findings.

Controlled Feeding of an 8-d, High-Dairy Cheese Diet Prevents Sodium-Induced Endothelial Dysfunction in the Cutaneous Microcirculation of Healthy, Older Adults through Reductions in Superoxide.

BACKGROUND: While excess dietary sodium impairs vascular function by increasing oxidative stress, the dietary incorporation of dairy foods improves vascular health. We demonstrated that single-meal cheese consumption ameliorates acute, sodium-induced endothelial dysfunction. However, controlled feeding studies examining the inclusion of cheese, a dairy product that contains both bioactive constituents and sodium, are lacking. OBJECTIVES: We tested the hypothesis that microcirculatory endothelium-dependent dilation (EDD) would be impaired by a high-sodium diet, but a sodium-matched diet high in dairy cheese would preserve EDD through oxidant stress mechanisms. METHODS: We gave 11 adults without salt-sensitive blood pressure (<10 mmHg Δ mean arterial pressure; 64 ± 2 y) 4 separate 8-d controlled dietary interventions in a randomized, crossover design: a low-sodium, no-dairy intervention (LNa; 1500 mg/d sodium); a low-sodium, high-cheese intervention (LNaC; 1500 mg/d sodium, 170 g/d cheese); a high-sodium, no-dairy intervention (HNa; 5500 mg/d sodium); and a high-sodium, high-cheese intervention (HNaC; 5500 mg/d sodium, 170 g/d cheese). On Day 8 of each diet, EDD was assessed through a localized infusion (intradermal microdialysis) of acetylcholine (ACh), both alone and during coinfusion of NG-nitro-L-arginine methyl ester (NO synthase inhibitor), L-ascorbate (nonspecific antioxidant), apocynin [NAD(P)H oxidase inhibitor], or tempol (superoxide scavenger). RESULTS: Compared with LNa, microvascular responsiveness to ACh was attenuated during HNa (LNa: -4.82 ± 0.20 versus HNa: -3.21 ± 0.55 M logEC50; P = 0.03) but not LNaC (-5.44 ± 0.20 M logEC50) or HNaC (-4.46 ± 0.50 M logEC50). Further, ascorbate, apocynin, and tempol administration each increased ACh-induced vasodilation during HNa only (Ringer's: 38.9 ± 2.4; ascorbate: 48.0 ± 2.5; tempol: 45.3 ± 2.7; apocynin: 48.5 ± 2.6% maximum cutaneous vascular conductance; all P values < 0.01). CONCLUSIONS: These results demonstrate that incorporating dairy cheese into a high-sodium diet preserves EDD by decreasing the concentration of superoxide radicals. Consuming sodium in cheese, rather than in nondairy sources of sodium, may be an effective strategy to reduce cardiovascular disease risk in salt-insensitive, older adults. This trial was registered at clinicaltrials.gov as NCT03376555.

Cold-induced cutaneous vasoconstriction in humans: Function, dysfunction and the distinctly counterproductive.

NEW FINDINGS: What is the topic of this review? This review presents an update and synthesis of normal mechanisms of human cutaneous vasoconstriction in response to cold stress. It then discusses conditions in which cutaneous vasoconstrictor responses are excessive or insufficient and cases in which cold-induced vasoconstrictor responses become counter to maintaining thermal and haemodynamic homeostasis. What advances does it highlight? The review highlights our current understanding of the mechanisms that mediate alterations in cold-induced cutaneous vasoconstriction in pathology and environmental extremes, which has important clinical implications for preventing cold- and cardiovascular-related deaths. ABSTRACT: In humans, cold-induced peripheral vasoconstriction is an essential element of body temperature regulation. Given that the thermoregulatory system responds rapidly to changes in skin temperature, sympathetically mediated cutaneous vasoconstriction represents a crucial 'first line of defense' against excessive reduction in body temperature. Sympathetic noradrenergic vasoconstrictor nerves cause a rapid decrease in skin blood flow, thus increasing the insulative capacity of the skin and decreasing heat loss from the body. Small changes in the activity of these nerves are also responsible for the subtle changes in skin blood flow that occur with normal daily activities or minor changes in environmental temperature. With ageing, hypertension and other conditions, the cutaneous reflex vasoconstrictor response can become excessive or insufficient. Healthy older adults have impaired reflex vasoconstriction, which may result in an impaired ability to defend body temperature in some circumstances. Hypertension is associated with augmented vasoconstriction, which could have pathological implications for left ventricular afterload in individuals already at risk for cardiovascular events. Finally, in some cases, the reflex vasoconstrictor response becomes distinctly counterproductive to its own goals of maintaining cardiovascular and thermoregulatory homeostasis. Examples include Raynaud's phenomenon, in which exaggerated vasoconstriction can produce ischaemia in the periphery, and the cutaneous vasoconstrictor response to therapeutic body cooling in severe hyperthermia, which can limit the heat exchange necessary to prevent serious heat illness.

