Patient-Reported Decisional Regret After Operative Otolaryngology Procedures: A Scoping Review.

OBJECTIVE: To review the published literature on decisional regret in adult patients undergoing operative otolaryngology procedures. The primary outcome was decisional regret scale (DRS) scores. DRS scores of 0 indicate no regret, 1-25 mild regret, and >25 moderate to strong/severe regret. DATA SOURCES: A comprehensive librarian-designed strategy was used to search MEDLINE, Embase, and CINAHL from inception to September 2023. REVIEW METHODS: Inclusion criteria consisted of English-language studies of adult patients who underwent operative otolaryngology treatments and reported DRS scores. Data was extracted by two independent reviewers. Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines were followed. Oxford Centre's Levels of Evidence were used for quality assessment. RESULTS: In total, 6306 studies were screened by two independent reviewers; 13 studies were included after full-text analysis. Subspecialties comprised: Head and neck (10), endocrine (1), general (1), and rhinology (1). The DRS results of the included studies spanned a mean range of 10.1-23.9 or a median range of 0-20.0. There was a trend toward more decisional regret after large head and neck procedures or when patients underwent multiple treatment modalities. Depression, anxiety, and patient-reported quality of life measures were all correlated with decisional regret. Oxford Centre's Levels of Evidence ranged from 2 to 4. CONCLUSION: This is the first comprehensive review of decisional regret in otolaryngology. The majority of patients had no or mild (DRS <25) decisional regret after otolaryngology treatments. Future research on pre-operative counseling and shared decision-making to further minimize patient decisional regret is warranted. LEVEL OF EVIDENCE: N/A Laryngoscope, 2023.

KCa and KV channels modulate the venoarteriolar reflex in non-glabrous human skin with no roles of KATP channels, NOS, and COX.

The venoarteriolar reflex is a local mechanism that induces vasoconstriction during venous congestion in various tissues, including skin. This response is thought to play a critical role in minimizing capillary damage or edema resulting from overperfusion, though factors that modulate this response remain largely unknown. Here, we hypothesized that nitric oxide synthase (NOS), cyclooxygenase (COX), and Ca2+-activated, ATP-sensitive, and voltage-gated K+ channels (KCa, KATP, and KV channels, respectively) modulate the venoarteriolar reflex in human skin. Cutaneous blood flow (laser-Doppler flowmetry) was monitored during a 3-min pre-occlusion baseline and following a 3-min venous occlusion of 45 mmHg, the latter maneuver was used to induce the venoarteriolar reflex. The venoarteriolar reflex was assessed at the following forearm skin sites: Experiment 1 (n = 11): 1) lactated Ringer solution (Control), 2) 10 mM Nω-nitro-L-arginine (NOS inhibitor), 3) 10 mM ketorolac (COX inhibitor), and 4) combined NOS + COX inhibition; Experiment 2 (n = 15): 1) lactated Ringer solution (Control), 2) 50 mM tetraethylammonium (KCa channel blocker), 3) 5 mM glybenclamide (KATP channel blocker), and 4) 10 mM 4-aminopyridine (KV channel blocker). Separate and combined NOS and COX inhibition as well as KATP channel blocker had no effect on venoarteriolar reflex. Conversely, venoarteriolar reflex was attenuated by KCa channel blockade (36-38%) and augmented by KV channel blockade (38-55%). We showed that KCa and KV channels modulate the venoarteriolar reflex with minimum roles of NOS, COX, and KATP channels in human non-glabrous forearm skin in vivo. Thus, cutaneous venoarteriolar reflex changes could reflect altered K+ channel function.

Superoxide and NADPH oxidase do not modulate skin blood flow in older exercising adults with and without type 2 diabetes.

