Calcium‐activated Chloride Channel TMEM16A/ANO1 Does Not Mediate the Regulation of Sweating and Cutaneous Vasodilation in Humans In Vivo
Bibliographic record
Abstract
The regulation of human body temperature during a heat stress is dependent on the activation of the heat loss responses of cutaneous vasodilation and eccrine sweating. While significant advancements have been made in our understanding of the mechanisms governing their regulation, new potential modifiers such as transmembrane member 16A (TMEM16A), a Ca 2+ ‐activated Cl ‐ channel also known as anoctamin 1 (ANO1), continue to be identified. In vitro and animal studies suggest a role for TMEM16A in the regulation of sweat secretion and vascular tone. For example, Ca 2+ induced Cl ‐ current was abolished in TMEM16A deficit, but not BEST2 deficit, NCL‐SG3 human eccrine sweat gland cell lines. Further, animal models showed the activation of TMEM16A on vascular smooth muscle cells blunts vasodilation. However, direct evidence supporting a role of TMEM16 in mediating cutaneous vasodilation as well as eccrine sweating in humans in vivo remains to be established. Therefore, we evaluated the hypothesis that TMEM16A mediates the regulation of sweating and cutaneous vasodilation during a whole‐body heat stress in young adults. Twelve young (24 ± 2 years) adults (6 females) underwent a whole‐body heat stress induced by a water‐perfused suit to raise core temperature 1.1±0.1ºC above baseline resting levels. Sweat rate (ventilated capsule) and cutaneous vascular conductance (assessed as skin blood flow/mean arterial pressure and normalised to maximal conductance achieved via simultaneous local skin heating to 44°C and administration of sodium nitroprusside) were assessed at four skin sites on the forearm treated with 1) lactated Ringers (control), 2) 5 % dimethyl sulfoxide serving as a vehicle control, 3) 1 mM T16Ainh‐A01 (a TMEM16A blocker) or 4) 2 mM benzbromarone (another TMEM16A blocker). All drugs were administered continuously via intradermal microdialysis. Sweat rate increased as heating continued at all skin sites (P < 0.001 for a main effect of heating stage). Neither the main effect of treatment site nor the interaction between treatment site and heating stage was significant (both P ≥ 0.318). Cutaneous vascular conductance increased in parallel to elevations in core temperature (P < 0.001 for a main effect of heating stage). Although no main effect of treatment site was observed (P = 0.109), a significant interaction between heating stage and treatment site was measured (P < 0.001). Post‐hoc analysis revealed that cutaneous vascular conductance at the DMSO‐treated site was higher than the control site at baseline (P = 0.047). By contrast, cutaneous vascular conductance at moderate elevations in core temperature (i.e., ≥0.4‐0.8 °C) was greater at the control site relative to the DMSO‐treated site (all P ≤ 0.013). Importantly, no differences were measured in cutaneous vascular conductance between the DMSO‐treated site and TMEM16A blocker‐treated sites (all P ≥ 0.073). Taken together, our findings demonstrate for the first time that TMEM16A does not contribute to the regulation of sweating and cutaneous vasodilation during whole‐body heating in young adults in vivo.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".