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J Appl Physiol 103: 963-968, 2007. First published June 28, 2007; doi:10.1152/japplphysiol.00278.2007
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Cholinergic mechanisms of cutaneous active vasodilation during heat stress in cystic fibrosis

D. L. Kellogg, Jr.,1,2 G. J. Hodges,3 C. R. Orozco,4 T. M. Phillips,4 J. L. Zhao,1,2 and J. M. Johnson3

1Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs, South Texas Veterans Health Care System, Audie L. Murphy Memorial Veterans Hospital Division; 2Division of Geriatrics and Gerontology, Department of Medicine, and 3Department of Physiology, University of Texas Health Science Center at San Antonio; and 4Adult Cystic Fibrosis Clinic, Christus Santa Rosa Hospital, San Antonio, Texas

Submitted 12 March 2007 ; accepted in final form 25 June 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
To test the hypothesis that cutaneous active vasodilation in heat stress is mediated by a redundant cholinergic cotransmitter system, we examined the effects of atropine on skin blood flow (SkBF) increases during heat stress in persons with (CF) and without cystic fibrosis (non-CF). Vasoactive intestinal peptide (VIP) has been implicated as a mediator of cutaneous vasodilation in heat stress. VIP-containing cutaneous neurons are sparse in CF, yet SkBF increases during heat stress are normal. In CF, augmented ACh release or muscarinic receptor sensitivity could compensate for decreased VIP; if so, active vasodilation would be attenuated by atropine in CF relative to non-CF. Atropine was administered into skin by iontophoresis in seven CF and seven matched non-CF subjects. SkBF was monitored by laser-Doppler flowmetry (LDF) at atropine treated and untreated sites. Blood pressure [mean arterial pressure (MAP)] was monitored (Finapres), and cutaneous vascular conductance was calculated (CVC = LDF/MAP). The protocol began with a normothermic period followed by a 3-min cold stress and 30–45 min of heat stress. Finally, LDF sites were warmed to 42°C to effect maximal vasodilation. CVC was normalized to its site-specific maximum. During heat stress, CVC increased in both CF and non-CF (P < 0.01). CVC increases were attenuated by atropine in both groups (P < 0.01); however, the responses did not differ between groups (P = 0.99). We conclude that in CF there is not greater dependence on redundant cholinergic mechanisms for cutaneous active vasodilation than in non-CF.

vasoactive intestinal peptide; acetylcholine; human; skin blood flow; thermoregulation

IN HUMANS, THE CUTANEOUS CIRCULATION plays a major role in maintaining thermoregulatory stability. During periods of heat exposure, increases in body temperature are minimized by increases in skin blood flow (SkBF) and sweating. SkBF responses to heat are mediated by increased activity of cutaneous cholinergic sympathetic nerves that innervate sweat glands and blood vessels. Whether the same cholinergic nerves are common to blood vessels and sweat glands is not settled. This system of nerves, sweat glands, and blood vessels is collectively known as the cutaneous active vasodilator system (4, 8, 22, 27, 28). An integral part of active vasodilation is cholinergic cotransmission; it is a powerful mechanism that is responsible for increases in SkBF during heat stress and can direct 60% of cardiac output to skin at the peak of heat stress (29).

Numerous studies over the last half-century have made it clear that active vasodilation includes the release of acetylcholine (ACh) (6, 7, 20, 26, 27). For example, Roddie et al. (27) found that intra-arterial infusions of atropine that completely abolished sweating and vasodilator responses to exogenous ACh and that it delayed and attenuated the forearm vasodilation induced by indirect body heating. Thus, although complete atropinization attenuated active vasodilation, it did not abolish it. In addition, these authors reported that atropine did not reduce forearm vasodilation if infused during established vasodilation at the height of heat stress. Their results were subsequently corroborated by several laboratories using a variety of different techniques (20, 23, 32).

In addition to the clear role of ACh in active vasodilation, release of a cotransmitter, or co-transmitters, from cholinergic sympathetic vasodilator nerves is also involved in the process (20). Although the identify of the cotransmitters is unclear, one candidate is vasoactive intestinal peptide (VIP). The possible involvement of VIP was proposed by Hökfelt and colleagues (12) based on studies of cholinergic cotransmitter systems in the cat paw. According to their proposal, a single set of neurons could control both active vasodilation of cutaneous arterioles and sweating by releasing both ACh and the neuropeptide cotransmitter VIP. In their original proposal, ACh would cause sweating and some vasodilation, whereas VIP would effect the majority of active vasodilation (12). Such a cotransmitter mechanism could explain why atropine completely abolishes sweating but only attenuates cutaneous active vasodilation in humans (20, 27, 32).

