Effect of reflex and mechanical decreases in skin perfusion on thermal- and agonist-induced eccrine sweating in humans.

In humans, skin blood flux (SkBF) and eccrine sweating are tightly coupled, suggesting common neural control and regulation. This study was designed to separate these two sympathetic nervous system end-organ responses via nonadrenergic SkBF-decreasing mechanical perturbations during heightened sudomotor drive. We induced sweating physiologically via whole body heat stress using a high-density tube-lined suit (protocol 1; 2 women, 4 men), and pharmacologically via forearm intradermal microdialysis of two steady-state doses of a cholinergic agonist, pilocarpine (protocol 2; 4 women, 3 men). During sweating induction, we decreased SkBF via three mechanical perturbations: arm and leg dependency to engage the cutaneous venoarteriolar response (CVAR), limb venous occlusion to engage the CVAR and decrease perfusion pressure, and limb arterial occlusion to cause ischemia. In protocol 1, heat stress increased arm cutaneous vascular conductance and forearm sweat rate (capacitance hygrometry). During heat stress, despite decreases in SkBF during each of the acute (3 min) mechanical perturbations, eccrine sweat rate was unaffected. During heat stress with extended (10 min) ischemia, sweat rate decreased. In protocol 2, both pilocarpine doses (ED50 and EMAX) increased SkBF and sweat rate. Each mechanical perturbation resulted in decreased SkBF but minimal changes in eccrine sweat rate. Taken together, these data indicate that a wide range of acute decreases in SkBF do not appear to proportionally decrease either physiologically- or pharmacologically induced eccrine sweating in peripheral skin. This preservation of evaporative cooling despite acutely decreased SkBF could have consequential impacts for heat storage and balance during changes in body posture, limb position, or blood flow restrictive conditions.

Role of Bradykinin Type 2 Receptors in Human Sweat Secretion: Translational Evidence Does Not Support a Functional Relationship.

Bradykinin increases skin blood flow via a cGMP mechanism but its role in sweating in vivo is unclear. There is a current need to translate cell culture and nonhuman paw pad studies into in vivo human preparations to test for therapeutic viability for disorders affecting sweat glands. Protocol 1: physiological sweating was induced in 10 healthy subjects via perfusing warm (46-48°C) water through a tube-lined suit while bradykinin type 2 receptor (B2R) antagonist (HOE-140; 40 µM) and only the vehicle (lactated Ringer's) were perfused intradermally via microdialysis. Heat stress increased sweat rate (HOE-140 = +0.79 ± 0.12 and vehicle = +0.64 ± 0.10 mg/cm2/min), but no differences were noted with B2R antagonism. Protocol 2: pharmacological sweating was induced in 6 healthy subjects via intradermally perfusing pilocarpine (1.67 mg/mL) followed by the same B2R antagonist approach. Pilocarpine increased sweating (HOE-140 = +0.38 ± 0.16 and vehicle = +0.32 ± 0.12 mg/cm2/min); again no differences were observed with B2R antagonism. Last, 5 additional subjects were recruited for various control experiments which identified that a functional dose of HOE-140 was utilized and it was not sudorific during normothermic conditions. These data indicate B2R antagonists do not modulate physiologically or pharmacologically induced eccrine secretion volumes. Thus, B2R agonist/antagonist development as a potential therapeutic target for hypo- and hyperhidrosis appears unwarranted.

Effect of Suboccipital Release on Pain Perception and Autonomic Reflex Responses to Ischemic and Cold Pain.