OBJECTIVE: High aerobic fitness may prevent age-related decrements in cutaneous vasodilation while type 2 diabetes may exacerbate this decline. The mechanisms underlying these responses remain unclear, but may be due to an excess of reactive oxygen species. We hypothesized that superoxide scavenging or NADPH oxidase inhibition would improve cutaneous vasodilation in older adults exercising in the heat, particularly in healthy low-fit individuals and those with type 2 diabetes. METHODS: Twenty seven older adults were evenly separated into three groups (healthy low-fit: VO2peak = 24.4 ±â€¯2.4 ml·kg-1·min-1, 61 ±â€¯8 years; healthy high-fit: 42.5 ±â€¯9.7 ml·kg-1·min-1, 56 ±â€¯6 years; type 2 diabetes: 30.0 ±â€¯7.6, ml·kg-1·min-1, 58 ±â€¯7 years). The healthy low-fit and type 2 diabetes groups performed two successive 30-min cycling bouts at 65%VO2peak in the heat (35°C), separated by 30-min rest. The high-fit group cycled at the same absolute heat load (and therefore requirement for heat loss) as their healthy low-fit counterparts during the first exercise bout (Ex1) and at the same relative intensity (65%VO2peak) during the second (Ex2). Forearm cutaneous vascular conductance (CVC%max) was measured at microdialysis sites perfused with: 1) lactated Ringer's solution (control); 2) 10 mM NG-nitro-L-arginine-methyl-ester (L-NAME, nitric oxide synthase inhibitor); 3) 100 µM apocynin (NADPH oxidase inhibitor); 4) 10 µM tempol (superoxide dismutase mimetic), with responses compared at baseline, end-Ex1, and end-Ex2. RESULTS: In all groups, L-NAME consistently reduced CVC%max relative to the other treatment sites by ~16-21% during Ex1 and by ~22-27% during Ex2 (all P < 0.05). Conversely, superoxide scavenging and NADPH oxidase inhibition did not influence CVC%max (all P > 0.05). CONCLUSION: Superoxide and NADPH oxidase do not modulate cutaneous vasodilation in healthy low- or high-fit older adults exercising in the heat, regardless of aerobic fitness level or relative exercise intensity employed, nor do they influence cutaneous vasodilation during an exercise-heat stress in those with type 2 diabetes. However, NOS remains an important modulator of cutaneous vasodilation during exercise in all groups.

Cyclooxygenase-1 and -2 modulate sweating but not cutaneous vasodilation during exercise in the heat in young men.

We recently reported that the nonselective cyclooxygenase (COX) inhibitor ketorolac attenuated sweating but not cutaneous vasodilation during moderate-intensity exercise in the heat. However, the specific contributions of COX-1 and COX-2 to the sweating response remained to be determined. We tested the hypothesis that COX-1 but not COX-2 contributes to sweating with no role for either COX isoform in cutaneous vasodilation during moderate-intensity exercise in the heat. In thirteen young males (22 ± 2 years), sweat rate and cutaneous vascular conductance were measured at three forearm skin sites that were continuously treated with (1) lactated Ringer's solution (Control), (2) 150 µmmol·L-1 celecoxib, a selective COX-2 inhibitor, or (3) 10 mmol L-1 ketorolac, a nonselective COX inhibitor. Participants first rested in a non heat stress condition (≥85 min, 25°C) followed by a further 70-min rest period in the heat (35°C). They then performed 50 min of moderate-intensity cycling (~55% peak oxygen uptake) followed by a 30-min recovery period. At the end of exercise, sweat rate was lower at the 150 µmol·L-1 celecoxib (1.51 ± 0.25 mg·min-1 ·cm-2 ) and 10 mmol·L-1 ketorolac (1.30 ± 0.30 mg·min-1 ·cm-2 ) treated skin sites relative to the Control site (1.89 ± 0.27 mg·min-1 ·cm-2 ) (both P ≤ 0.05). Additionally, sweat rate at the ketorolac site was attenuated relative to the celecoxib site (P ≤ 0.05). Neither celecoxib nor ketorolac influenced cutaneous vascular conductance throughout the experiment (both P > 0.05). We showed that both COX-1 and COX-2 contribute to sweating but not cutaneous vasodilation during moderate-intensity exercise in the heat in young men.

Type 2 diabetes specifically attenuates purinergic skin vasodilatation without affecting muscarinic and nicotinic skin vasodilatation and sweating.

