BACKGROUND: Mucopolysaccharide polysulfate (MPS) is widely used as an active ingredient in topical preparations for the treatment of asteatosis and blood flow disorders. Although topical MPS products can increase cutaneous blood flow (CBF), the underlying mechanism remains unclear.
OBJECTIVE: In this study, we aimed to elucidate how MPS increases CBF. We investigated the association of nitric oxide (NO), a powerful mediator associated with increased local blood volume, with the blood flow-accelerating action of MPS in mice. In addition, we verified the effects of MPS on NO production in different skin cell types, such as keratinocytes (KCs), endothelial cells (ECs), and dermal fibroblasts (DFs).
METHODS: We used raster-scanning optoacoustic imaging mesoscopy to observe in vivo changes in the skin blood volume. NO production was determined in each cell using an NO indicator. An enzyme-linked immunoassay was used to measure the phosphorylated nitric oxide synthase (NOS) levels in ECs, DFs, and KCs in the presence or absence of MPS.
RESULTS: Topical application of MPS increased the skin blood volume in mice, and this increase was abolished through the addition of NOS inhibitors. MPS promoted the dose-dependent production of NO in various cells, which caused alterations in the phosphorylation state of NOS.
CONCLUSIONS: Our findings demonstrate that MPS promotes an increase in skin blood volume and NO production in various skin cell types. These results suggest that MPS can potentially accelerate CBF through the NO biosynthesis pathway in different skin cell types.

Remote ischemic preconditioning (RIPC) has been shown to minimize subsequent ischemia-reperfusion injury (IRI), whereas obesity has been suggested to attenuate the efficacy of RIPC in animal models. The primary objective of this study was to investigate the effect of a single bout of RIPC on the vascular and autonomic response after IRI in young obese men. A total of 16 healthy young men (8 obese and 8 normal weight) underwent two experimental trials: RIPC (three cycles of 5 min ischemia at 180 mmHg + 5 min reperfusion on the left thigh) and SHAM (the same RIPC cycles at resting diastolic pressure) following IRI (20 min ischemia at 180 mmHg + 20 min reperfusion on the right thigh). Heart rate variability (HRV), blood pressure (SBP/DBP), and cutaneous blood flow (CBF) were measured between baseline, post-RIPC/SHAM, and post-IRI. The results showed that RIPC significantly improved the LF/HF ratio (p = 0.027), SBP (p = 0.047), MAP (p = 0.049), CBF (p = 0.001), cutaneous vascular conductance (p = 0.003), vascular resistance (p = 0.001), and sympathetic reactivity (SBP: p = 0.039; MAP: p = 0.084) after IRI. However, obesity neither exaggerated the degree of IRI nor attenuated the conditioning effects on the measured outcomes. In conclusion, a single bout of RIPC is an effective means of suppressing subsequent IRI and obesity, at least in Asian young adult men, does not significantly attenuate the efficacy of RIPC.

Harmful health effects of exposure to low-frequency noise (LFN) defined as noise with frequencies at ≤100 Hz on the circulatory system have been a concern. However, there has been no study on the effects of exposure to LFN on the circulatory system with consideration of its frequencies and decibels. In this study, the effects of short-term exposure to broad-band LFNs and their pure-tone components (pure-tone LFNs) on cutaneous blood flow in the extremities including the hands were investigated. In our fieldwork study, we first sampled some kinds of common broad-band LFNs. Our human study then showed that broad-band LFN with a narrower frequency range more strongly increased cutaneous blood flow than did broad-band LFN with a wider frequency range. Pure-tone LFNs of 70-100 Hz at ≤85 dB(Z), but not pure-tone LFNs exceeding 100 Hz, further increased levels of cutaneous blood flow. Our wavelet-transform spectrum analysis of cutaneous blood flow next revealed that the nitric oxide (NO)-dependent and -independent vascular activities of the vascular endothelium were specifically increased by exposure to pure-tone LFN. Our animal study again indicated that exposure to pure-tone LFN increased cutaneous blood flow in mice with impairments of bilateral inner ears as well as cutaneous blood flow in control mice, suggesting a limited effect of inner ear function on the LFN-mediated increase in cutaneous blood flow. The NO-dependent suppressive effect of pure-tone LFN on cutaneous blood flow was confirmed by inhibition of vascular endothelial activity through intravenous injection of an NO inhibitor in wild-type mice. Taken together, the results of this study demonstrated that the vascular endothelium is a target tissue of LFN and that NO is an effector of the LFN-mediated increase in cutaneous blood flow. Since improvement of peripheral circulation could generally promote human health, short-term exposure to LFN may be beneficial for health.