Endothelial function is impaired in the cutaneous microcirculation of adults with psoriasis through reductions in nitric oxide-dependent vasodilation.

Psoriasis is an independent risk factor for cardiovascular disease; however, the underlying mechanisms are not fully understood. Deficits in conduit arterial function are evident in patients with psoriasis, but potential impairments in microcirculatory endothelial function remain unclear. We hypothesized that cutaneous microvascular dysfunction would be detectable in otherwise healthy individuals with psoriasis. Two intradermal microdialysis fibers were placed in (nonlesional) forearm skin of nine patients (3 men and 6 women, 39 ± 5 yr) with moderate (16 ± 2% of body surface area) plaque psoriasis and nine healthy (nonpsoriatic) control subjects (3 men and 6 women, 38 ± 5 yr) for local delivery of 1) lactated Ringer solution (control) and 2) 10 mM l-ascorbate (a nonspecific antioxidant). An index of skin blood flow was measured using laser-Doppler flowmetry during local heating (42°C). Nitric oxide (NO)-dependent vasodilation was directly quantified after perfusion of the nonspecific NO synthase inhibitor NG-nitro-l-arginine methyl ester (15 mM). A third fiber was perfused with increasing concentrations (10-10 - 10-2 M) of norepinephrine to elicit adrenoreceptor-mediated cutaneous vasoconstriction. NO-dependent vasodilation was attenuated in patients with psoriasis (57 ± 5% and 39 ± 7% maximum cutaneous vascular conductance in control subjects and adults with psoriasis, respectively, P < 0.01). l-Ascorbate did not improve NO-dependent vasodilation ( P > 0.05). There was no group difference in maximal vasoconstriction or microvascular sensitivity to norepinephrine ( P > 0.05). These data suggest that NO bioavailability is reduced in otherwise healthy individuals with psoriasis, which contributes to systemic microvascular dysfunction. NEW & NOTEWORTHY In adults with psoriasis, reduced nitric oxide bioavailability mediates impaired endothelium-dependent vasodilation, independent of increases in oxidative stress. Furthermore, the degree of psoriatic symptomology is directly related to greater reductions in nitric oxide-dependent vasodilation.

Dairy cheese consumption ameliorates single-meal sodium-induced cutaneous microvascular dysfunction by reducing ascorbate-sensitive oxidants in healthy older adults.

Chronic dairy product intake is associated with improved cardiovascular outcomes, whereas high dietary Na impairs endothelial function through increased oxidative stress and reduced nitric oxide (NO) bioavailability. The purpose of this study was to compare the effect of acute cheese consumption with consumption of Na from non-dairy sources on microvascular function. We hypothesised that dairy cheese ingestion would augment NO-dependent vasodilation compared with Na from non-dairy sources. On five visits, fourteen subjects (61 (sem 2) years, eight male/six female) consumed either 85 g dairy cheese (560 mg Na), 85 g soya cheese (560 mg Na), 65 g pretzels (560 mg Na), 170 g dairy cheese (1120 mg Na) or 130 g pretzels (1120 mg Na). Two intradermal microdialysis fibres were inserted in the ventral forearm for delivery of lactated Ringer's solution or 10 mm-ascorbate (antioxidant) during local skin heating (approximately 50 min). Erythrocyte flux was measured continuously by laser-Doppler flowmetry (LDF), and cutaneous vascular conductance (CVC=LDF/mean arterial pressure) was normalised as %CVCmax (28 mm-sodium nitroprusside). Following a plateau in CVC, 15 mm-N G -nitro-l-arginine-methyl-ester was perfused to quantify NO-dependent vasodilation (approximately 45 min). NO-dependent vasodilation was greater following consumption of dairy products (560 mg Na 57 (sem 3) %) (1120 mg Na 55 (sem 5) %) compared with soya (560 mg Na 42 (sem 3) %; P=0·002) or pretzels (560 mg Na 43 (sem 4) %; P=0·004) (1120 mg Na 46 (sem 3) %; P=0·04). Ascorbate augmented NO-dependent vasodilation following intake of soya (control: 42 (sem 3) v. ascorbate: 54 (sem 3) %; P=0·01) or pretzels (560 mg Na; control: 43 (sem 4) v. ascorbate: 56 (sem 3) %; P=0·006) (1120 mg Na; control: 46 (sem 5) v. ascorbate: 56 (sem 3) %; P=0·02), but not dairy products. Na ingestion via dairy products was associated with greater NO-dependent vasodilation compared with non-dairy products, a difference that was ameliorated with ascorbate perfusion. The antioxidant properties of dairy proteins may protect against Na-induced reductions in NO-dependent dilation.