The Hökfelt hypothesis provides an attractive mechanism for cutaneous active vasodilation for several reasons: 1) VIP is a vasodilator (2, 24); 2) it is found in human nerve endings associated with sweat glands (39) and blood vessels (10); and, 3) it is colocalized with ACh (39). VIP has also been implicated in the control of sweat glands (35, 47). For example, exogenous VIP appears to increase muscarinic receptor affinity for methacholine (a muscarinic receptor agonist) and may thus promote sweat production as well as active vasodilation (35, 47).

The initial test of the Hökfelt hypothesis in human active vasodilation was reported by Savage et al. (31), who based their test on the knowledge that cutaneous nerves from patients with cystic fibrosis (CF) contain little or no VIP (11), Savage et al. reasoned that if VIP is involved in cutaneous active vasodilation, CF patients would manifest a reduced increase in SkBF during heat stress. These authors compared the heat stress responses on four CF and four matched non-CF persons and found SkBF responses in the two groups to be essentially identical. The responses were so similar that they appropriately deemed it unethical to study more persons. Skin biopsies of their patients confirmed very sparse levels of VIP with normal levels of calcitonin gene-related peptide (CGRP) and substance P in cutaneous nerves. They concluded that VIP probably was not the elusive transmitter that effected cutaneous active vasodilation (31).

In contrast to the conclusions of Savage et al. (31), recent work by Bennett et al. (2) supports the involvement of VIP as a cotransmitter in cutaneous active vasodilation. This work tested whether active vasodilation is a redundant system in which ACh and VIP are coreleased from cholinergic nerves. The neuropeptide fragment VIP10—28, an inhibitor of VIP at VIP type 1 and 2 receptors, was given alone or in combination with atropine. VIP10—28, alone or combined with atropine, attenuated (but did not abolish) the rise of SkBF during heat stress. This finding supported a role for VIP in active vasodilation (2). However, subsequent studies with this antagonist have not replicated this work (44), thus firm conclusions about the role of VIP in cutaneous active vasodilation remain problematic.

An alternative explanation that could unify many of the foregoing, and seemingly divergent findings is based on the possibility of redundancy in the cotransmitter mechanisms that cause cutaneous active vasodilation during heat stress, whereby lack of one neurotransmitter can be compensated for by augmented release of another (1, 24). According to this explanation, in CF an apparently normal increase in SkBF during heat stress could be caused by an increased release for ACh and/or muscarinic receptor responsiveness, compensating for reduced VIP release. Indeed, evidence from studies in human skin suggests that both increased release of ACh and increased muscarinic receptor responsiveness to ACh occur in CF (3, 5). Given these findings, the active vasodilator system in CF patients could be more dependent on ACh-mediated vasodilation and hence more sensitive to muscarinic receptor blockade than in persons with normal levels of VIP in whom coreleased ACh and VIP both contribute to cutaneous active vasodilation during heat stress. We tested this hypothesis by comparing the effects of atropine on cutaneous active vasodilation during heat stress in non-CF persons with those in patients with CF.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Seven healthy patients (4 men and 3 women) with CF and seven age and gender-matched healthy persons without CF participated in this institutionally approved study. The groups did not differ in average age (CF 21 ± 1 yr vs. non-CF 21 ± 1 yr; P > 0.05), average height (CF 169 ± 3 cm vs. non-CF 174 ± 3 cm; P > 0.05) or weight (CF 69 ± 4 kg vs. non-CF 69 ± 7 cm; P > 0.05). Menstrual cycle phase was the same for female subjects.

All CF subjects were experiencing no acute medical problems and were functioning optimally at the time of their participation in the study. They were continued on all of their prescribed medications, requisite for optimal maintenance of their health. Several CF subjects took medications that included agents with known anticholinergic effects: metoclopramide and ipratropium. Other medications taken by CF subjects included montelukast, paroxetine, cetirizine, fexofenidine, famotidine, esomeprazole, ranitidine, guaifenesin, celecoxib, and naprosyn. All control subjects were in good health and were taking no medications. All subjects were nonsmokers and were asked to refrain from caffeinated beverages on the day before the study and on the study day. All subjects gave informed consent to participate. All studies took place in the early afternoon.