What is the central question of this study? Facial skin blood flow (SBF) might increase during head-down tilt (HDT). However, the effect of HDT on facial SBF remains controversial. In addition, the changes in facial SBF in the cheek (cheek SBF) during a steeper angle of HDT (>-12° HDT) have not been investigated. What is the main finding and its importance? This study showed that cheek SBF decreased during -30° HDT, alongside increased vascular resistance. Furthermore, vascular impedance was suggested to be elevated, accompanied by an increased hydrostatic pressure gradient caused by HDT. Constriction of the facial skin vascular bed and congestion of venous return owing to the steep angle of HDT can decrease facial SBF.
Head-down tilt (HDT) has been used to simulate microgravity in ground-based studies and clinical procedures including the Trendelenburg position or in certain surgical operations. Facial skin blood flow (SBF) might be altered by HDT, but the effect of a steeper angle of HDT (>-12° HDT) on facial SBF remains unclear. We examined alterations in facial SBF in the cheek (cheek SBF) using two different angles (-10 and -30°) of HDT and lying horizontal (0°) in a supine position for 10 min, to test the hypothesis that cheek SBF would increase with a steeper angle of HDT. Cheek SBF was measured continuously by laser Doppler flowmetry. Cheek skin vascular resistance and the pulsatility index of cheek SBF were calculated to assess the circulatory effects on the facial skin vascular bed in the cheek. Cheek SBF decreased significantly during -30° HDT. In addition, the resistance in cheek SBF increased significantly during -30° HDT. The pulsatility index of cheek SBF increased during both -10 and -30° HDT. Contrary to our hypothesis, cheek SBF decreased during -30° HDT along with increased skin vascular resistance. Vascular impedance, estimated by the pulsatility index in the cheek SBF, was elevated during both -10 and -30° HDT, and elevated vascular impedance would be related to increased hydrostatic pressure induced by HDT. Skin vascular constriction and venous return congestion would be induced by -30° HDT, leading to deceased cheek SBF. The present study suggested that facial SBF in the cheek decreased during acute exposure to a steep angle of HDT (∼-30° HDT).

It is unclear if cutaneous microvascular dysfunction associated with diabetes and obesity can be ameliorated with exercise. We investigated the effect of 12-weeks of exercise training on cutaneous microvascular reactivity in the foot. Thirty-three inactive adults with type 2 diabetes and obesity (55% male, 56.1 ± 7.9 years, BMI: 35.8 ± 5, diabetes duration: 7.9 ± 6.3 years) were randomly allocated to 12-weeks of either (i) moderate-intensity continuous training [50−60% peak oxygen consumption (VO2peak), 30−45 min, 3 d/week], (ii) low-volume high-intensity interval training (90% VO2peak, 1−4 min, 3 d/week) or (iii) sham exercise placebo. Post-occlusive reactive hyperaemia at the hallux was determined by laser-Doppler fluxmetry. Though time to peak flux post-occlusion almost halved following moderate intensity exercise, no outcome measure reached statistical significance (p > 0.05). These secondary findings from a randomised controlled trial are the first data reporting the effect of exercise interventions on cutaneous microvascular reactivity in the foot in people with diabetes. A period of 12 weeks of moderate-intensity or low-volume high-intensity exercise may not be enough to elicit functional improvements in foot microvascular reactivity in adults with type 2 diabetes and obesity. Larger, sufficiently powered, prospective studies are necessary to determine if additional weight loss and/or higher exercise volume is required.

