CHRNA1 promotes the pathogenesis of primary focal hyperhidrosis.

The aim of the study was to elucidate the involvement of cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) in the pathogenesis of primary focal hyperhidrosis (PFH). The hyperhidrosis mouse model was constructed using pilocarpine injection. The expression levels of CHRNA1 in sweat gland tissues of PFH patients and hyperhidrosis mice were compared using Western blots and quantitative real-time PCR (qRT-PCR) analyses. Sweat secretion in hyperhidrosis mice treated with small-interfering RNA (siRNA) targeting CHRNA1 (si-CHRNA1) or non-specific siRNA were compared. Sweat secretory granules in the sweat gland cells of hyperhidrosis mice were examined using transmission electron microscopy. The serum level of acetylcholine was measured using enzyme-linked immunosorbent assay, while markers associated with PFH, including Aquaporin 5 (AQP5) and Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C), were assessed using immunohistochemical assay and Western blots. Brain-derived neurotrophic factor (BDNF) and Neuregulin 1 (NRG-1) in sympathetic ganglia axons of hyperhidrosis mice were quantified using Western blots. CHRNA1 up-regulation is a characteristic of the sweat glands of PFH patients and Hyperhidrosis mice. Silencing CHRNA1 decreased sweat secretion and the number of sweat secretory granules of hyperhidrosis mice. Serum acetylcholine, as well as AQP5 and CACNA1C expression in the sweat glands, was reduced by siCHRNA1. BDNF1 and NRG-1 levels in the sympathetic ganglia axons were also attenuated by siCHRNA1 treatment. CHRNA1 up-regulation is a potential biomarker of PFH and downregulating CHRNA1 could alleviate the symptoms of PFH through inactivating the sympathetic system.

Is sweat testing for cystic fibrosis feasible in patients with down syndrome?

BACKGROUND: Recurrent airway infections are common in patients with Down's syndrome (DS). Hence, ruling out Cystic Fibrosis (CF) in these patients is often required. In the past, the value of sweat testing - the gold standard to diagnose CF - has been questioned in DS as false positive results have been reported. However, these reports are based on measurements of sweat osmolality or sodium concentrations, not chloride concentrations. This study analyses sweat secretion rate and chloride concentration in sweat samples of patients with DS in comparison to healthy controls. METHODS: We assessed sweat samples in 16 patients with DS and 16 healthy controls regarding sweat secretion rate (SSR) and sweat chloride concentration. RESULTS: All measured chloride concentrations were within the normal range. The chloride concentrations were slightly, but not significantly lower in patients with DS (15,54 mmol/l (±4,47)) compared to healthy controls (18,31 mmol/l (±10,12)). While no gender gap in chloride concentration could be found, chloride concentration increased with age in both groups. Insufficient sweat was collected in 2 females with DS (12.5% of the study group) but not in an individual of the control group. A significant lower sweat secretion rate was found in the DS group (27,6 µl/30 min (± 12,18)) compared to the control group (42,7 µl/30 min (± 21,22)). In a sub-analysis, female patients produced significantly less sweat (20,8 ± 10,6 µl/30 min) than male patients with DS (36,4 ± 7,8 µl/30 min), which accounts for the difference between patients and controls. Furthermore, while the sweating secretion rate increased with age in the control group, it did not do so in the DS group. Once again this was due to female patients with DS, who did not show a significant increase of sweat secretion rate with age. CONCLUSIONS: Sweat chloride concentrations were within the normal range in patients with DS and therefore seem to be a reliable tool for testing for CF in these patients. Interestingly, we found a reduced sweat secretion rate in the DS group. Whether the last one has a functional and clinical counterpart, possibly due to a disturbed thermoregulation in DS patients, requires further investigation.

K+ channel mechanisms underlying cholinergic cutaneous vasodilation and sweating in young humans: roles of KCa, KATP, and KV channels?