To achieve local muscarinic receptor blockade, atropine, dissolved in propylene glycol, was administered into forearm skin by iontophoresis at a dose of 400 µA/cm2 for 45 s to an area of 0.64 cm2 as previously done (20). This approach obviates systemic effects of atropine but provides a complete blockade of muscarinic receptors locally (20).

SkBF was monitored by laser-Doppler flowmetry (LDF; Moorlab, Moore Instruments, Axminster, Devon, UK). LDF probes were placed over the atropine-treated site and an adjacent, untreated skin site. Sweat rate (SR) was monitored simultaneously from the atropine-treated and untreated sites by relative humidity monitors (HX92V, Omega Engineering; IH3602-L humidity sensors, HY-CAL Engineering) incorporated into the LDF probe holders. Pulse rate (PR) and blood pressure [mean arterial pressure (MAP)] were monitored by Finapres (Finapres BP Monitor, Ohmeda, Madison, WI). MAP was the electrical integration of the continuous blood pressure signal. Cutaneous vascular conductance (CVC) was calculated as CVC = LDF/MAP.

Body cooling and heating were accomplished with water-perfused suits, used to control skin temperature (Tsk) by perfusion with water of different temperatures. The suit was perfused with 33°C water during periods of normothermia, water of 18°C to effect periods of cold stress, and water of ~48°C to raise Tsk to 38–39°C to cause periods of heat stress. A water-impermeable plastic garment was worn over the tube-lined suit. The suit and garment covered the entire body surface with the exception of the head, the forearm used for SkBF measurements, as well as the hands and feet (16, 30).

Internal temperature was monitored from a thermocouple held in the sublingual sulcus (Tor). Subjects were instructed to hold the probe in one place in the sulcus and not to speak during the study. Tsk was monitored as the surface-area-weighted electrical average of six thermocouples taped on six body sites and covered by the water perfused suits (37).

Data collection began with a 10- to 15-min normothermic control period followed by a 3-min period of cold stress to verify that atropine iontophoresis had had no unanticipated effects on sympathetic noradrenergic function, after which subjects were returned to normothermia. Following a second period of normothermia, Tsk was raised to 38–39°C for 45–55 min to increase body temperature, induce heat stress, and thus activate the cutaneous active vasodilator system. Body heating continued until a plateau in the SkBF response to heat stress occurred. After heat stress, subjects were cooled to normothermia and the sites of SkBF measurement were warmed to 42°C and maintained at that temperature for 20–40 min until LDF values had reached a maximal plateau (15, 19, 38). Local warming was ended when the LDF had not changed for at least 7 min at both sites. Comparisons between the absolute CVC values achieved with local warming of the skin to 42°C showed no difference between groups or between atropine treated and untreated sites. In addition, recent work by Wilkins et al. (43) found that the vasodilator responses to local warming of the skin to 42°C are preserved in CF, thus CVC values were normalized to the maximal levels achieved with local skin warming to 42°C for data analysis.

Tor thresholds at which the cutaneous active vasodilator system was activated were identified at untreated and atropine-treated sites based on the initiation of CVC increases during the period of body warming for heat stress. Tor thresholds for active vasodilator system activation were determined from separate plots of CVC vs. Tor during body heating by an investigator blinded to subject and drug treatment. Differences in Tor ({Delta}Tor) between preheating and threshold temperatures within groups were calculated from absolute Tor values.

The cutaneous vascular responses to cold stress were analyzed by comparing CVC values from normothermia to those levels achieved in the final minute of cold stress. The effect of muscarinic receptor blockade on cutaneous active vasodilation was assessed by the difference in responses of CVC at untreated and atropine-treated sites and between CF and non-CF groups.

The cutaneous vascular responses to heat stress were analyzed in several ways. To evaluate potential differences in the drug treatment sites between groups in the early and later phases of the SkBF responses, slopes of the CVC-Tor relationships for an increase of 0.15°C from the threshold for active vasodilation and for increases in Tor from 0.15°C to 0.30°C above the active vasodilator threshold were compared between groups and treatments. CVC values themselves were also examined for Tor increases of 0.15°C and 0.30°C over Tor threshold values. CVC responses at the peak of heat stress, when Tor had increased by 0.8°C and CVC increases had reached a plateau, were also compared.