NEW FINDINGS: What is the central question of this study? It remains to be determined whether type 2 diabetes attenuates muscarinic and nicotinic cutaneous vasodilatation and sweating as well as purinergic cutaneous vasodilatation. What is the main finding and its importance? We show that type 2 diabetes specifically attenuates purinergic cutaneous vasodilatation without influencing muscarinic and nicotinic cutaneous vasodilatation and sweating. Our results provide valuable new information regarding the receptor-specific influence of type 2 diabetes on microvascular and sudomotor function. ABSTRACT: The present study evaluated whether type 2 diabetes (T2D) attenuates muscarinic and/or nicotinic cutaneous vasodilatation and sweating as well as purinergic cutaneous vasodilatation. Cutaneous vascular conductance and sweat rate were evaluated in 12 healthy non-diabetic older adults (Control, 60 ± 8 years) and 13 older adults with T2D (62 ± 10 years) at three intradermal forearm skin sites perfused with the following: (i) methacholine (muscarinic receptor agonist, five doses: 0.0125, 0.25, 5, 100 and 2000 mm); (ii) nicotine (nicotinic receptor agonist, five doses: 1.2, 3.6, 11, 33 and 100 mm); or (iii) ATP (purinergic receptor agonist, five doses: 0.03, 0.3, 3, 30 and 300 mm). Each agonist was administered for 25 min per dose. At the end of the protocol, 50 mm sodium nitroprusside was administered to all skin sites to elicit maximal cutaneous vasodilatation. Cutaneous vascular conductance during methacholine and nicotine administration did not differ between groups (all P > 0.05). In contrast, cutaneous vascular conductance during administration of 30 mm (42 ± 28 versus 63 ± 26% maximum, P ≤ 0.05) and 300 mm ATP (56 ± 24 versus 71 ± 20% maximum, P ≤ 0.05) was attenuated in individuals with T2D in comparison to the Control participants. Furthermore, cutaneous vascular conductance during administration of 50 mm sodium nitroprusside was lower in individuals with T2D relative to Control subjects (P = 0.04). Methacholine- and nicotine-induced sweating was similar between groups (all P > 0.05). Thus, T2D attenuates purinergic cutaneous vasodilatation without affecting muscarinic and nicotinic cutaneous vascular and sweating responses.

Fluid replacement modulates oxidative stress- but not nitric oxide-mediated cutaneous vasodilation and sweating during prolonged exercise in the heat.

The roles of nitric oxide synthase (NOS), reactive oxygen species (ROS), and angiotensin II type 1 receptor (AT1R) activation in regulating cutaneous vasodilation and sweating during prolonged (≥60 min) exercise are currently unclear. Moreover, it remains to be determined whether fluid replacement (FR) modulates the above thermoeffector responses. To investigate, 11 young men completed 90 min of continuous moderate intensity (46% V̇o2peak) cycling performed at a fixed rate of metabolic heat production of 600 W (No FR condition). On a separate day, participants completed a second session of the same protocol while receiving FR to offset sweat losses (FR condition). Cutaneous vascular conductance (CVC) and local sweat rate (LSR) were measured at four intradermal microdialysis forearm sites perfused with: 1) lactated Ringer (Control); 2) 10 mM NG-nitro-l-arginine methyl ester (l-NAME, NOS inhibition); 3) 10 mM ascorbate (nonselective antioxidant); or 4) 4.34 nM losartan (AT1R inhibition). Relative to Control (71% CVCmax at both time points), CVC with ascorbate (80% and 83% CVCmax) was elevated at 60 and 90 min of exercise during FR (both P < 0.02) but not at any time during No FR (all P > 0.31). In both conditions, CVC was reduced at end exercise with l-NAME (60% CVCmax; both P < 0.02) but was not different relative to Control at the losartan site (76% CVCmax; both P > 0.19). LSR did not differ between sites in either condition (all P > 0.10). We conclude that NOS regulates cutaneous vasodilation, but not sweating, irrespective of FR, and that ROS influence cutaneous vasodilation during prolonged exercise with FR.