Acetylcholine released from cholinergic nerves is involved in heat loss responses of cutaneous vasodilation and sweating. K(+) channels are thought to play a role in regulating cholinergic cutaneous vasodilation and sweating, though which K(+) channels are involved in their regulation remains unclear. We evaluated the hypotheses that 1) Ca(2+)-activated K(+) (KCa), ATP-sensitive K(+) (KATP), and voltage-gated K(+) (KV) channels all contribute to cholinergic cutaneous vasodilation; and 2) KV channels, but not KCa and KATP channels, contribute to cholinergic sweating. In 13 young adults (24 ± 5 years), cutaneous vascular conductance (CVC) and sweat rate were evaluated at intradermal microdialysis sites that were continuously perfused with: 1) lactated Ringer (Control), 2) 50 mM tetraethylammonium (KCa channel blocker), 3) 5 mM glybenclamide (KATP channel blocker), and 4) 10 mM 4-aminopyridine (KV channel blocker). At all sites, cholinergic cutaneous vasodilation and sweating were induced by coadministration of methacholine (0.0125, 0.25, 5, 100, and 2,000 mM, each for 25 min). The methacholine-induced increase in CVC was lower with the KCa channel blocker relative to Control at 0.0125 (1 ± 1 vs. 9 ± 6%max) and 5 (2 ± 5 vs. 17 ± 14%max) mM methacholine, whereas it was lower in the presence of KATP (69 ± 7%max) and KV (57 ± 14%max) channel blocker compared with Control (79 ± 6%max) at 100 mM methacholine. Furthermore, methacholine-induced sweating was lower at the KV channel blocker site (0.42 ± 0.17 mg·min(-1)·cm(-2)) compared with Control (0.58 ± 0.15 mg·min(-1)·cm(-2)) at 2,000 mM methacholine. In conclusion, we show that KCa, KATP, and KV channels play a role in cholinergic cutaneous vasodilation, whereas only KV channels contribute to cholinergic sweating in normothermic resting humans.

Hyperhidrosis: A Central Nervous Dysfunction of Sweat Secretion.

Hyperhidrosis (HH) is a central nervous dysfunction characterized by abnormally increased sweating due to a central dysregulation of sweat secretion. HH significantly affects the quality of life of patients in their private, social and professional environments. Physiologically, sweating is a mechanism that regulates body temperature, but it may also be triggered by emotional or gustatory stimuli. There are two main types of sweat glands: eccrine and apocrine glands. The central nervous system controls sweat secretion through the release of neurotransmitters into the autonomous nervous system (ANS) that activate the sweat glands. The hypothalamus has two separate neuronal pathways, one for thermoregulation and one for emotions. HH may thus be due to either a neuronal dysfunction of ANS regulation leading to a hyperactivity of the sympathetic nervous system, or to abnormal central processing of emotions. Crucially, there is no dysfunction of the sweat glands themselves. Various pathogenic mechanisms have been proposed to be involved in pathological sweat secretion in HH, ranging from structural changes within the ANS to increased expression of aquaporin 5 and upregulation of activin A receptor type 1 in eccrine sweat glands. Although a genetic predisposition has been demonstrated, it remains unclear exactly which genes are involved. To identify new, potential therapeutic targets and to improve treatment options, a good understanding of the signaling pathways involved, the underlying mechanisms, and the genetic components is essential. In this review we discuss the various aspects of sweat physiology and function that are necessary to explain pathological sweating. Our aim is to raise awareness of the complexity of HH to promote a better understanding of the disorder.

Cholinergic- rather than adrenergic-induced sweating play a role in developing and developed rat eccrine sweat glands.

Both cholinergic and adrenergic stimulation can induce sweat secretion in human eccrine sweat glands, but whether cholinergic and adrenergic stimulation play same roles in rat eccrine sweat glands is still controversial. To explore the innervations, and adrenergic- and cholinergic-induced secretory response in developing and developed rat eccrine sweat glands, rat hind footpads from embryonic day (E) 15.5-20.5, postanal day (P) 1-14, P21 and adult were fixed, embedded, sectioned and subjected to immunofluorescence staining for general fiber marker protein gene product 9.5 (PGP 9.5), adrenergic fiber marker tyrosine hydroxylase (TH) and cholinergic fiber marker vasoactive intestinal peptide (VIP), and cholinergic- and adrenergic-induced sweat secretion was detected at P1-P21 and adult rats by starch-iodine test. The results showed that eccrine sweat gland placodes of SD rats were first appeared at E19.5, and the expression of PGP 9.5 was detected surrounding the sweat gland placodes at E19.5, TH at P7, and VIP at P11. Pilocarpine-induced sweat secretion was first detected at P16 in hind footpads by starch-iodine test. There was no measurable sweating when stimulated by alpha- or beta-adrenergic agonists at all the examined time points. We conclude that rat eccrine sweat glands, just as human eccrine sweat glands, co-express adrenergic and cholinergic fibers, but different from human eccrine sweat glands, cholinergic- rather than adrenergic-induced sweating plays a role in the developing and developed rat eccrine sweat glands.