Acute dairy milk ingestion does not improve nitric oxide-dependent vasodilation in the cutaneous microcirculation.

In epidemiological studies, chronic dairy milk consumption is associated with improved vascular health and reduced age-related increases in blood pressure. Although milk protein supplementation augments conduit artery flow-mediated dilation, whether or not acute dairy milk intake may improve microvascular function remains unclear. We hypothesised that dairy milk would increase direct measurement of endothelial nitric oxide (NO)-dependent cutaneous vasodilation in response to local skin heating. Eleven men and women (61 (sem 2) years) ingested two or four servings (473 and 946 ml) of 1 % dairy milk or a rice beverage on each of 4 separate study days. In a subset of five subjects, an additional protocol was completed after 473 ml of water ingestion. Once a stable blood flow occurred, 15 mm-N G -nitro-l-arginine methyl ester was perfused (intradermal microdialysis) to quantify NO-dependent vasodilation. Red-blood-cell flux (RBF) was measured by laser-Doppler flowmetry, and cutaneous vascular conductance (CVC=RBF/mean arterial pressure) was calculated and normalised to maximum (%CVCmax; 28 mm-sodium nitroprusside). Full expression of cutaneous vasodilation was not different among dairy milk, rice beverage and water, and there was no effect of serving size on the total vasodilatory response. Contrary to our hypothesis, NO-dependent vasodilation was lower for dairy milk than rice beverage (D: 49 (sem 5), R: 55 (sem 5) %CVCmax; P<0·01). Acute dairy milk ingestion does not augment NO-dependent vasodilation in the cutaneous microcirculation compared with a rice beverage control.

Sex differences in thermal sensitivity and perception: Implications for behavioral and autonomic thermoregulation.

Temperature sensitive receptors in the skin and deep body enable the detection of the external and internal environment, including the perception of thermal stimuli. Changes in heat balance require autonomic (e.g., sweating) and behavioral (e.g., seeking shade) thermoeffector initiation to maintain thermal homeostasis. Sex differences in body morphology can largely, but not entirely, account for divergent responses in thermoeffector and perceptual responses to environmental stress between men and women. Thus, it has been suggested that innate differences in thermosensation may exist between men and women. Our goal in this review is to summarize the existing literature that investigates localized and whole-body cold and heat exposure pertaining to sex differences in thermal sensitivity and perception, and the interplay between autonomic and behavioral thermoeffector responses. Overall, it appears that local differences in thermal sensitivity and perception are minimized, yet still apparent, when morphological characteristics are well-controlled. Sex differences in the early vasomotor response to environmental stress and subsequent changes in blood flow likely contribute to the heightened thermal awareness observed in women. However, the contribution of thermoreceptors to observed sex differences in thermal perception and thermoeffector function is unclear, as human studies investigating these questions have not been performed.

Influences of ovarian hormones on physiological responses to cold in women.

