Lacy M. Alexander

Heat waves, aging and human cardiovascular health

This brief review is based on a Presidents Lecture presented at the Annual Meeting of the American College of Sports Medicine in 2013. The purpose of this review was to assess the effects of climate change and consequent increases in environmental heat stress on the aging cardiovascular system. The earths average global temperature is slowly but consistently increasing, and along with mean temperature changes come increases in heat wave frequency and severity. Extreme passive thermal stress resulting from prolonged elevations in ambient temperature and prolonged physical activity in hot environments creates a high demand on the left ventricle to pump blood to the skin to dissipate heat. Even healthy aging is accompanied by altered cardiovascular function, which limits the extent to which older individuals can maintain stroke volume, increase cardiac output, and increase skin blood flow when exposed to environmental extremes. In the elderly, the increased cardiovascular demand during heat waves is often fatal because of increased strain on an already compromised left ventricle. Not surprisingly, excess deaths during heat waves 1) occur predominantly in older individuals and 2) are overwhelmingly cardiovascular in origin. Increasing frequency and severity of heat waves coupled with a rapidly growing at-risk population dramatically increase the extent of future untoward health outcomes.

Nonuniform, age-related decrements in regional sweating and skin blood flow

Aging is associated with attenuated thermoregulatory function that varies regionally over the body. Decrements in vasodilation and sweating are well documented with age, yet limited data are available concerning the regional relation between these responses. We aimed to examine age-related alterations in the relation between regional sweating (RSR) and skin blood flow (SkBF) to thermal and pharmacological stimuli. Four microdialysis fibers were inserted in the ventral forearm, abdomen, thigh, and lower back of eight healthy aged subjects (64 ± 7 yr) and nine young (23 ± 3 yr) during 1) ACh dose response (1 × 10(-7) to 0.1 M, mean skin temperature 34°C) and 2) passive whole body heating to Δ1°C rise in oral temperature (Tor). RSR and SkBF were measured over each microdialysis membrane using ventilated capsules and laser-Doppler flowmetry. Maximal SkBF was measured at the end of both protocols (50 mM SNP). Regional sweating thresholds and RSR were attenuated in aged vs. young at all sites (P < 0.0001) during whole body heating. Vasodilation thresholds were similar between groups (P > 0.05). Attenuated SkBF were observed at the arm and back in the aged, representing 56 and 82% of those in the young at these sites, respectively (0.5 ΔTor). During ACh perfusion, SkBF (P = 0.137) and RSR were similar between groups (P = 0.326). Together these findings suggest regional age-related decrements in heat-activated sweat gland function but not cholinergic sensitivity. Functional consequences of such thermoregulatory impairment include the compromised ability of older individuals to defend core temperature during heat exposure and a subsequently greater susceptibility to heat-related illness and injury.

Endothelial nitric oxide synthase mediates the nitric oxide component of reflex cutaneous vasodilatation during dynamic exercise in humans

Increases in skin blood flow and sweating also occur during exercise; however, it is not known if the mechanisms controlling these responses are the same during passive heat stress and exercise. The prevailing thought has been that mechanisms of cutaneous vasodilatation during passive heat stress and sustained dynamic exercise are the same, or very similar. Nitric oxide (NO) has been shown to be important for increasing skin blood flow during passive heat stress but it is unknown if this molecule is also involved during sustained dynamic exercise. The findings from our study suggest NO is involved in increasing skin blood flow during sustained dynamic exercise in humans but the NO is produced from a different enzyme compared to passive heat stress. These findings may help us better understand and aid individuals who have difficulty regulating their body temperature during sustained dynamic exercise (e.g. ageing).