OBJECTIVE/SUBJECTS: To determine the autonomic effects of suboccipital release (SOR) during experimentally induced pain, 16 healthy subjects (eight women, eight men) experienced ischemic (forearm postexercise muscle ischemia [PEMI]) and cold (cold pressor test [CPT]) pain. DESIGN: Beat-to-beat heart rate (electrocardiogram), mean arterial blood pressure (finger photoplethysmography), baroreflex sensitivity (transfer function analysis), and pain perception were measured. SOR or a sham (modified yaw; 30 cycles/min) was performed in minute 2 of pain. RESULTS: PEMI increased blood pressure by 23 ± 2 and 20 ± 2 mmHg; no differences occurred between SOR or yaw. PEMI modestly elevated heart rate during ischemia, followed by significant reduction from baseline with SOR (-3 ± 2 bpm) and yaw (-4 ± 2 bpm); no differences were observed between treatments. CPT increased blood pressure (SOR = 11 ± 1, yaw = 9 ± 2 mmHg) and heart rate (SOR = 10 ± 2, yaw = 8 ± 3 bpm) before SOR and yaw. Neither treatment nor sham blunted blood pressure increases (SOR = 25 ± 2, yaw = 22 ± 2 mmHg) during CPT; both decreased heart rate (SOR = -3 ± 2, yaw = -2 ± 2 bpm) from baseline. PEMI and CPT caused increased pain without treatment modulation. Following pain and manual intervention, SOR increased baroreflex sensitivity in the 0.15-0.35 Hz range and decreased R-R interval power spectral density in the 0.03-0.5 Hz range compared with yaw. To probe potential mechanisms and interactions between manual treatment and a prototypic analgesic, oral aspirin (967 mg) was given 60 minutes before testing to reduce prostaglandin synthesis. Aspirin slightly attenuated pain but neither altered cardiovascular changes to PEMI nor interacted with SOR or yaw. CONCLUSIONS: SOR has the capacity to modulate pain-induced autonomic control and regulation.

Augmented supraorbital skin sympathetic nerve activity responses to symptom trigger events in rosacea patients.

Facial flushing in rosacea is often induced by trigger events. However, trigger causation mechanisms are currently unclear. This study tested the central hypothesis that rosacea causes sympathetic and axon reflex-mediated alterations resulting in trigger-induced symptomatology. Twenty rosacea patients and age/sex-matched controls participated in one or a combination of symptom triggering stressors. In protocol 1, forehead skin sympathetic nerve activity (SSNA; supraorbital microneurography) was measured during sympathoexcitatory mental (2-min serial subtraction of novel numbers) and physical (2-min isometric handgrip) stress. In protocol 2, forehead skin blood flow (laser-Doppler flowmetry) and transepithelial water loss/sweat rate (capacitance hygrometry) were measured during sympathoexcitatory heat stress (whole body heating by perfusing 50°C water through a tube-lined suit). In protocol 3, cheek, forehead, forearm, and palm skin blood flow were measured during nonpainful local heating to induce axon reflex vasodilation. Heart rate (HR) and mean arterial pressure (MAP) were recorded via finger photoplethysmography to calculate cutaneous vascular conductance (CVC; flux·100/MAP). Higher patient transepithelial water loss was observed (rosacea 0.20 ± 0.02 vs. control 0.10 ± 0.01 mg·cm(-2)·min(-1), P < 0.05). HR and MAP changes were not different between groups during sympathoexcitatory stressors or local heating. SSNA during early mental (32 ± 9 and 9 ± 4% increase) and physical (25 ± 4 and 5 ± 1% increase, rosacea and controls, respectively) stress was augmented in rosacea (both P < 0.05). Heat stress induced more rapid sweating and cutaneous vasodilation onset in rosacea compared with controls. No axon reflex vasodilation differences were observed between groups. These data indicate that rosacea affects SSNA and that hyperresponsiveness to trigger events appears to have a sympathetic component.

Extracellular calcium chelation and attenuation of calcium entry decrease in vivo cholinergic-induced eccrine sweating sensitivity in humans.