Tor thresholds for activation of sweating were determined from separate plots of SR vs. Tor during body heating by an investigator blinded to subject and drug treatment. SR responses during heat stress were analyzed by comparing SR values from normothermia to the final levels achieved during heat stress.

CVC, SR, and Tor responses for the two groups and the two treatments were analyzed by repeated-measures ANOVA (2 within and 1 between factors) to analyze differences between groups at the drug-treated sites. Post hoc planned comparisons, including Student-Newman-Keuls tests, were done to further elucidate significant differences found between groups and drug treatment effects. Statistical significance was taken at the 5% confidence level.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
All subjects tolerated atropine iontophoresis, cold stresses, and heat stresses without complications. The effectiveness of the antagonism of muscarinic receptors by atropine treatment was demonstrated by abolition of sweating at all atropine treated sites in all CF and non-CF subjects (P < 0.05 untreated vs. atropine).

Under normothermic conditions, in the CF group Tor was 36.8 ± 0.1°C, PR was 88 ± 5 bests/min, and MAP was 84 ± 4 mmHg. In the non-CF group, Tor was 36.6 ± 0.1°C, PR was 60 ± 3 beats/min, and MAP was 77 ± 3 mmHg. Comparisons between the groups showed that Tor and MAP tended to be greater in the CF group, but this trend did not reach statistical significance (Tor, P = 0.09 and MAP, P = 0.12). In contrast, PR did differ significantly between groups (P < 0.01) in normothermia.

During cold stress, CVC decreased at untreated control sites and at atropine-treated sites in both CF (12 ± 2 to 7 ± 2% maximum untreated; 10 ± 2 to 7 ± 2% maximum atropine; P < 0.05 normothermia vs. cold stress) and non-CF subjects (10 ± 2 to 6 ± 1% maximum untreated; 12 ± 2 to 8 ± 2% maximum atropine; P < 0.05 normothermia vs. cold stress). These responses, illustrated in Fig. 1, did not differ between CF and non-CF (P > 0.05) and were unaltered by atropine (P > 0.05).


Figure 1
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  		Fig. 1. Summary of cutaneous vascular conductance (CVC) responses to thermoregulatory reflexes and the effects of atropine in subjects with and without cystic fibrosis. Compared with normothermic levels, CVC fell significantly during cold stress in both subject groups, P < 0.05. Atropine did not alter this response. During heat stress, CVC increased significantly in both groups, P < 0.05. Atropine significantly attenuated the response in each group, P < 0.05. No differences were found between subject groups. {Delta}Tor, difference in internal temperature threshold ({Delta}Tor = Tor threshold for cutaneous active vasodilation – Tor in normothermia); %max, Percentage of maximum.

 
The Tor at which the active vasodilator system was activated was greater in CF than non-CF (untreated sites 37.1 ± 0.1°C for CF vs. 36.7 ± 0.1°C for non-CF; P < 0.05). Atropine treatment did not alter this threshold in the CF group; however, atropine treatment did increase the threshold in the non-CF group (untreated sites 37.1 ± 0.1°C vs. 37.1 ± 0.1°C atropine for CF, P > 0.05; untreated sites 36.7 ± 0.1°C vs. 36.9 ± 0.1°C atropine for non-CF, P < 0.01). Because normothermic Tor values differed between CF and non-CF groups, threshold comparisons were also made between the increase in Tor relative to each group's initial Tor values ({Delta}Tor) and their thresholds. For CF, {Delta}Tor at untreated sites was 0.25 ± 0.05°C and 0.28 ± 0.07°C at atropine-treated sites (P > 0.05 between sites). For non-CF, {Delta}Tor at untreated sites was 0.17 ± 0.06°C and 0.29 ± 0.08°C at atropine-treated sites (P < 0.05 between sites). {Delta}Tor at untreated sites was significantly greater in non-CF subjects compared with CF subjects (P < 0.05). These results are summarized in Fig. 2.


Figure 2
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  		Fig. 2. Summary of the effect of atropine on the {Delta}Tor at which cutaneous active vasodilation began during heat stress. {Delta}Tor was not altered by atropine in CF subjects (P > 0.05). Atropine increased {Delta}Tor in the non-CF subjects (P < 0.05).

