Brett J. Wong

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).

Short-term dietary nitrate supplementation augments cutaneous vasodilatation and reduces mean arterial pressure in healthy humans

Nitrate supplementation in the form of beetroot juice has been shown to increase nitric oxide (NO) where nitrate can be reduced to nitrite and, subsequently, to NO through both nitric oxide synthase (NOS)-dependent and -independent pathways. We tested the hypothesis that nitrate supplementation would augment the NO component of the cutaneous vasodilatation to local skin heating in young, healthy humans. Participants reported to the lab for pre- and post-supplement local heating protocols. Nitrate supplementation consisted of one shot (70 ml) of beetroot juice (0.45 g nitrate; 5mM) for three days. Six participants were equipped with two microdialysis fibers on the ventral forearm and randomly assigned to lactated Ringers (control) or continuous infusion of 20mM l-NAME (NOS inhibitor). The control site was subsequently perfused with l-NAME once a plateau in skin blood flow was achieved to quantify NOS-dependent cutaneous vasodilatation. Skin blood flow via laser-Doppler flowmetry (LDF) and mean arterial pressure (MAP) were measured; cutaneous vascular conductance (CVC) was calculated as LDF/MAP and normalized to %CVCmax. Beetroot juice reduced MAP (Pre: 90 ± 1 mmHg vs. Post: 83 ± 1 mmHg) and DBP (Pre: 74 ± 2 mmHg vs. Post: 62 ± 3 mmHg) (P<0.05). The plateau phase of the local heating response at control sites was augmented post-beetroot juice (91 ± 5%CVCmax) compared to pre-beetroot juice (79 ± 2%CVCmax) (P<0.05). There was no difference in the %NOS-dependent vasodilatation from pre- to post-beetroot juice. These data suggest that nitrate supplementation via beetroot juice can reduce MAP and DBP as well as augment NOS-independent vasodilatation to local heating in the cutaneous vasculature of healthy humans.

Augmented reflex cutaneous vasodilatation following short‐term dietary nitrate supplementation in humans

What is the central question of this study? Nitrate supplementation via beetroot juice has been shown to have several benefits in healthy humans, including reduced blood pressure and increased blood flow to exercising muscle. Whether nitrate supplementation can improve blood flow to the skin in heat‐stressed humans has not been investigated. What is the main finding and its importance? Similar to previous studies, we found that nitrate supplementation reduces blood pressure. Nitrate supplementation increased vasodilatation in the skin of heat‐stressed humans but did not directly increase skin blood flow.

Heat therapy promotes the expression of angiogenic regulators in human skeletal muscle.

Heat therapy has been shown to promote capillary growth in skeletal muscle and in the heart in several animal models, but the effects of this therapy on angiogenic signaling in humans are unknown. We evaluated the acute effect of lower body heating (LBH) and unilateral thigh heating (TH) on the expression of angiogenic regulators and heat shock proteins (HSPs) in healthy young individuals. Exposure to LBH (n = 18) increased core temperature (Tc) from 36.9 ± 0.1 to 37.4 ± 0.1°C (P < 0.01) and average leg skin temperature (Tleg) from 33.1 ± 0.1 to 39.6 ± 0.1°C (P < 0.01), but did not alter the levels of circulating angiogenic cytokines and bone marrow-derived proangiogenic cells (CD34(+)CD133(+)). In skeletal muscle, the change in mRNA expression from baseline of vascular endothelial growth factor (VEGF), angiopoietin 2 (ANGPT2), chemokines CCL2 and CX3CL1, platelet factor-4 (PF4), and several members of the HSP family was higher 30 min after the intervention in the individuals exposed to LBH (n = 11) compared with the control group (n = 12). LBH also reduced the expression of transcription factor FOXO1 (P = 0.03). Exposure to TH (n = 14) increased Tleg from 32.8 ± 0.2 to 40.3 ± 0.1°C (P < 0.05) but Tc remained unaltered (36.8 ± 0.1°C at baseline and 36.9 ± 0.1°C at 90 min). This intervention upregulated the expression of VEGF, ANGPT1, ANGPT2, CCL2, and HSPs in skeletal muscle but did not affect the levels of CX3CL1, FOXO-1, and PF4. These findings suggest that both LBH and TH increase the expression of factors associated with capillary growth in human skeletal muscle.

Thermotherapy reduces blood pressure and circulating endothelin-1 concentration and enhances leg blood flow in patients with symptomatic peripheral artery disease.