NEW FINDINGS: What is the central question of this study? Calcium is an important second messenger in eccrine sweating; however, whether modulation of extracellular Ca(2+) and Ca(2+) entry has the capacity to modulate sweat rate in non-glabrous human skin has not been explored. What is the main finding and its importance? Acetylcholine to sweat rate dose-response relationships identify that local in vivo Ca(2+) chelation and L-type Ca(2+) channel antagonism have the capacity to attenuate the cholinergic sensitivity of eccrine sweat glands. Importantly, these data translate previous glabrous in vitro animal studies into non-glabrous in vivo human skin. Calcium is an important second messenger in eccrine sweating, with both internal and external sources being identified in vitro. It is unclear whether in vivo modulation of extracellular Ca(2+) levels or influx has the capacity to modulate sweat rate in non-glabrous human skin. To test the hypothesis that lowering interstitial Ca(2+) levels would decrease the sensitivity of the ACh to sweat rate (via capacitance hygrometry) dose-response relationship, nine healthy subjects received six ACh doses (1 × 10(-5) to 1 × 10(0) m in 10-fold increments) with and without a Ca(2+) chelator (12.5 mg ml(-1) EDTA) via forearm intradermal microdialysis (protocol 1). To test the hypothesis that attenuating Ca(2+) influx via L-type Ca(2+) channels would also decrease the sensitivity of the ACh to sweat rate dose-response relationship, 10 healthy subjects received similar ACh doses with and without a phenylalkylamine Ca(2+) channel blocker (1 mm verapamil; protocol 2). Non-linear regression curve fitting identified a right-shifted ED50 in EDTA-treated sites compared with ACh alone (-1.0 ± 0.1 and -1.5 ± 0.1 logm, respectively; P < 0.05), but unchanged maximal sweat rate (0.60 ± 0.07 and 0.58 ± 0.11 mg cm(-2) min(-1), respectively; P > 0.05) in protocol 1. Protocol 2 also resulted in a right-shifted ED(50) (verapamil, -0.9 ± 0.1 logm; ACh alone, -1.6 ± 0.2 logm; P < 0.05), with unchanged maximal sweat rate (verapamil, 0.45 ± 0.08 mg cm(-2) min(-1); ACh alone, 0.35 ± 0.06 mg cm(-2) min(-1); P > 0.05). Thus, local in vivo Ca(2+) chelation and L-type Ca(2+) channel antagonism have the capacity to attenuate in vivo cholinergic sensitivity of eccrine sweat glands. These data suggest that interstitial Ca(2+) and its influx via Ca(2+) channels play a functional role in eccrine sweating in intact non-glabrous human skin.

Effect of sensory blockade and rate of sensory stimulation on local heating induced axon reflex response in facial skin.

Local neuronal circuits in non-glabrous skin drive the initial increase of the biphasic cutaneous vasodilation response to fast non-noxious heating. Voltage-sensitive Na+ (NaV) channel inhibition blocks the afferent limb of the non-glabrous forearm cutaneous axon reflex. Slow local heating does not engage this response. These mechanisms have not been adequately investigated or extended into areas associated with flushing pathology. We hypothesized that despite regional differences in sensory afferents, both sensory blockade and slowing the heating rate would abate the cutaneous axon reflex-mediated vasodilator responses in facial skin. We measured skin blood flow responses (laser-Doppler flowmetry) of 6 healthy subjects (5 female) to non-noxious forearm, cheek, and forehead local heating, expressed as a percentage of cutaneous vascular conductance at plateau (CVC = flux/mean arterial pressure). We assessed CVC during fast (1 °C/30s) and slow (1 °C/10 min) local heating to 43 °C in both NaV inhibition (topical 2.5% lidocaine/prilocaine) and control conditions. NaV inhibition decreased forearm (control: 84 ± 4, block: 34 ± 9%plateau, p < 0.001) and trended toward decreased forehead (control: 90 ± 3, block: 68 ± 3%plateau, p = 0.057) initial CVC peaks but did not alter cheek responses (control: 90 ± 3, block: 92 ± 13%plateau, p = 0.862) to fast heating. Slow heating eliminated the initial CVC peak incidence for all locations, and we observed similar results with combined slow heating and NaV inhibition. Slower sensory afferent activation rate eliminated the axon reflex response in facial and non-glabrous skin, but topical sensory blockade did not block axon reflex responses in flushing-prone cheek skin. Thus, slower heating protocols are needed to abate facial, particularly cheek, axon reflex responses.

Interexaminer reliability study of a standardized myofascial diagnostic technique of the superior thoracic inlet.