Aspirin and Clopidogrel Alter Core Temperature and Skin Blood Flow during Heat Stress

UNLABELLED Antithrombotic therapy with oral aspirin (ASA) or clopidogrel (CLO) (Plavix; Bristol-Myers Squibb, Bridgewater, NJ) is associated with an attenuated skin vasodilator response and a greater rate of rise in core temperature in healthy, middle-age individuals during passive heating in a water perfused suit. PURPOSE The present double-blind, crossover study examined the functional consequences of 7 d of low-dose ASA (81 mg·d) versus CLO (75 mg·d) treatment in 14 healthy, middle-age (50-65 yr) men and women during passive heating in air (40 min at 30°C, 40% relative humidity) followed by exercise (60% V˙O2peak). METHODS Oral temperature (Tor) was measured in the antechamber (23.0°C ± 0.1°C) before entering a warm environmental chamber. After 40 min of rest, subjects cycled on a recumbent cycle ergometer for up to 120 min. Esophageal temperature (Tes) and laser Doppler flux were measured continuously, and the latter was normalized to maximal cutaneous vascular conductance (%CVCmax). RESULTS Before entry into the environmental chamber there were no differences in Tor among treatments; however, after 40 min of rest in the heat, Tes was significantly higher for ASA and CLO versus placebo (37.2°C ± 0.1°C, 37.3°C ± 0.1°C, vs 37.0°C ± 0.1°C, both P < 0.001), a difference that persisted throughout exercise (P < 0.001 vs placebo). The mean body temperature thresholds for the onset of cutaneous vasodilation were shifted to the right for both ASA and CLO during exercise (P < 0.05). CONCLUSION ASA and CLO resulted in elevated core temperatures during passive heat stress and shifted the onset of peripheral thermoeffector mechanisms toward higher body temperatures during exercise heat stress.

Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms

Older adults have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)-dependent cutaneous vasodilatation. Folic acid and its metabolite, 5-methyltetrahydrofolate (5-MTHF), are reported to improve vessel function. We hypothesized that (i) local 5-MTHF administration and (ii) chronic folic acid supplementation would improve cutaneous microvascular function in ageing through NO-dependent mechanisms. There were two separate studies in which there were 11 young (Y: 22 ± 1 years) and 11 older (O: 71 ± 3 years) participants. In both studies, two intradermal microdialysis fibres were placed in the forearm skin for local delivery of lactated Ringers solution with or without 5 mM 5-MTHF. Red cell flux was measured by laser-Doppler flowmetry. Cutaneous vascular conductance [CVC=red cell flux/mean arterial pressure] was normalized as percentage maximum CVC (%CVCmax) (28 mM sodium nitroprusside, local temperature 43°C). In study 1 after CVC plateaued during local heating, 20 mM NG-nitro-L-arginine methyl ester (L-NAME) was perfused at each site to quantify NO-dependent vasodilatation. The local heating plateau (%CVCmax: O = 82 ± 3 vs Y = 96 ± 1, P = 0.002) and NO-dependent vasodilatation (%CVCmax: O = 26 ± 6% vs Y = 49 ± 5, P = 0.03) were attenuated in older participants. 5-MTHF augmented the overall (%CVCmax = 91 ± 2, P = 0.03) and NO-dependent (%CVCmax = 43 ± 9%, P = 0.04) vasodilatation in older but not young participants. In study 2 the participants ingested folic acid (5 mg/day) or placebo for 6 weeks in a randomized, double-blind, crossover design. A rise in oral temperature of 1°C was induced using a water-perfused suit, body temperature was held and 20 mM L-NAME was perfused at each site. Older participants had attenuated reflex (%CVCmax: O = 31 ± 8 vs Y = 44 ± 5, P = 0.001) and NO-dependent (%CVCmax: O = 9 ± 2 vs Y = 21 ± 2, P = 0.003) vasodilatation. Folic acid increased CVC (%CVCmax = 47 ± 5%, P = 0.001) and NO-dependent vasodilatation (20 ± 3%, P = 0.003) in the older but not the young participants. Both local perfusion of 5-MTHF and supplementation with folic acid increase vasodilatation in ageing individuals through NO-dependent mechanisms.