Heat shock protein 90 contributes to cutaneous vasodilation through activating nitric oxide synthase in young male adults exercising in the heat.

While the mechanisms underlying the control of cutaneous vasodilation have been extensively studied, there remains a lack of understanding of the different factors that may modulate cutaneous perfusion during an exercise-induced heat stress. We evaluated the hypothesis that heat shock protein 90 (HSP90) contributes to the heat loss response of cutaneous vasodilation via the activation of nitric oxide synthase (NOS) during exercise in the heat. In 11 young males (25 ± 5 yr), cutaneous vascular conductance (CVC) was measured at four forearm skin sites that were continuously treated with 1) lactated Ringer solution (control), 2) NOS inhibition with 10 mM NG-nitro-l-arginine methyl ester (l-NAME), 3) HSP90 inhibition with 178 µM geldanamycin, or 4) a combination of 10 mM l-NAME and 178 µM geldanamycin. Participants rested in a moderate heat stress (35°C) condition for 70 min. Thereafter, they performed a 50-min bout of moderate-intensity cycling (~52% V̇o2peak) followed by a 30-min recovery period. We showed that NOS inhibition attenuated CVC (~40-50%) relative to the control site during pre- and postexercise rest in the heat (P ≤ 0.05); however, no effect of HSP90 inhibition was observed (P > 0.05). During exercise, we observed an attenuation of CVC with the separate inhibition of NOS (~40-50%) and HSP90 (~15-20%) compared with control (both P ≤ 0.05). However, the effect of HSP90 inhibition was absent in the presence of the coinhibition of NOS (P > 0.05). We show that HSP90 contributes to cutaneous vasodilation in young men exposed to the heat albeit during exercise only. We also show that the HSP90 contribution is due to NOS-dependent mechanisms.NEW & NOTEWORTHY We show that heat shock protein 90 functionally contributes to the heat loss response of cutaneous vasodilation during exercise in the heat, and this response is mediated through the activation of nitric oxide synthase. Therefore, interventions that may activate heat shock protein 90 may facilitate an increase in heat dissipation through an augmentation of cutaneous perfusion. In turn, this may attenuate or reduce the increase in core temperature and therefore the level of heat strain.

Prostacyclin does not affect sweating but induces skin vasodilatation to a greater extent in older versus younger women: roles of NO and KCa channels.

NEW FINDINGS: What is the central question of this study? It remains unknown whether ageing modulates prostacyclin-induced cutaneous vasodilatation in women. What is the main finding and its importance? Prostacyclin induced cutaneous vasodilatation, albeit the magnitude of increase at lower concentrations of prostacyclin was greater in older relative to young women. This response was associated with greater contributions of nitric oxide synthase and calcium-activated potassium channels. Our results suggest that administration of prostacyclin might be an effective therapy to reverse microvascular hypoperfusion, especially in older women. We previously reported that prostacyclin induces cutaneous vasodilatation but not sweating in younger and older men. Furthermore, we demonstrated that nitric oxide synthase and calcium-activated potassium (KCa ) channels contribute to the prostacyclin-induced cutaneous vasodilatation in younger men, although these contributions are diminished in older men. Given that the effects of ageing might differ between men and women, the above results cannot simply be applied to women. In this study, cutaneous vascular conductance and sweat rate were evaluated in younger (mean ± SD, 22 ± 3 years old) and older (55 ± 7 years old) women (10 per group) at four intradermal forearm skin sites treated as follows: (i) lactated Ringer solution without any drug (control); (ii) 10 mm NG -nitro-l-arginine (l-NNA), a non-specific nitric oxide synthase inhibitor; (iii) 50 mm tetraethylammonium (TEA), a non-specific KCa channel blocker; or (iv) 10 mm l-NNA plus 50 mm TEA. All four sites were co-administered with prostacyclin in an incremental manner (0.04, 0.4, 4, 40 and 400 µm, each for 25 min). Surprisingly, increases in cutaneous vascular conductance in response to 0.04-4 µm prostacyclin were greater in older relative to younger women (all P ≤ 0.05), and these age-related differences were diminished when both l-NNA and TEA were administered simultaneously (all P > 0.05). No effect on sweat rate was observed in either group (all concentrations, P > 0.05). We show that although prostacyclin does not mediate sweating, it induces cutaneous vasodilatation, and this response elicited by lower concentrations of prostacyclin is greater in older relative to younger women. This greater cutaneous vasodilatation in older women is likely to be attributable to nitric oxide synthase- and KCa channel-dependent mechanisms.

