Jian Cui

Absence of arterial baroreflex modulation of skin sympathetic activity and sweat rate during whole‐body heating in humans

1 Prior findings suggest that baroreflexes are capable of modulating skin blood flow, but the effects of baroreceptor loading/unloading on sweating are less clear. Therefore, this project tested the hypothesis that pharmacologically induced alterations in arterial blood pressure in heated humans would lead to baroreflex‐mediated changes in both skin sympathetic nerve activity (SSNA) and sweat rate. 2 In seven subjects mean arterial blood pressure was lowered (≈8 mmHg) and then raised (≈13 mmHg) by bolus injections of sodium nitroprusside and phenylephrine, respectively. Moreover, in a separate protocol, arterial blood pressure was reduced via steady‐state administration of sodium nitroprusside. In both normothermia and heat‐stress conditions the following responses were monitored: sublingual and mean skin temperatures, heart rate, beat‐by‐beat blood pressure, skin blood flow (laser‐Doppler flowmetry), local sweat rate and SSNA (microneurography from peroneal nerve). 3 Whole‐body heating increased skin and sublingual temperatures, heart rate, cutaneous blood flow, sweat rate and SSNA, but did not change arterial blood pressure. Heart rate was significantly elevated (from 74 ± 3 to 92 ± 4 beats min−1; P < 0.001) during bolus sodium nitroprusside‐induced reductions in blood pressure, and significantly reduced (from 92 ± 4 to 68 ± 4 beats min−1; P < 0.001) during bolus phenylephrine‐induced elevations in blood pressure, thereby demonstrating normal baroreflex function in these subjects. 4 Neither SSNA nor sweat rate was altered by rapid (bolus infusion) or sustained (steady‐state infusion) changes in blood pressure regardless of the thermal condition. 5 These data suggest that SSNA and sweat rate are not modulated by arterial baroreflexes in normothermic or moderately heated individuals.

Effect of whole-body and local heating on cutaneous vasoconstrictor responses in humans

Animal studies suggest that alpha-adrenergic-mediated vasoconstriction is compromised during whole-body heating. The purpose of this study was to identify whether whole-body heating and/or local surface heating reduce cutaneous alpha-adrenergic vasoconstrictor responsiveness in human skin. Protocol I: Six subjects were exposed to neutral skin temperature (i.e., 34 degrees C), whole-body heating, and local heating of forearm skin to increase skin blood flow to the same relative magnitude as that observed during whole-body heating. Protocol II: In eight subjects forearm skin was locally heated to 34, 37, 40, and 42 degrees C. During both protocols, alpha-adrenergic vasoconstrictor responsiveness was assessed by local delivery of norepinephrine (NE) via intradermal microdialysis. Skin blood flow was continuously monitored over each microdialysis membrane via laser-Doppler flowmetry. In protocol I, whole-body and local heating caused similar increases in cutaneous vascular conductance (CVC). The EC50 (log NE dose) of the dose-response curves for both whole body (-4.2 +/- 0.1 M) and local heating (-4.7 +/- 0.4 M) were significantly greater (i.e., high dose required to cause 50% reduction in CVC) relative to neutral skin temperature (- 5.6 +/- 0.0 M; P<0.05 for both). In both local and whole-body heated conditions CVC did not return to pre-heating values even at the highest dose of NE. In protocol II, calculated EC50 for 34, 37, 40, and 42 degrees C local heating was - 5.5 +/- 0.4, -4.6 +/- 0.3, -4.5 +/- 0.3, - 4.2 +/- 0.4 M, respectively. Statistical analyses revealed that the EC50 for 37,40 and 42 degrees C were significantly greater than the EC50 for 34 degrees C. These results indicate that even during administration of high concentrations of NE, alpha-adrenergic vasoconstriction does not fully compensate for local heating and whole-body heating induced vasodilatation in young, healthy subjects. Moreover, these data suggest that elevated local temperatures, above 37 degrees C, and whole-body heating similarly attenuate cutaneous alpha-adrenergic vasoconstriction responsiveness.