 
The slopes of the CVC-Tor relationships were attenuated by atropine during the initial 0.15°C increase from the active vasodilator threshold in both groups (P < 0.05). No statistically significant differences were found between CF and non-CF groups. These results are summarized in Table 1.


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  		Table 1. Slope of cutaneous vascular conductance increases with oral temperature in heat stress

 
Throughout heat stress, CVC increased at untreated and atropine-treated sites in both CF and non-CF (normothermia vs. all heat stress points for both CF and non-CF, P < 0.05). Atropine treatment attenuated the increase in CVC at all points during heat stress in both groups (P < 0.05 untreated vs. atropine); however, this effect of atropine did not differ between groups (P = 0.93). These responses are summarized in Fig. 1.

The Tor threshold for the initiation of sweating did not differ significantly between the CF group the non-CF group (CF, 37.0 ± 0.1°C vs. non-CF, 36.8 ± 0.1°C; P = 0.17). SR was abolished by atropine in both CF and non-CF subjects (P < 0.01 untreated vs. atropine). SR, as reflected by percent relative humidity, increased to a maximal value of 0.76 ± 0.17% relative humidity in CF and to 1.41 ± 0.24% relative humidity in non-CF. Maximal SR was greater in non-CF compared with CF subjects (P < 0.01).

At the peak of heat stress in the CF group, Tor was 37.6 ± 0.1°C, PR was 112 ± 3 beats/min, and MAP was 84 ± 6 mmHg. In the non-CF group, Tor was 37.5 ± 0.1°C, PR was 85 ± 6 beats/min, and MAP was 72 ± 4 mmHg. Comparisons between the groups showed that maximal PR in the CF group was significantly higher (P < 0.05); however, neither Tor nor MAP differed significantly between the CF and non-CF groups (P > 0.05 between groups).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
In their original paper, Savage et al. reported the increase in SkBF in CF patients during heat stress to be normal, despite sparse VIP in skin as revealed by skin biopsies (31). Based on these results, they concluded that VIP was not a contributor to cutaneous active vasodilation. This conclusion did not entertain the possibility that both VIP and ACh could act as redundant cotransmitters. In such a setting, ACh could be released in increased quantities or with increased effect (i.e., receptor sensitivity) to mask the lack of VIP. We sought to take the same advantage of the paucity of VIP in cutaneous neurons of CF patients to learn more about such potential redundancies of the active vasodilator cotransmitter system. Cotransmitter systems can be redundant, whereby increased effects of one cotransmitter will compensate for reduced effects of another cotransmitter (1). Our approach was based on the knowledge that CF patients have a biopsy-proven paucity of VIP-containing neurons in their skin when compared with non-CF persons (11, 31) and that there is evidence to support VIP as a mediator of cutaneous active vasodilation (2). We reasoned that if cutaneous active vasodilation is a composite of VIP and ACh actions, then in CF patients a deficiency of VIPergic neurotransmission would be compensated for by an augmented role for ACh. Such a redundant compensatory mechanism would explain how the SkBF response to heat stress could appear to be normal, despite the documented paucity of the presumed cotransmitter, VIP. Furthermore, if CF patients were more dependent on ACh for cutaneous active vasodilation, then heat stress-induced increases in SkBF in CF would be attenuated to a greater extent by atropine, a selective inhibitor of muscarinic receptors. Our finding of no significant differences in the effects of atropine on active vasodilator responses between CF and non-CF groups suggests that an enhanced role for ACh-mediated vasodilation does not occur during heat stress in CF, a finding that is incompatible with the foregoing proposal.

Our results mirror those of Wilkins et al. (43) in CF, who hypothesized that preserved SkBF responses to heat stress could be preserved in CF through enhanced nitric oxide (NO)-dependent vasodilation to compensate for sparse cutaneous VIP. NO has been well documented to play a role in the cutaneous active vasodilator response to heat stress (18, 21, 32–34, 42). Wilkins et al. used delivery on the NO synthase inhibitor NG-nitro-L-arginine (L-NAME) to antagonize NO production in a heat stress protocol very similar to ours. They found that cutaneous active vasodilator responses to a Tor increase of 0.8°C was similar during heat stress in CF and non-CF subjects at L-NAME treated and untreated sites. They concluded that enhanced NO-dependent mechanisms do not explain normal cutaneous active vasodilator responses in CF. The findings of Wilkins et al. and those of the present study exclude NO-dependent and ACh-dependent mechanisms as mediators of preserved cutaneous active vasodilation in CF.