The roles of KCa, KATP, and KV channels in regulating cutaneous vasodilation and sweating during exercise in the heat.

We recently showed the varying roles of Ca2+-activated (KCa), ATP-sensitive (KATP), and voltage-gated (KV) K+ channels in regulating cholinergic cutaneous vasodilation and sweating in normothermic conditions. However, it is unclear whether the respective contributions of these K+ channels remain intact during dynamic exercise in the heat. Eleven young (23 ± 4 yr) men completed a 30-min exercise bout at a fixed rate of metabolic heat production (400 W) followed by a 40-min recovery period in the heat (35°C, 20% relative humidity). Cutaneous vascular conductance (CVC) and local sweat rate were assessed at four forearm skin sites perfused via intradermal microdialysis with: 1) lactated Ringer solution (control); 2) 50 mM tetraethylammonium (nonspecific KCa channel blocker); 3) 5 mM glybenclamide (selective KATP channel blocker); or 4) 10 mM 4-aminopyridine (nonspecific KV channel blocker). Responses were compared at baseline and at 10-min intervals during and following exercise. KCa channel inhibition resulted in greater CVC versus control at end exercise (P = 0.04) and 10 and 20 min into recovery (both P < 0.01). KATP channel blockade attenuated CVC compared with control during baseline (P = 0.04), exercise (all P ≤ 0.04), and 10 min into recovery (P = 0.02). No differences in CVC were observed with KV channel inhibition during baseline (P = 0.15), exercise (all P ≥ 0.06), or recovery (all P ≥ 0.14). With the exception of KV channel inhibition augmenting sweating during baseline (P = 0.04), responses were similar to control with all K+ channel blockers during each time period (all P ≥ 0.07). We demonstrated that KCa and KATP channels contribute to the regulation of cutaneous vasodilation during rest and/or exercise and recovery in the heat.

Mechanisms of nicotine-induced cutaneous vasodilation and sweating in young adults: roles for KCa, KATP, and KV channels, nitric oxide, and prostanoids.

We evaluated the influence of K+ channels (i.e., Ca2+-activated K+ (KCa), ATP-sensitive K+ (KATP), and voltage-gated K+ (KV) channels) and key enzymes (nitric oxide synthase (NOS) and cyclooxygenase (COX)) on nicotine-induced cutaneous vasodilation and sweating. Using intradermal microdialysis, we evaluated forearm cutaneous vascular conductance (CVC) and sweat rate in 2 separate protocols. In protocol 1 (n = 10), 4 separate sites were infused with (i) lactated Ringer (Control), (ii) 50 mmol·L-1 tetraethylammonium (KCa channel blocker), (iii) 5 mmol·L-1 glybenclamide (KATP channel blocker), and (iv) 10 mmol·L-1 4-aminopyridine (KV channel blocker). In protocol 2 (n = 10), 4 sites were infused with (i) lactated Ringer (Control), (ii) 10 mmol·L-1 Nω-nitro-l-arginine (NOS inhibitor), (iii) 10 mmol·L-1 ketorolac (COX inhibitor), or (iv) a combination of NOS+COX inhibitors. At all sites, nicotine was infused in a dose-dependent manner (1.2, 3.6, 11, 33, and 100 mmol·L-1; each for 25 min). Nicotine-induced increase in CVC was attenuated by the KCa, KATP, and KV channel blockers, whereas nicotine-induced increase in sweat rate was reduced by the KCa and KV channel blockers (P ≤ 0.05). COX inhibitor augmented nicotine-induced increase in CVC (P ≤ 0.05), which was absent when NOS inhibitor was co-administered (P > 0.05). In addition, our secondrary experiment (n = 7) demonstrated that muscarinic receptor blockade with 58 µmol·L-1 atropine sulfate salt monohydrate abolished nicotine-induced increases in CVC (1.2-11 mmol·L-1) and sweating (all doses). We show that under a normothermic resting state: (i) KCa, KATP, and KV channels contribute to nicotinic cutaneous vasodilation, (ii) inhibition of COX augments nicotinic cutaneous vasodilation likely through NOS-dependent mechanism(s), and (iii) KCa and KV channels contribute to nicotinic sweating.