Heat stress enhances arterial baroreflex control of muscle sympathetic nerve activity via increased sensitivity of burst gating, not burst area, in humans

The relationship between muscle sympathetic nerve activity (MSNA) and diastolic blood pressure has been used to describe two sites for arterial baroreflex control of MSNA. By determining both the likelihood of occurrence for sympathetic bursts and the area of each burst for a given diastolic blood pressure, both a ‘gating’ and an ‘area’ control site has been described in normothermic humans. Assessing the effect of heat stress on these mechanisms will improve the understanding of baroreflex control of arterial blood pressure under this thermal condition. Therefore, the purpose of this study was to test the hypothesis that heat stress enhances arterial baroreflex control of burst gating and area. In 10 normotensive subjects (age, 32 ± 2 years; mean ±s.e.m.), MSNA (peroneal) was assessed using standard microneurographic techniques. Five minute periods of data were examined during normothermic and whole‐body heating conditions. The burst incidence (i.e. number of sympathetic bursts per 100 cardiac cycles) and the area of each burst were determined for each cardiac cycle and were placed into 3 mmHg intervals of diastolic blood pressure. During normotheric conditions, there was a moderate, negative relationship between burst incidence and diastolic blood pressure (slope =−2.49 ± 0.38; r2= 0.73 ± 0.06; mean ±s.e.m.), while area per burst relative to diastolic blood pressure exhibited a less strong relationship (slope =–1.13 ± 0.46; r2= 0.45 ± 0.09). During whole‐body heating there was an increase in the slope of the relationship between burst incidence and diastolic blood pressure (slope =–4.69 ± 0.44; r2= 0.84 ± 0.03) compared to normothermia (P < 0.05), while the relationship between area per burst and diastolic blood pressure was unchanged (slope =–0.92 ± 0.29; r2= 0.41 ± 0.08) (P= 0.50). The primary finding of this investigation is that, at rest, whole‐body heating enhanced arterial baroreflex control of MSNA through increased sensitivity of a ‘gating’ mechanism, as indicated by an increase in the slope of the relationship between burst incidence and diastolic blood pressure. This occurrence is likely to afford protection against potential decreases in arterial blood pressure in an effort to preserve orthostatic tolerance during heat stress.

Effects of Heat Stress on Thermoregulatory Responses in Congestive Heart Failure Patients

Background— Clinical observations suggest that tolerance to heat stress may be impaired in patients with cardiovascular diseases, particularly those associated with impaired ventricular function and congestive heart failure (CHF). However, thermoregulatory function during a controlled heat stress challenge in patients with CHF has not been studied. Methods and Results— To test the hypothesis that thermoregulatory responses are attenuated in such patients, we assessed cutaneous vasodilation and sweat rate in patients with stable class II–III CHF and in matched healthy subjects during passive whole-body heating. Whole-body heating induced a similar increase in internal temperature (≈0.85°C) in both groups. The sweating responses in patients with CHF were not significantly different from that in control subjects. In contrast, the elevation in forearm cutaneous vascular conductance in patients with CHF was reduced by nearly 50% relative to the control subjects (3.8±0.8 versus 6.9±1.0 mL/100 mL tissue per minute per 100 mm Hg, P=0.04). Moreover, maximal cutaneous vasodilator capacity to direct local heating in patients with CHF was also significantly lower than in control subjects, suggesting that vascular remodeling may be limiting cutaneous vasodilation during hyperthermia. Conclusions— These observations suggest that patients with CHF exhibit attenuated cutaneous vasodilator responses to both whole-body and local heating, whereas sweating responses are preserved. Attenuated cutaneous vasodilation may be a potential mechanism for heat intolerance in patients with CHF.

Orthostatic challenge does not alter skin sympathetic nerve activity in heat-stressed humans.

Perturbations that load or unload baroreceptors do not alter skin sympathetic nerve activity (SSNA) in normothermic individuals. However, in pronounced heat-stressed individuals, when a significant component of the SSNA signal is sudomotor and possibly vasodilator in origin, the effects of baroreceptor unloading via an orthostatic stress on SSNA remain unclear. The purpose of the present study was to test the hypothesis that low and moderate levels of orthostatic stress via lower body negative pressure (LBNP) alter SSNA in pronounced heat-stressed individuals. In both normothermic and heat-stressed conditions, progressive LBNP at -3, -6, -9, -12, -15, -18, -21 and -40 mm Hg were applied to 11 subjects for 2 min per stage. Whole-body heating increased sublingual temperature by 0.7+/-0.1 degrees C, heart rate by 28+/-2.1 bpm, SSNA by 259+/-76 %, forearm skin blood flow by 631+/-142% and forearm sweat rate to 0.68+/-0.14 mg/cm(2)/min (all p<0.005), but did not change mean arterial blood pressure (MAP) (p>0.05). LBNP did not change total SSNA in normothermic or heat-stressed conditions (both p>0.05), although skin blood flow and sweat rate decreased during moderate levels of LBNP while heat stressed. These data suggest that in pronounced heat-stressed individuals, when a significant component of the SSNA signal contains sudomotor and possibly cutaneous active vasodilator activities, low and moderate levels of baroreceptor unloading via LBNP do not alter total SSNA. This observation, coupled with reductions in skin blood flow and sweating during moderate levels of LBNP, suggests that integrated SSNA should not be used as an indicator of baroreflex modulation of the cutaneous vasculature or sweat rate in heat-stressed subjects.