Role of nitric oxide synthase in human sweat gland output.

The mechanism by which nitric oxide synthase (NOS) inhibition impacts human sweating is unknown. We tested the hypothesis that the activation of NOS and release on nitric oxide acts to open K+ channels and enhance sweat gland output. Local sweat rate (LSR) was measured with a small sweat capsule mounted on the skin while sweating was initiated by intradermal electrical stimulation. Sigmoid shape stimulus-response curves were generated by plotting the area under the LSR-time curve (LSR AUC) versus log10 stimulus frequency and normalized to the peak AUC response during control trials. NOS inhibition alone reduced the peak sweat rate response to 81.5 ± 4.5% peak LSR AUC of that seen with lactated Ringer's (P = 0.0004). Fifty mM of tetraethylammonium chloride (TEA) alone reduced peak LSR (0.317 ± 0.060 vs. 0.511 ± 0.104 mg·min-1·cm-2, P = 0.03) and the peak LSR AUC response from 0.193 ± 0.170 to 0.158 ± 0.127 mg·cm-2 (P = 0.004). Delivery of a 20 mM nitro-l-arginine methyl ester (l-NAME) following 50 mM TEA produced a further decrease in the peak LSR AUC response to 0.095 ± 0.064 mg·cm-2 (≈20% reduction, P = 0.0145). These data support the hypothesis that sudomotor control of sweat gland activity is locally modulated by a functioning NOS system that appears to be additive and independent to the effect of blockade of K+ channels with TEA.NEW & NOTEWORTHY The contribution of nitric oxide synthase (NOS) to the process of cholinergic-mediated human eccrine sweat production is unclear. Using a novel model for cholinergic-mediated sweating in humans, I demonstrate that blocking the NOS system led to a reduction in local sweat rate (LSR). This reduction in LSR was maintained in the presence of K+ channel blockade with tetraethylammonium.

TEA-sensitive K+ channels and human eccrine sweat gland output.

Cholinergic-activated sweating depends on an influx of Ca2+ from extracellular fluid. It is thought that the opening of K+ channels on secretory epithelial cells facilitates Ca2+ entry. We examined the hypothesis that tetraethylammonium (TEA)-sensitive K+ channels participate in sweat production. We used a pre-post experimental design and initiated cholinergic-mediated sweating with intradermal electrical stimulation, monitored local sweat rate (SR) with a small sweat capsule mounted on the skin, and delivered 50 mM TEA via intradermal microdialysis. Local SR was activated by intradermal stimulation frequencies of 0.2-64 Hz, and we generated a sigmoid-shaped stimulus-response curve by plotting the area under the SR-time curve versus log10 stimulus frequency. Peak local SR was reduced from 0.372 ± 0.331 to 0.226 ± 0.190 mg·min-1·cm-2 (P = 0.0001) during application of 50 mM TEA, whereas the EC50 and Hill slopes were not altered. The global sigmoid-shaped stimulus-response curves for control and 50 mM TEA were significantly different (P < 0.0001), and the plateau region was significantly reduced (P = 0.0023) with the TEA treatment. The effect of TEA on peak local SR was similar in male and female subjects. However, we did note a small effect of sex on the shape of the stimulus-response curves during intradermal electrical stimulation. Overall, these data support the hypothesis that cholinergic control of sweat gland activity is modulated by the presence of TEA-sensitive K+ channels in human sweat gland epithelial cells.NEW & NOTEWORTHY The contribution of various potassium channels to the process of cholinergic-mediated human eccrine sweat production is unclear. Using a novel model for cholinergic-mediated sweating in humans, we provide evidence that tetraethylammonium-sensitive K+ channels (KCa1.1 and Kv channels) contribute to eccrine sweat production.