Regional fascial motion palpation is often incorporated by osteopathic practitioners to enable them to identify superior thoracic inlet (STI) myofascial somatic dysfunction motion patterns; however without standardized instruction, diagnostic outcomes may vary between examiners. This study proposes a protocol for diagnosing the STI motion pattern that standardizes examiner hand placement, palpatory discrimination, posture, and relative body positioning. The study design incorporated useful infrastructure recommended by the Fédération Internationale de Médecine Manuelle (FIMM) including protocol agreement steps prior to conducting the formal interexaminer reliability study with the goals of attaining >80% interexaminer agreement and kappa values >0.6 for each cardinal plane. The agreement phase comprised of testing 52 participants acquired agreements of 92.3% (rotation), 88.9% (translation), and 94.2% (sagittal). Kappa value testing involving an additional 82 participants obtained values of 0.65 (rotation), 0.59 (translation), and 0.70 (sagittal). Such kappa values endorse fair-to-excellent positive interexaminer correlations, demonstrating utility of this standardized palpatory protocol for STI myofascial dysfunctional diagnosis.

Differential vasodilatory responses to local heating in facial, glabrous and hairy skin.

BACKGROUND AND AIMS: Local heating induces biphasic cutaneous vasodilation in non-glabrous skin of the forearm. However, little data exist in other skin regions, despite the prevalence of facial flushing disorders. We hypothesized that facial skin will have greater initial peak responses to local heating than forearm skin because of neural differences between sites and, furthermore, axon reflex vasodilation will be eliminated in facial sites with sensory blockade. METHODS: Skin blood flow (laser-Doppler flowmetry) responses of healthy, non-obese subjects to local heating (32-42°C in ~5 min, held 40 min) in the forehead (n = 22), cheek (n = 22), forearm (n = 22) and palm (n = 13) were expressed as percentage of maximum cutaneous vascular conductance (CVC; flux/mean arterial pressure). In an additional group (n = 7), sensation was blocked (topical prilocaine-lidocaine) prior to the local heating protocol. RESULTS: Prior to heating, CVC differences were noted (forearm = 10 ± 3, cheek = 19 ± 3, forehead = 16 ± 1 and palm = 65 ± 11%CVC; P<0·05). Initial peak CVC was similar between forehead, cheek and forearm (85 ± 3, 92 ± 2, and 91 ± 6%CVC, respectively), but elevated in the palm (120 ± 8%CVC; P<0·05). Compared to facial control sites, sensory blockade delayed increases in both cheek and forehead (P<0·05) CVC but did not change magnitude of the biphasic response (P>0·05). CONCLUSIONS: These data indicate that facial skin initial CVC peaks to local heating are similar to non-glabrous skin. In contrast to forearm responses, facial topical sensory blockade does not abate axon reflex responses to local heating. Palm skin data indicate that maximal skin blood flow is not obtained during local heating as it is in non-glabrous skin.

Acupuncture attenuates exercise-induced increases in skin sympathetic nerve activity.

To identify the effect of acupuncture on skin sympathetic nerve activity (SSNA), 17 healthy subjects (7 male and 10 female) underwent LI4 acupuncture and sham needle insertion during resting or elevated SSNA conditions. In Protocol 1 (resting SSNA), subjects received a 10 min sham followed by 10 min of LI4 acupuncture during resting conditions. In Protocol 2 (elevated SSNA), subjects performed 10 min of submaximal intermittent handgrip (2:4s work to rest interval at 37±3% of maximal voluntary contraction) during sham and LI4 acupuncture conditions. SSNA (peroneal nerve microneurography), heart rate (ECG), and mean arterial blood pressure (finger photoplethysmography) were measured and normalized to baseline. SSNA, heart rate, and mean arterial blood pressure were not significantly altered during resting conditions (Protocol 1). During handgrip (Protocol 2), SSNA significantly increased with the sham treatment (+15.3±8.8, +11.1±5.9, and +24.3±13.0% at minutes 1, 5, and 10, respectively), while LI4 acupuncture attenuated this increase (-1.6±7.6, 0.0±4.3, and +2.2±11.2% at minutes 1, 5, and 10, respectively). Heart rate and mean arterial blood pressure increased during handgrip (Protocol 2), but no differences were observed between sham and LI4 acupuncture treatments. These results suggest that acupuncture does not affect resting SSNA in healthy subjects, however if SSNA is acutely elevated above baseline levels, acupuncture has the capacity to attenuate the increased SSNA.