Endogenous nitric oxide attenuates neutrally mediated cutaneous vasoconstriction

Cutaneous vasoconstrictor responsiveness may be impaired by substance(s) directly or indirectly responsible for cutaneous active vasodilatation. In this study, we tested the hypothesis that endogenous nitric oxide (NO) attenuates the reduction in cutaneous vascular conductance (CVC) during an orthostatic challenge combined with whole‐body heating, as well as during whole‐body cooling. In protocol 1, healthy subjects were pretreated with an intradermal injection of botulinum toxin A (BTX) to block the release of neurotransmitters from nerves responsible for cutaneous active vasodilatation. On the experimental day, a microdialysis probe was placed at the BTX‐treated site as well as at two adjacent untreated sites. NG‐nitro‐l‐arginine methyl ester (l‐NAME, 10 mm) was perfused through the probe placed at the BTX‐treated site and at one untreated site. After confirmation of the absence of cutaneous vasodilatation at the BTX site during whole‐body heating, adenosine was infused through the microdialysis probe at this site to increase skin blood flow to a level similar to that at the untreated site. Subsequently, 30 and 40 mmHg lower‐body negative pressures (LBNPs) were applied. The reduction in CVC to LBNP was greatest at the BTX‐treated site (15.0 ± 2.4% of the maximum level (% max)), followed by the l‐NAME‐treated site (11.3 ± 2.6% max), and then the untreated site (3.8 ± 3.0% max; P < 0.05 for all comparisons). In protocol 2, two microdialysis membranes were inserted in the dermal space of one forearm. Adenosine alone was infused at one site while the other site received adenosine and l‐NAME. The reduction in CVC in response to whole‐body cooling was significantly greater at the l‐NAME‐treated site than at the adjacent adenosine alone site. These results suggest that endogenous NO is capable of attenuating cutaneous vasoconstrictor responsiveness.

Neurally mediated vasoconstriction is capable of decreasing skin blood flow during orthostasis in the heat‐stressed human

Given the large increase in cutaneous vascular conductance (CVC) during whole‐body heat stress, this vascular bed is important in the regulation of blood pressure during orthostatic stress. In this thermal state, changes in CVC are reported to be due to withdrawal of active vasodilator activity. The purpose of this study was to identify, contrary to the current line of thinking, whether cutaneous vasoconstrictor neural activity is enhanced and capable of contributing to reductions in CVC during an orthostatic challenge of heat‐stressed individuals. Healthy normotensive subjects were pretreated, subcutaneously, with botulinum toxin A (BTX‐A) to inhibit the release of neurotransmitters from cutaneous active vasodilator nerves. On the experimental day, microdialysis probes were placed in the BTX‐A‐treated site and in an adjacent untreated site. In protocol 1, internal temperature was elevated ∼0.7°C, followed by the application of lower body negative pressure (LBNP; −30 mmHg). LBNP reduced CVC at the BTX‐A‐treated sites (Δ4.2 ± 2.9%max), as well as at the control site (Δ9.8 ± 4.1%max). In protocol 2, after confirming the absence of cutaneous vasodilatation at the BTX‐A‐treated site during whole‐body heating, CVC at this site was elevated to a similar level relative to the control site (55.4 ± 13.4 versus 60.7 ± 10.4%max, respectively) via intradermal administration of isoproterenol prior to LBNP. Similarly, when flow was matched between sites, LBNP reduced CVC at both the BTX‐A‐treated (Δ15.3 ± 4.6%max) and the control sites (Δ8.8 ± 5.6%max). These data suggest that the cutaneous vasoconstrictor system is engaged and is capable of decreasing CVC during an orthostatic challenge in heat‐stressed individuals.