BACKGROUND: Glucagon and insulin are the two most important hormones in glucose metabolism and have been incorporated in the dual-hormonal artificial pancreas, a device for automated glucose regulation for people with diabetes type 1. Currently the subcutis is the preferred site of hormone delivery for insulin-only as well as dual-hormonal artificial pancreas systems. The delay in glucose-lowering effect after subcutaneous injection of insulin is substantial, in contrast to the elevation of blood glucose values after subcutaneously injected glucagon which is occurs shortly after injection. We hypothesize that this is caused by properties of glucagon and have investigated the vasodilative effect of glucagon on subcutaneous blood flow in this proof-of-concept study.
METHODS: Twenty-two volunteers received subcutaneous injections of 0.1 mg and 0.01 mg glucagon, and saline on the abdomen. Blood flow was measured by a laser doppler blood flowmeter for 35 min after injections.
RESULTS: Injection of 0.1 mg glucagon resulted in a significant increase in blood flow compared with baseline blood flow for all time intervals. Significant increase was also observed after the 0.01 mg glucagon injection, except between two- and five-min post injection. The inter-individual variance was large and a third of the subjects did not show an apparent increase in local subcutaneous blood flow after the 0.1 mg glucagon injection.
CONCLUSIONS: This proof-of-concept study shows that micro-boluses of glucagon increases local subcutaneous blood flow on the abdomen of non-diabetic subjects. However, the vasodilative effect of glucagon is not observed in all subjects. The trial was not registered to protect intellectual property rights.

This study was designed to identify the effects of a 12-h nicotine patch administration on cold induced vasodilation (CIVD) in healthy young chronic smokers following 16 h of abstinence from smoking. Two laser Doppler probes and temperature thermocouples were placed on the dorsal part of the distal phalanx of the middle and ring fingers of 7 smokers (>12 cigarettes/day). Following 16 h of abstinence from smoking, smokers were tested with and without administration of a 21 mg transdermal nicotine patch (NicoDerm® ). Each participant\'s right hand was immersed in cold (~5°C) water for 40 min. Cutaneous vascular conductance (CVC) was calculated from non-invasive arterial finger blood pressure and skin blood flow and expressed as a percentage of peak CVC observed during hand skin heating to 44°C. For comparison purposes, the CIVD response of a non-smoking cohort without nicotine patch (n = 10) was also examined. Baseline CVC was similar in smokers and non-smokers (27.8 ± 12.6 CVC % peak). The initial vasoconstriction during cold-water immersion decreased skin blood flow to 4.0 ± 3.9 CVC % peak in both smokers and non-smokers. The onset of CIVD in smokers (4.5 ± 1.5 min) was delayed compared to non-smoker (3.3 ± 0.8 min, p < .05). The area under the CVC %peak-time curve during cold-water immersion averaged 1250 ± 388 CVC %peak · min in non-smokers which was larger (p < .05) than smokers with or without nicotine (789 ± 542 and 862 ± 517 CVC %peak · min, respectively). Chronic smoking impaired the CIVD response to cold-water immersion of the hand; however, the impaired CIVD response in 16 h of abstinence from smoking was not influenced by application of a 21 mg transdermal nicotine patch.