Activation of protease-activated receptor 2 mediates cutaneous vasodilatation but not sweating: roles of nitric oxide synthase and cyclo-oxygenase.

NEW FINDINGS: What is the central question of this study? Protease-activated receptor 2 (PAR2) is located in the endothelial cells of skin vessels and eccrine sweat glands. However, a functional role of PAR2 in the control of cutaneous blood flow and sweating remains to be assessed in humans in vivo. What is the main finding and its importance? Our results demonstrate that in normothermic resting humans in vivo, activation of PAR2 elicits cutaneous vasodilatation partly through nitric oxide synthase-dependent mechanisms, but does not mediate sweating. These results provide important new insights into the physiological significance of PAR2 in human skin. Protease-activated receptor 2 (PAR2) is present in human skin, including keratinocytes, endothelial cells of skin microvessels and eccrine sweat glands. However, whether PAR2 contributes functionally to the regulation of cutaneous blood flow and sweating remains entirely unclear in humans in vivo. We hypothesized that activation of PAR2 directly stimulates cutaneous vasodilatation and sweating via actions of nitric oxide synthase (NOS) and cyclo-oxygenase (COX). In 12 physically active young men (29 ± 5 years old), cutaneous vascular conductance (CVC) and sweat rate were measured at four intradermal microdialysis forearm skin sites that were treated with the following: (i) lactated Ringer's solution (control); (ii) 10 mm NG -nitro-l-arginine (NOS inhibitor); (iii) 10 mm ketorolac (COX inhibitor); or (iv) a combination of both inhibitors. At all sites, a PAR2 agonist (SLIGKV-NH2 ) was co-administered in a dose-dependent fashion (0.06, 0.18, 0.55, 1.66 and 5 mm, each for 25 min). The highest dose of SLIGKV-NH2 (5 mm) increased CVC from baseline at the control site (P ≤ 0.05). This increase in CVC associated with PAR2 activation was attenuated by NOS inhibition regardless of the presence or absence of simultaneous COX inhibition (both P ≤ 0.05). However, COX inhibition alone did not affect the PAR2-mediated increase in CVC (P > 0.05). No increase in sweat rate was measured at any administered dose of SLIGKV-NH2 (all P > 0.05). We show that in normothermic resting humans in vivo, PAR2 activation does not increase sweat rate, whereas it does modulate cutaneous vasodilatation through NOS-dependent mechanisms.

Nitric oxide synthase and cyclooxygenase modulate ß-adrenergic cutaneous vasodilatation and sweating in young men.