One explanation for our failure to find different effects of atropine on cutaneous active vasodilation in CF is that VIP is not a major contributor to increased SkBF during heat stress. Although in our hands, the VIP antagonist VIP10—28 reduced the vasodilator response to heat stress, it is also true that the role of VIP as a major effector of cutaneous active vasodilation has been questioned (41, 44). Wilkins et al. (41, 44) were unable to replicate antagonist properties of VIP10—28 in human skin during heat stress, thus shedding doubt on the role of VIP as an active vasodilation cotransmitter.

A second possibility is that a cotransmitter other than VIP is involved in cutaneous active vasodilation. Among the neuropeptides found in skin is substance P (36). Substance P is a potent vasodilator and is found in normal levels in cutaneous nerves of CF patients (31). Recently Wong, et al. (45) provided evidence favoring neurokinin type 1 receptor involvement, suggesting substance P involvement in cutaneous active vasodilation. Certainly, substance P has vasodilator properties, however, it has not been found colocalized with ACh or in other than sensory nerves, so how substance P could play a role in the mechanism for cutaneous active vasodilation needs clarification (14).

Another neuropeptide found in normal levels in the skin of CF patients is CGRP (31). Skin biopsies of CF patients showed that CGRP occurs in normal levels in nerves surrounding blood vessels and sweat glands (31). Exogenous CGRP is a potent cutaneous vasodilator in humans (13, 40); however, like substance P, CGRP is primarily located in cutaneous sensory nerves (9).

Alternatively, other agents such as histamine (46) and/or prostaglandins (25) could make up for sparse VIPergic cutaneous innervation in CF (17). Attenuation of cutaneous active vasodilation during heat stress has also been reported during blockade of prostaglandin production (25) and by histamine type 1 receptor antagonists (46). Either of those agents could play an augmented role in CF.

Given our results, we can exclude the simple hypothesis that AVD is mediated by a relatively simple dual cotransmitter system involving VIP and ACh. It seems quite likely that cutaneous active vasodilation involves multiple transmitters from the foregoing candidates. Given that there is evidence favoring each of several, such a scenario is supportable, but portends difficulty in studying such a multiply redundant system.

For ethical reasons, all volunteers of our CF group were continued on their physician-prescribed medications. The numbers of medications and dosages varied somewhat among CF subjects; however, several CF subjects were taking one or more medications with known anticholinergic effects such as metoclopramide. The increased PR in normothermia in the CF group is consistent with a systemic anticholinergic effect. In addition, the failure of peripheral administration of atropine to alter {Delta}Tor in CF may relate to systemic anticholinergic effects of drugs present in this group. Whether the chronic use of such medications leads to alterations in the cutaneous active vasodilator system and cutaneous vascular responses to heat stress is uncertain, but this possibility should be entertained before drawing conclusions about the physiology of the cutaneous active vasodilator system from our study.

The lack of significant effects of atropine on cutaneous active vasodilation in the CF group does have clinical implications. Because CF patients are not particularly more dependent on ACh-mediated cutaneous vasodilation in response to heat challenges, use of drugs with anticholinergic effects does not appear to place them at increased risk of heat-related illness compared with non-CF persons. In particular, because the only physiologically active cholinergic receptors in cutaneous blood vessels are muscarinic (20), agents with muscarinic antagonist properties do not appear to be more problematic in their effects on cutaneous active vasodilation in CF.

Overall, our results showed that atropine did not abolish cutaneous active vasodilation during heat stress in CF. Since this muscarinic antagonist had similar effects in CF and non-CF persons, we conclude that dependence of cutaneous active vasodilation on cholinergic nerve release of ACh and muscarinic receptor sensitivity during heat stress does not differ between CF and non-CF persons.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-065599 (to D. L. Kellogg) and HL-059166 (to J. M. Johnson).


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors thank the volunteers for their participation and cooperation.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. L. Kellogg, Jr., Div. of Geriatrics and Gerontology, Dept. of Medicine, Univ. of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229 (e-mail: kelloggd{at}uthscsa.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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