Regional Relation between Skin Blood Flow and Sweating to Passive Heating and Local Administration of Acetylcholine in Young, Healthy Humans

Regional variation in sweating over the human body is widely recognized yet variation in vasomotor responses and mechanisms causing this variation remain unclear. This study aimed to explore the relation between regional sweating rates (RSR) and skin blood flow (SkBF) responses to thermal and pharmacological stimuli in young, healthy subjects. In nine subjects (23 ± 3 yr), intradermal microdialysis (MD) probes were inserted into the ventral forearm, abdomen, thigh, and lower back and perfused with lactated Ringer solution. RSR over each MD membrane were measured using ventilated capsules with a laser Doppler probe housed in each capsule for measurement of red cell flux (laser Doppler flux, LDF) as an index of SkBF. Subjects completed a whole body heating protocol to 1°C rise in oral temperature and an acetylcholine dose response (ACh 1 × 10(-7)-0.1 M; mean skin temperature 34°C). Maximal LDF were obtained at the end of both protocols (50 mM sodium nitroprusside).During heating RSR varied among sites (P < 0.0001) and was greater on the back versus other sites (P < 0.05), but LDF was similar between sites (P = 0.343). RSR and SkBF showed a strong relation during initial (arm: r = 0.77 ± 0.09, thigh: r = 0.81 ± 0.08, abdomen: r = 0.89 ± 0.04, back: r = 0.86 ± 0.04) but not latter stages of heating. No differences in RSR (P = 0.160) or SkBF (LDF, P = 0.841) were observed between sites during ACh perfusion. Taken together, these data suggest that increases in SkBF are necessary to initiate and increase sweating, but further rises in RSR are not fully dependent on SkBF in a dose-response manner. Furthermore, RSR cannot be explained by cholinergic sensitivity or variation in SkBF.

Evidence for a functional vasodilatatory role for hydrogen sulphide in the human cutaneous microvasculature.

Hydrogen sulphide (H2S) is vasoprotective, attenuates inflammation and modulates blood pressure in animal models; however, its specific mechanistic role in the human vasculature remains unclear. In the present study, we report the novel finding that the enzymes responsible for endogenous H2S production, cystathionine‐γ‐lyase and 3‐mercaptopyruvate sulphurtransferase, are expressed in the human cutaneous circulation. Functionally, we show that H2S‐induced cutaneous vasodilatation is mediated, in part, by tetraethylammonium‐sensitive calcium‐dependent potassium channels and not by ATP‐sensitive potassium channels. In addition, nitric oxide and cyclo‐oxygenase‐derived byproducts are required for full expression of exogenous H2S‐mediated cutaneous vasodilatation. Future investigations of the potential role for H2S with respect to modulating vascular function in humans may have important clinical implications for understanding the mechanisms underlying vascular dysfunction characteristic of multiple cardiovascular pathologies.

Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms

Functional constitutive nitric oxide synthase (NOS) and its cofactor tetrahydrobiopterin (BH4) are required for full reflex cutaneous vasodilation and are attenuated in primary aging. Acute, locally administered BH4 increases reflex vasodilation through NO-dependent mechanisms in aged skin. We hypothesized that oral sapropterin (Kuvan, shelf-stable pharmaceutical formulation of BH4) would augment reflex vasodilation in aged human skin during hyperthermia. Nine healthy human subjects (76 ± 1 yr) ingested sapropterin (10 mg/kg) or placebo in a randomized double-blind crossover design. Venous blood samples were collected prior to, and 3 h following, ingestion of sapropterin for measurement of plasma BH4. Three intradermal microdialysis fibers were placed in the forearm skin for local delivery of 1) lactated Ringers solution, 2) 10 mM BH4, and 3) 20 mM N(G)-nitro-l-arginine methyl ester (l-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced using a water-perfused suit. At 1°C rise in oral temperature, mean body temperature was clamped and 20 mM l-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC = LDF/MAP) and expressed as a percentage of maximum (%CVCmax 28 mM sodium nitroprusside and local heat 43°C). Plasma concentrations of BH4 were significantly elevated 3 h after ingestion of sapropterin (0 h: 19.1 ± 2 pmol/ml vs. 3 h: 43.8 ± 3 pmol/ml; P < 0.001). Sapropterin increased NO-dependent vasodilation at control site (placebo: 14 ± 1 %CVCmax vs. sapropterin: 25 ± 4 %CVCmax; P = 0.004). Local BH4 administration increased NO-dependent vasodilation compared with control in placebo trials only (control: 14 ± 1 %CVCmax vs. BH4-treated: 24 ± 3 %CVCmax; P = 0.02). These data suggest oral sapropterin increases bioavailable BH4 in aged skin microvasculature sufficiently to increase NO synthesis through NOS and that sapropterin may be a viable intervention to increase skin blood flow during hyperthermia in healthy aged humans.

Blood pressure regulation III: what happens when one system must serve two masters: temperature and pressure regulation?

When prolonged intense exercise is performed at high ambient temperatures, cardiac output must meet dual demands for increased blood flow to contracting muscle and to the skin. The literature has commonly painted this scenario as a fierce competition, wherein one circulation preserves perfusion at the expense of the other, with the regulated maintenance of blood pressure as the ultimate goal. This review redefines this scenario as commensalism, an integrated balance of regulatory control where one circulation benefits with little functional effect on the other. In young, healthy subjects, arterial pressure rarely falls to any great extent during either extreme passive heating or prolonged dynamic exercise in the heat, nor does body temperature rise disproportionately due to a compromised skin blood flow. Rather, it often takes the superimposition of additional stressors—e.g., dehydration or simulated hemorrhage—upon heat stress to substantially impact blood pressure regulation.

Rho-Kinase activity and cutaneous vasoconstriction is upregulated in essential hypertensive humans

Essential hypertension (HT) is associated with endothelial dysfunction augmented vasoconstriction (VC) which may be secondary to increased Rho/Rho-Kinase (ROCK)-dependent mechanisms. Our aim was to assess the in vivo magnitude of cutaneous VC to local cooling as a ROCK specific stimulus, and in vitro evaluate ROCK activity in the skin from HT humans. Four microdialysis fibers were placed in the forearm of 9 pre- to stage I hypertensive (MAP: 106±3 mm Hg) and 11 normotensive (NT; 86±1 mm Hg) men and women: Ringers (control), 3mM fasudil (ROCK inhibited), 5mM yohimbine+1mM proprananol (α- and β-adrenoceptor inhibited; Y+P), Y+P+3mM fasudil (ROCK and adrenocepor inhibited). Skin blood flow was measured during local cooling (Tskl 24°C) and ROCK activity in the skin biopsy samples was determined with western blot. In vitro phosphorylated myosin phosphatase target subunit 1 (pMYPT-1)/ROCK was increased in the HT skin samples (p=0.0018). Functionally, no difference in basal vasomotor tone (Tskl 34°C) was observed between the groups (HT: 0.36±0.07 vs. NT: 0.31±0.07 CVC), nor at the control site during local cooling. Pre- to stage 1 hypertensives show greater ROCK-mediated vasoconstriction at early (1-5 min; HT: -0.8±0.2 versus NT: -0.3±0.2 ΔCVC baseline 1; P<0.0001) and late (36-40 min; HT: -0.9±0.1 versus NT: -0.5±0.2 ΔCVC baseline 1; P<0.0001) phases of local cooling. These data suggest that the magnitude of cutaneous vasoconstriction to local cooling does not differ in normotensive and pre- to stage I essential hypertensive humans; however, ROCK activity is increased and functional vasoconstriction is increasingly dependent upon Rho/ROCK mechanisms with essential hypertension.