Leg thermotherapy (TT) application reduces blood pressure (BP) and increases both limb blood flow and circulating levels of anti-inflammatory mediators in healthy, young humans and animals. The purpose of the present study was to determine the impact of TT application using a water-circulating garment on leg and systemic hemodynamics and on the concentrations of circulating cytokines and vasoactive mediators in patients with symptomatic peripheral artery disease (PAD). Sixteen patients with PAD and intermittent claudication (age: 63 ± 9 yr) completed three experimental sessions in a randomized order: TT, control intervention, and one exercise testing session. The garment was perfused with 48°C water for 90 min in the TT session and with 33°C water in the control intervention. A subset of 10 patients also underwent a protocol for the measurement of blood flow in the popliteal artery during 90 min of TT using phase-contrast MRI. Compared with the control intervention, TT promoted a significant reduction in systolic (∼11 mmHg) and diastolic (∼6 mmHg) BP (P < 0.05) that persisted for nearly 2 h after the end of the treatment. The serum concentration of endothelin-1 (ET-1) was significantly lower 30 min after exposure to TT (Control: 2.3 ± 0.1 vs. TT: 1.9 ± 0.09 pg/ml, P = 0.026). In addition, TT induced a marked increase in peak blood flow velocity (∼68%), average velocity (∼76%), and average blood flow (∼102%) in the popliteal artery (P < 0.01). These findings indicate that TT is a practical and effective strategy to reduce BP and circulating ET-1 concentration and enhance leg blood flow in patients with PAD.

Current concepts of active vasodilation in human skin

ABSTRACT In humans, an increase in internal core temperature elicits large increases in skin blood flow and sweating. The increase in skin blood flow serves to transfer heat via convection from the body core to the skin surface while sweating results in evaporative cooling of the skin. Cutaneous vasodilation and sudomotor activity are controlled by a sympathetic cholinergic active vasodilator system that is hypothesized to operate through a co-transmission mechanism. To date, mechanisms of cutaneous active vasodilation remain equivocal despite many years of research by several productive laboratory groups. The purpose of this review is to highlight recent advancements in the field of cutaneous active vasodilation framed in the context of some of the historical findings that laid the groundwork for our current understanding of cutaneous active vasodilation.

Cutaneous reactive hyperaemia is unaltered by dietary nitrate supplementation in healthy humans

The purpose of this study was to determine whether nitrate supplementation augments cutaneous reactive hyperaemia. Seven participants were tested pre‐ and postnitrate supplementation (25 ml beetroot juice); participants consumed one shot per day for 3 days. Participants were instrumented with two microdialysis fibres: control (Ringers solution) and NO synthase inhibition (20 mM L‐NAME). Skin blood flow was measured via laser‐Doppler flowmetry (LDF). A blood pressure cuff was placed on the experimental arm and inflated to 250 mmHg for 5 mins to occlude arterial inflow. The cuff was released, and the resultant reactive hyperaemia was measured. Blood pressure was continuously measured via plethysmography from a finger on the non‐experimental arm. Cutaneous vascular conductance was calculated (LDF/MAP) and normalized to maximal vasodilatation (%CVCmax). Only diastolic blood pressure was reduced following nitrate supplementation (71 ± 2 vs. 66 ± 1 mmHg; P<0·05). There was no effect of nitrate supplementation on peak reactive hyperaemia at control (Pre: 52 ± 3 vs. Post: 57 ± 2%CVCmax) or L‐NAME (Pre: 52 ± 2 vs. Post: 59 ± 4%CVCmax) sites. There was no effect of nitrate supplementation on total reactive hyperaemia at either control (Pre: 4197 ± 943 vs. Post: 4523 ± 1040%CVCmax * sec) or L‐NAME (Pre: 5108 ± 997 vs. Post: 5694 ± 1002%CVCmax * sec) sites. These data suggest cutaneous reactive hyperaemia is unaffected by dietary nitrate supplementation in healthy humans.

Acute Thermotherapy Prevents Impairments in Cutaneous Microvascular Function Induced by a High Fat Meal

We tested the hypothesis that a high fat meal (HFM) would impair cutaneous vasodilation, while thermotherapy (TT) would reverse the detrimental effects. Eight participants were instrumented with skin heaters and laser-Doppler (LD) probes and tested in three trials: control, HFM, and HFM + TT. Participants wore a water-perfused suit perfused with 33°C (control and HFM) or 50°C (HFM + TT) water. Participants consumed 1 g fat/kg body weight. Blood samples were taken at baseline and two hours post-HFM. Blood pressure was measured every 5–10 minutes. Microvascular function was assessed via skin local heating from 33°C to 39°C two hours after HFM. Cutaneous vascular conductance (CVC) was calculated and normalized to maximal vasodilation (%CVCmax). HFM had no effect on initial peak (48 ± 4 %CVCmax) compared to control (49 ± 4 %CVCmax) but attenuated the plateau (51 ± 4 %CVCmax) compared to control (63 ± 4 %CVCmax, P < 0.001). Initial peak was augmented in HFM + TT (66 ± 4 %CVCmax) compared to control and HFM (P < 0.05), while plateau (73 ± 3 % CVCmax) was augmented only compared to the HFM trial (P < 0.001). These data suggest that HFM negatively affects cutaneous vasodilation but can be minimized by TT.