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 non-adrenergic 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 2 steady-state doses of a cholinergic agonist, pilocarpine (Protocol 2; 4 women, 3 men). During sweating induction, we decreased SkBF via 3 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. 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. 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.

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.

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 non-human 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 Ringers) 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. Lastly, 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.

Human skin blood flow (SkBF) and sweating increase concurrently during increases in skin sympathetic nerve activity and subsequent neurotransmitter release to these cutaneous appendages. Previous studies have blocked sweating without affecting SkBF with the use of the muscarinic agonist atropine, but few have altered SkBF without affecting sweating because standard methods such as introducing an α‐adrenergic agonist decrease SkBF but also can engage eccrine sweat gland receptors. Thus, this study aimed to utilize non‐adrenergic mechanical perturbations to decrease SkBF during intradermal perfusion of a cholinergic agonist. Three intradermal microdialysis fibers were placed in dorsal forearm skin of 4 women and 3 men (age 24±1 yr, height 173±4 cm, weight 80±8 kg) to perfuse 2 doses of pilocarpine nitrate (0.01 and 1.66 mg/ml, corresponding to the ED50 and EMAX from previous dose‐response modeling) or the vehicle (lactated Ringer's). Forearm SkBF (laser‐Doppler flowmetry) was decreased for 3 min by engaging the venoarteriolar response (arm lowered ~30 cm from heart level; CVAR), venoarteriolar response plus decreased perfusion pressure (venous occlusion by proximal cuff inflation; CVAR with ΔPP), and ischemia (arterial occlusion by proximal cuff inflation); sweat rate was measured by perfusing anhydrous medical air through a ventilated capsule (capacitance hygrometry). Drug infusions significantly increased SkBF (+87±18 and +57±16 units) and sweating (+0.37±0.20 and +0.64±0.15 mg/ml/min, for pilocarpine ED50 and EMAX, respectively) compared to vehicle control in which SkBF minimally increased (+8±4 units) and there was no alteration in sweating (−0.02±0.09). Decreased SkBF was observed with CVAR (−26±14, −33±9, and −38±9%), CVAR with ΔPP (−62±7, −42±20 and −61±8%), and ischemia (−99±1, −92±5 and −93±2% for pilocarpine ED50, pilocarpine EMAX, and vehicle control, respectively). Despite these significant decreases in SkBF, changes in eccrine sweat rate were minimal (CVAR = −1±12, +3±3, and −2±5%; CVAR with ΔPP = +3±7, −2±4, and −3±4%; and ischemia = +5±10, +5±5, and +6±5% for pilocarpine ED50, pilocarpine EMAX, and vehicle control, respectively). These data suggest that very acute decreases in SkBF do not proportionally decrease cholinergic‐induced sweating in human forearm skin.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The classification of hyperhidrosis and hypohidrosis requires a precise quantification of sweat secretion. Recent studies have asserted a non‐invasive electrical conductance could be used to quantify precursor sweat formation. Precursor sweat is the isotonic fluid formed in the bulbous coil and the cell type most likely responsible for sweat gland pathology, rather than the modified fluid that reaches the skin surface. This study was designed to compare electrodermal activity (EDA), capacitance hygrometry, and skin blood flow (SkBF) during steady‐state and dose‐response sweating induced by cholinergic agonists to determine measurement congruence. 3 intradermal microdialysis fibers were placed in the dorsal forearm skin of 4 women and 3 men (age 22±2 years, BMI 25±6 k/m2) to perfuse pilocarpine nitrate (1.66 mg/ml for 60 min), 5 doses of acetylcholine (1•10−5 to 1M via 1•10−1 increments per dose for 5 min each), or the vehicle (lactated Ringer's). Perfusate flow rates were standardized at 5 μL/min. Forearm SkBF (laser‐Doppler flowmetry), EDA (constant voltage of 0.5 V and gain of 5 μS/V), and sweat rate (capacitance hygrometry) were measured directly over the microdialysis membrane. Cholinergic dose‐response relations increased sweat rate (0.0 to 0.56 mg/ml/min), SkBF (16 to 279 units), and EDA (0.61 to 0.91 μS). ACh dose dependent increases in sweat rate and SkBF were similarly correlated to EDA (r = 0.52 and 0.48), although SkBF increased from the first dose and sweat rate and EDA increased from the 3rd dose of ACh. EDA was correlated to SkBF (r = 0.52) but not sweat rate (r = −0.17) during the initial climb to steady‐state sweating, while during state‐steady sweating induced by pilocarpine EDA correlated to sweat rate (r = 0.59) but less so to SkBF (r = 0.21). The lactated Ringer's site did not induce changes in sweat rate, SkBF, or EDA; suggesting that the intradermal microdialysis technique does not affect EDA values. Combined, these data indicate EDA does not track capacitance hygrometry derived sweat rate or laser‐Doppler indexed SkBF consistently in either steady state or transient cholinergic‐induced sweating conditions.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.