While it is clear that the ovarian hormones estradiol and progesterone have important influences on physiological thermoregulation in women, the influences of these hormones on responses to cold exposure are not well understood. Both heat conservation and heat production must increase to offset heat losses that decrease body temperature in cold ambient conditions. Cutaneous vasoconstriction conserves heat, whereas shivering and non-shivering thermogenesis produce heat - all as part of reflex physiological responses to cold exposure. Our goal in this brief review is to highlight existing knowledge and recent advances pertaining to sex and sex hormone influences on thermoeffector responses to cold stress. Estrogens have multiple influences that contribute to heat dissipation and a lower body temperature, while the influence of progesterone appears to primarily increase body temperature. Fluctuations in estrogen and progesterone across the menstrual cycle can alter the level at which body temperature is regulated. Recent evidence suggests that female reproductive hormones can modulate the cutaneous vasoconstrictor response, and may influence metabolic mechanisms such as substrate utilization during shivering and non-shivering thermogenesis. Overall, it appears that quantitative differences in cold thermoregulation between sexes are minimal when anthropometric measures are minimized, such that women do not have a strong "advantage" or "disadvantage" in terms of overall ability to tolerate cold. Thermoregulatory physiology in women during cold exposure remains relatively understudied and many mechanisms require further elucidation.

Human cold habituation: Physiology, timeline, and modifiers.

Habituation is an adaptation seen in many organisms, defined by a reduction in the response to repeated stimuli. Evolutionarily, habituation is thought to benefit the organism by allowing conservation of metabolic resources otherwise spent on sub-lethal provocations including repeated cold exposure. Hypermetabolic and/or insulative adaptations may occur after prolonged and severe cold exposures, resulting in enhanced cold defense mechanisms such as increased thermogenesis and peripheral vasoconstriction, respectively. Habituation occurs prior to these adaptations in response to short duration mild cold exposures, and, perhaps counterintuitively, elicits a reduction in cold defense mechanisms demonstrated through higher skin temperatures, attenuated shivering, and reduced cold sensations. These habituated responses likely serve to preserve peripheral tissue temperature and conserve energy during non-life threatening cold stress. The purpose of this review is to define habituation in general terms, present evidence for the response in non-human species, and provide an up-to-date, critical examination of past studies and the potential physiological mechanisms underlying human cold habituation. Our aim is to stimulate interest in this area of study and promote further experiments to understand this physiological adaptation.

Influence of Acetazolamide on Hand Strength and Manual Dexterity During a 30-h Simulated High Altitude Exposure.

INTRODUCTION: High altitude missions pose significant challenges to Warfighter medical readiness and performance. Decreased circulating oxygen levels cause a decrease in exercise performance and can cause debilitating symptoms associated with acute mountain sickness, especially with rapid ascent. Acetazolamide (AZ) is known to minimize symptoms of acute mountain sickness, but it is unknown whether this medication alters hand strength and manual dexterity during altitude exposure. MATERIALS AND METHODS: Ten male volunteers (22 ± 4 yr, 75.9 ± 13.7 kg, 174.9 ± 9.3 cm) participated in two separate 30 h simulated altitude exposures (496 mmHg, equivalent to 3,500 m, 20°C, 20% RH) in a hypobaric chamber. Participants were given either a placebo or 250 mg of AZ twice daily for 3.5 d (2 sea-level [SL] days + the 30 h altitude exposure) in a randomized, single-blind, crossover design. During SL and both altitude (ALT) exposures, hand function tests were performed, including hand grip and finger pinch strength tests, as well as the Purdue Pegboard (PP) and magazine loading tests to assess manual dexterity. Paired T tests and two-way repeated measure analysis of variance were used as appropriate to evaluate the effects of AZ and ALT. The value of p < 0.05 was accepted for statistical significance. RESULTS: There were no influences of acute ALT exposure or AZ treatment on hand strength (eg, grip strength; SL: 39.2 ± 5.5 kg vs. ALT: 41.5 ± 6.9 kg, p > 0.05) or dexterity (eg, PPassembly; placebo: 35.5 ± 5.3 vs. AZ: 34.3 ± 4.6, p > 0.05) in our volunteers. Two dexterity tests (PPsum and magazine loading) showed improvements over time at ALT, regardless of treatment, where scores were improved after 10 h of exposure compared to at 1 h (eg, magazine loading: 56 ± 12 vs. 48 ± 10, p < 0.001). This pattern was not seen in the PPassembly test or any strength measurements. CONCLUSIONS: Our results suggest that 500 mg/d of AZ does not influence hand strength or manual dexterity during a 30 h exposure to 3,500 m simulated ALT. Acute ALT exposure (1 h) did not influence dexterity or strength, although some measures of dexterity showed improvements as exposure time increased. We conclude that use of AZ to optimize medical readiness at ALT is unlikely to impair the Warfighter's ability to complete mission tasks that depend on hand function.