BACKGROUND: The biophysical interaction induced by low energy pulsed electromagnetic field therapy (PEMFT) on the capillary microcirculation is not well understood. Several studies indicate a significant effect of PEMFT in patients with chronic medical conditions.
OBJECTIVE: The aim of this study was to evaluate the influence of PEMFT on skin microcirculation in healthy volunteers.
METHODS: 15 healthy participants were included. Nine PEMF treatments were applied over three weeks in an 48-hour interval. The PEMFT system (BEMER) was placed beneath one of the participants\' leg with the contralateral side serving as a control. A forty-minute application period was preceded by a 10-minute resting phase. Measuring was done using two Laser Doppler probes (LEA) placed on each anterior lateral thigh.
RESULTS: All outcome parameters including flow, mixed venous oxygen saturation and relative venous hemoglobin showed a significant increase during the experiment when compared to the baseline values of the resting phase in both groups (p < 0.01). Comparing both groups, the measurement values during the experiment did not differ (p > 0.05) except for higher flow values in the control group (P = 0.03). Over time, baseline values of both groups showed no significant difference (p > 0.05).
CONCLUSIONS: We found a significant increase of all measurement parameters during the study compared to the baseline values with no difference between the PEMF and control group.

Microvascular function has been assessed by determining the rhythmic oscillations in blood flow induced by the vasomotion of resistance vessels. Although laser-Doppler flowmetry (LDF) allows simple, non-invasive evaluation of this flow-motion in the cutaneous microcirculation, the temporal and spatial reproducibility of such assessments remains unclear.In the present study, we investigated cutaneous flow-motion in three consecutive years in eight skin regions using LDF in six healthy young volunteers. The characteristic flow-motion frequency was determined using fast-Fourier transformation. Additionally, in two years a more traditional measure of microvascular reactivity, postocclusive reactive hyperemia (PORH) was evoked in the forearm after transient brachial artery occlusion (1-2-3 min) induced by cuff inflation.Well-defined flow-motion was found in six regions showing significant differences in frequency: the highest flow-motion frequency was found in the frontal and temporal regions (8.0 ± 1.1 and 8.5 ± 1.0 cycles/min, cpm, respectively, mean ± SD) followed by the scapular, infraclavicular and coxal regions (7.5 ± 1.3; 6.7 ± 1.1 and 6.5 ± 1.2 cpm, respectively). The lowest, stable flow-motion was found in the posterior femoral region (5.5 ± 1.0 cpm), whereas flow-motion was detectable only sporadically in the limbs. The region-dependent flow-motion frequencies were very stable within individuals either between the body sides, or among the three measurements, only the infraclavicular region showed a small difference (114 ± 17%∗, % of value in 1st year; ∗P < 0.05). However, PORH indices differed after 2-3 min occlusions significantly in consecutive years.We report that flow-motion frequencies determined from LDF signals show both region-specificity and excellent intra-individual temporal and spatial reproducibility suggesting their usefulness for non-invasive follow-up of microvascular reactivity.

OBJECTIVE: A brief compressive stimulus is known to induce a rapid hyperemia in skeletal muscles, considered to contribute to the initial phase of functional hyperemia. Whether the same mechano-sensitivity characterizes the cutaneous circulation is debated. This study aims to investigate whether a rapid hyperemic response to compressive stimuli is also expressed by skin blood flow in humans.
METHODS: In 12 subjects, brief compressive stimuli were delivered to the forearm at varying pressures/durations (50/2, 100/2, 200/2, 200/1, 200/5 mmHg/s); the sequence was randomized and repeated with the arm above and below heart level. Laser Doppler flowmetry technique was used to monitor skin blood flow. The response was described in terms of peak skin blood flow normalized to baseline (nSBFpeak), time-to-peak from the release of compression, and excess blood volume (EBV, expressed in terms of seconds of basal flow, s-bf) received during the response.
RESULTS: The results consistently evidenced the occurrence of a compression-induced hyperemic response, with nSBFpeak = 2.9 ± 1.1, EBV = 17.0 ± 6.6 s-bf, time-to-peak = 7.0 ± 0.7 s (200 mmHg, 2 s, below heart level). Both nSBFpeak and EBV were significantly reduced (by about 50%) above compared to below heart level (p < 0.01). In addition, EBV slightly increased with increasing pressure (p < 0.05) and duration (p < 0.01) of the stimulus.
CONCLUSIONS: For the first time, the rapid dilatator response to compressive stimuli was demonstrated in human cutaneous circulation. The functional meaning of this response remains to be elucidated.