KEY POINTS: ß-Adrenergic receptor agonists such as isoproterenol induce cutaneous vasodilatation and sweating in humans, but the mechanisms underpinning this response remain unresolved. Using intradermal microdialysis, we evaluated the roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) in ß-adrenergic cutaneous vasodilatation and sweating elicited by administration of isoproterenol. We show that while NOS contributes to ß-adrenergic cutaneous vasodilatation, COX restricts cutaneous vasodilatation. We also show that combined inhibition of NOS and COX augments ß-adrenergic sweating These new findings advance our basic knowledge regarding the physiological control of cutaneous blood flow and sweating, and provide important and new information to better understand the physiological significance of ß-adrenergic receptors in the skin. ABSTRACT: ß-Adrenergic receptor agonists such as isoproterenol can induce cutaneous vasodilatation and sweating in humans, but the mechanisms underpinning this response remain unresolved. We evaluated the hypotheses that (1) nitric oxide synthase (NOS) contributes to ß-adrenergic cutaneous vasodilatation, whereas cyclooxygenase (COX) limits the vasodilatation, and (2) COX contributes to ß-adrenergic sweating. In 10 young males (25 ± 5 years), cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal forearm skin sites infused with (1) lactated Ringer solution (control), (2) 10 mm Nω -nitro-l-arginine (l-NNA), a non-specific NOS inhibitor, (3) 10 mm ketorolac, a non-specific COX inhibitor, or (4) a combination of l-NNA and ketorolac. All sites were co-administered with a high dose of isoproterenol (100 µm) for 3 min to maximally induce ß-adrenergic sweating (ß-adrenergic sweating is significantly blunted by subsequent activations). Approximately 60 min after the washout period, three incremental doses of isoproterenol were co-administered (1, 10 and 100 µm each for 25 min). Increases in CVC induced by the first and second 100 µm isoproterenol were attenuated by l-NNA alone, and those in response to all doses of isoproterenol were reduced by l-NNA with co-infusion of ketorolac (all P ≤ 0.05). Ketorolac alone augmented increases in CVC induced by 10 µm and by the second 100 µm isoproterenol (both P ≤ 0.05). While isoproterenol-induced sweating was not affected by the separate administration of l-NNA or ketorolac (all P > 0.05), their combined administration augmented sweating elicited by the first 3 min of 100 µm isoproterenol (P = 0.05). We show that while NOS contributes to ß-adrenergic cutaneous vasodilatation, COX restrains the vasodilatation. Finally, combined inhibition of NOS and COX augments ß-adrenergic sweating.

Nicotinic receptor activation augments muscarinic receptor-mediated eccrine sweating but not cutaneous vasodilatation in young males.

NEW FINDINGS: What is the central question of this study? Acetylcholine released from cholinergic nerves can activate both muscarinic and nicotinic receptors. Although each receptor can independently induce cutaneous vasodilatation and eccrine sweating, it remains to be elucidated whether the two receptors interact in order to mediate these responses. What is the main finding and its importance? We show that although nicotinic receptor activation does not modulate muscarinic cutaneous vasodilatation, it lowers the muscarinic receptor agonist threshold at which onset for eccrine sweating (augmentation of muscarinic eccrine sweating) occurs in young men in normothermic resting conditions. These results provide new insights into the physiological significance of nicotinic receptors in the regulation of cutaneous perfusion and eccrine sweating. Acetylcholine released from cholinergic nerves can activate both muscarinic and nicotinic receptors; each is known independently to induce cutaneous vasodilatation and eccrine sweating in humans. However, it is not known whether the two receptors interact in order to mediate cutaneous vasodilatation and eccrine sweating. In 10 young men (27 ± 6 years old), cutaneous vascular conductance and sweat rate were evaluated at intradermal microdialysis sites that were continuously perfused with either lactated Ringer's solution (control) or three different concentrations of nicotine (0.1, 1 and 10 mm), a nicotinic receptor agonist. Co-administration of methacholine, a muscarinic receptor agonist, was performed at all skin sites in a dose-proportional fashion (0.0125, 0.25, 5, 100 and 2000 mm, each for 25 min). Administration of nicotine alone caused dose-dependent transient increases in cutaneous vascular conductance and sweat rate (all P ≤ 0.05), which thereafter returned to pre-nicotine levels, except that a portion of transient responses remained with continuous administration of 10 mm nicotine (both P ≤ 0.05). Cutaneous vascular conductance was increased by administration of ≥0.25 mm methacholine at the control site, and this response was likewise observed in the presence of co-administration of all doses of nicotine used (all P ≤ 0.05). Sweat rate at the control site was increased by administration of ≥0.25 mm methacholine, but the lowest dose of methacholine (0.0125 mm) was able to increase sweat rate in the presence of 10 mm nicotine (P ≤ 0.05). We conclude that nicotinic receptor activation lowers the muscarinic receptor agonist threshold for eccrine sweating (augmentation of muscarinic sweating) but does not affect muscarinic cutaneous vasodilatation in young men in normothermic resting conditions.