Impaired cutaneous vasodilation and sweating in grafted skin during whole-body heating.

The aim of this investigation was to identify the consequences of skin grafting on cutaneous vasodilation and sweating in split-thickness grafted skin during indirect whole-body heating 5 to 9 months after surgery. In addition, thermoregulatory function was examined at donor skin sites on a separate day. Skin blood flow and sweat rate (SR) were assessed from both grafted (n = 14) or donor skin (n = 11) and compared with the respective adjacent control skin during indirect whole-body heating. Cutaneous vascular conductance (CVC) was calculated from the ratio of skin blood flow (arbitrary units; au) to mean arterial pressure. Whole-body heating significantly increased internal temperature (37.0 ± 0.1 °C to 37.8 ± 0.1 °C; P < .05). Cutaneous vasodilation (ie, the increase in CVC from baseline, &Dgr;CVC) during whole-body heating was significantly attenuated in grafted skin (&Dgr;CVC = 0.14 ± 0.15 au/mm Hg) compared with adjacent control skin (&Dgr;CVC = 0.84 ± 0.11 au/mm Hg; P < .05). Increases in sweat rate (&Dgr;SR) were also significantly lower in grafted skin (&Dgr;SR = 0.08 ± 0.08 mg/cm2/min) compared with adjacent control skin (&Dgr;SR = 1.16 ± 0.20 mg/cm2/min; P < .05). Cutaneous vasodilation and sweating during heating were not significantly different between donor sites (&Dgr;CVC = 0.71 ± 0.19 au/mm Hg; &Dgr;SR = 1.04 ± 0.15 mg/cm2/min) and adjacent control skin (&Dgr;CVC = 0.50 ± 0.10 au/mm Hg; &Dgr;SR = 0.83 ± 0.17 mg/cm2/min). Greatly attenuated or absence of cutaneous vasodilation and sweating suggests impairment of thermoregulatory function in grafted skin, thereby, diminishing the contribution of this skin to overall temperature control during a heat stress.

Skin grafting impairs postsynaptic cutaneous vasodilator and sweating responses.

This study tested the hypothesis that postsynaptic cutaneous vascular responses to endothelial-dependent and -independent vasodilators as well as sweat gland function, are impaired in split-thickness grafted skin 5 to 9 months after surgery. Intradermal microdialysis membranes were placed in grafted and adjacent control skin, thereby allowing local delivery of the endothelial-dependent vasodilator, acetylcholine (ACh 1 × 10–7 to 1 × 10-1 M at 10-fold increments) and the endothelial-independent nitric oxide donor, sodium nitroprusside (SNP; 5 × 10–8 to 5 × 10–2 M at 10-fold increments). Skin blood flow and sweat rate were simultaneously assessed over the semipermeable portion of the membrane. Cutaneous vascular conductance (CVC) was calculated from the ratio of laser Doppler-derived skin blood flow to mean arterial blood pressure. &Dgr;CVC responses from baseline to these drugs were modeled via nonlinear regression curve fitting to identify the dose of ACh and SNP causing 50% of the maximal vasodilator response (EC50). A rightward shift in the CVC dose response curve for ACh was observed in grafted (EC50 = –2.61 ± 0.44 log M) compared to adjacent control skin (EC50 = –3.34 ± 0.46 log M; P = .003), whereas the mean EC50 for SNP was similar between grafted (EC50 = –4.21 ± 0.94 log M) and adjacent control skin (EC50 = –3.87 ± 0.65 log M; P = 0.332). Only minimal sweating to exogenous ACh was observed in grafted skin whereas normal sweating was observed in control skin. Increased EC50 and decreased maximal CVC responses to the exogenous administration of ACh suggest impairment of endothelial-dependent cutaneous vasodilator responses in grafted skin 5 to 9 months after surgery. Greatly attenuated sweating responses to ACh suggests either abnormal or an absence of functional sweat glands in the grafted skin.

Botulinum toxin abolishes sweating via impaired sweat gland responsiveness to exogenous acetylcholine

Background  Botulinum toxin A (BTX) disrupts neurotransmitter release from cholinergic nerves. The effective duration of impaired sweat secretion with BTX is longer relative to that of impaired muscle contraction, suggesting different mechanisms in these tissues.