Intradermal administration of endothelin-1 attenuates endothelium-dependent and -independent cutaneous vasodilation via Rho kinase in young adults.

We recently showed that intradermal administration of endothelin-1 diminished endothelium-dependent and -independent cutaneous vasodilation. We evaluated the hypothesis that Rho kinase may be a mediator of this response. We also sought to evaluate if endothelin-1 increases sweating. In 12 adults (25 ± 6 yr), we measured cutaneous vascular conductance (CVC) and sweating during 1) endothelium-dependent vasodilation induced via administration of incremental doses of methacholine (0.25, 5, 100, and 2,000 mM each for 25 min) and 2) endothelium-independent vasodilation induced via administration of 50 mM sodium nitroprusside (20-25 min). Responses were evaluated at four skin sites treated with either 1) lactated Ringer solution (Control), 2) 400 nM endothelin-1, 3) 3 mM HA-1077 (Rho kinase inhibitor), or 4) endothelin-1+HA-1077. Pharmacological agents were intradermally administered via microdialysis. Relative to the Control site, endothelin-1 attenuated endothelium-dependent vasodilation (CVC at 2,000 mM methacholine, 80 ± 10 vs. 56 ± 15%max, P < 0.01); however, this response was not detected when the Rho kinase inhibitor was simultaneously administered (CVC at 2,000 mM methacholine for Rho kinase inhibitor vs. endothelin-1 + Rho kinase inhibitor sites: 73 ± 9 vs. 72 ± 11%max, P > 0.05). Endothelium-independent vasodilation was attenuated by endothelin-1 compared with the Control site (CVC, 92 ± 13 vs. 70 ± 14%max, P < 0.01). However, in the presence of Rho kinase inhibition, endothelin-1 did not affect endothelium-independent vasodilation (CVC at Rho kinase inhibitor vs. endothelin-1+Rho kinase inhibitor sites: 81 ± 9 vs. 86 ± 10%max, P > 0.05). There was no between-site difference in sweating throughout (P > 0.05). We show that in young adults, Rho kinase is an important mediator of the endothelin-1-mediated attenuation of endothelium-dependent and -independent cutaneous vasodilation, and that endothelin-1 does not increase sweating.

Intradermal administration of atrial natriuretic peptide has no effect on sweating and cutaneous vasodilator responses in young male adults.

Atrial natriuretic peptide (ANP) increases during exercise in the heat wherein heat loss responses of sweating and cutaneous vasodilatation are activated. Hence ANP might be involved in the regulation of sweating and cutaneous vasodilatation. However, whether ANP directly mediates sweating and cutaneous vasodilatation needs to be clarified. Also, muscarinic receptor activation induces sweating and cutaneous vasodilatation, however, it remains to be determined whether ANP modulates these responses. In this study, in 11 young males (25 ± 5 years), cutaneous vascular conductance and sweat rate were assessed at intradermal microdialysis sites that were continuously perfused with either lactated Ringer (Control) or 3 different concentrations of ANP (0.1, 1, 10 µM). All 4 sites were co-administrated with methacholine, a muscarinic receptor agonist, in a dose-dependent fashion (0.0125, 0.25, 5, 100, and 2000 mM, 25 min for each). ANP at all concentrations did not increase sweat rate and cutaneous vascular conductance as compared with pre-ANP infusion values (all P > 0.05). Methacholine increased both sweat rate and cutaneous vascular conductance (all P ≤ 0.05). However, the responses were unaffected by co-administration of ANP relative to methacholine only, even as assessed in context of the methacholine concentration required to elicit 50% of the maximal response (EC50) (all P > 0.05). We show that exogenous ANP administration intradermally does not directly modulate sweating and cutaneous vasodilatation under room temperature conditions in resting young adults. Further, there is no effect of ANP on muscarinic sweating and cutaneous vasodilatation.

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.