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J Appl Physiol 99: 2266-2270, 2005. First published July 21, 2005; doi:10.1152/japplphysiol.00271.2005
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Clonidine induces nitric oxide- and prostaglandin-mediated vasodilation in healthy human skin

Daniel Hermann, Tanja Schlereth, Thomas Vogt, and Frank Birklein

Department of Neurology, University of Mainz, Mainz, Germany

Submitted 7 March 2005 ; accepted in final form 18 July 2005


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Sustained sympathetic activation not only leads to vasoconstriction but also might induce paradox vasodilation. This study was performed to explore whether and how {alpha}2-receptor stimulation mediates this vasodilation. We investigated 11 healthy subjects in 33 dermal microdialysis (MD) sessions. After nerve trunk blockade, MD fibers were inserted and perfused with physiological saline until skin trauma-related vasodilation subsided. Thereafter, fibers were perfused with either clonidine solutions (10–3, 5 x 10–4, 10–4 mol/l), NG-monomethyl-l-arginine (L-NMMA; nitric oxide synthase blocker), acetylsalicylic acid (ASA; cyclooxygenase blocker), or combinations of these. Laser-Doppler scanning of the investigated skin revealed that clonidine not only induces vasoconstriction but subsequently also vasodilation with higher concentrations (P < 0.001). In contrast, both L-NMMA and ASA induced vasoconstriction (P < 0.001). By coapplication of 10–3 mol/l clonidine with L-NMMA or ASA, vasodilation was partially prevented (P < 0.001). Our results demonstrate that sustained {alpha}2-receptor stimulation induces vasodilation in a dose-dependent way, which is mediated by nitric oxide and prostaglandin mechanisms in human skin.

dermal microdialysis; sympathetic nervous system; alpha-adrenoreceptors; laser-Doppler imaging

VASOCONSTRICTION IN HUMAN blood vessels is mainly controlled by the sympathetic nervous system and the perivascular and adrenal release of catecholamines like norepinephrine or epinephrine. Under physiological conditions, sympathetic activity is essential for the maintenance of thermoregulation and blood pressure (15). Originally, norepinephrine receptors were subdivided into postsynaptically located {alpha}1-receptors and presynaptically located {alpha}2-receptors. However, detailed investigations revealed that there are also postsynaptic {alpha}2-receptors, in particular on cutaneous blood vessels. The {alpha}2-receptors, which are located on smooth muscle cells, predominantly mediate cold-induced vasoconstriction (7). There are, however, further {alpha}2-receptors located on endothelial cells inside blood vessels. In rodents, it has been shown that activation of these {alpha}2-receptors by sympathetic excitation simultaneously induces release of nitric oxide (NO), a strong vasodilator (4). Furthermore, activation of {alpha}2-receptors on endothelial cells also activates the release of prostacyclin, a possible alternative mechanism of smooth muscle relaxation (27). In vivo experiments in human skin have shown that endogenous NO attenuates vasoconstriction, which is induced by cutaneous injection of norepinephrine (5).

Some counteraction of catecholamine-induced vasoconstriction seems to be necessary. Otherwise, sustained activation of the sympathetic nervous system, e.g., during fear, stress, or prolonged exposure to cold, could induce hypoxia, in particular in the extremities. Hypoxia then induces local vasodilation probably by local {beta}-adrenergic or NO mechanisms (36). For cold-induced vasoconstriction, revasodilation in human skin has already been observed (1).

In the present investigation, we aimed to explore possible vasodilator mechanisms in human skin in which the sympathetic nervous system could be involved. On the basis of previous studies (13), {alpha}2-receptor on endothelial cells should be the right targets for our investigation. We therefore applied clonidine (CL), a preferentially {alpha}2-receptor agonist, which has been shown to be efficacious in rodent studies and which is available for human investigation. To further unravel the mechanisms of possible CL-induced vasodilation, we subsequently blocked endothelial second messengers, e.g., NO and prostaglandin (5). Stimulation of {alpha}1-receptors, which are located mainly on vascular smooth muscle cells, for the investigation of adrenergic vasodilation is unhelpful. In previous studies {alpha}1-receptor stimulation invariably led to vasoconstriction (23, 38).


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects.   Eleven healthy volunteers (all men) with an average age of 25.5 yr (range 24–29 yr) were investigated. All subjects participated three times, resulting in a total of 88 microdialysis (MD) fibers for perfusion analysis. The study was performed in a temperature (22°C)- and humidity (50% relative humidity)-controlled laboratory after a period of acclimatization of at least 30 min. The subjects' arms rested at heart level and were fixed in a vacuum cushion. Skin temperature at the forearm was measured before and after each experiment using an infrared thermometer and was found to be constant (32.2 ± 0.24 and 32.1 ± 0.24°C, respectively). Written, informed consent was obtained from all participants, and the study was approved by the local ethics committee.

Dermal microdialysis.   Dermal microdialysis was performed according to our previous study (38). In brief, the nerve trunk of the superficial branch of the radial nerve was blocked with 2% lidocaine. Thereby dorsal root reflexes and efferent sympathetic activity were blocked, and the fibers could be inserted pain free. Sterile MD fibers were inserted intradermally into the anaesthetized skin to a length of 1.5 cm. Three to six plasmapheresis fibers (depending on the area of analgesic skin) were inserted, and a distance of at least 1 cm was kept between each fiber. Some more fibers than necessary were initially inserted, because there is always a risk that some MD fibers might not operate properly. MD fibers were perfused with only one drug concentration. During the baseline period, which lasted 1 h, fibers were perfused with physiological saline employing a microdialysis pump (model PHD 2000, Harvard Apparatus) and a constant flow rate of 4 µl/min.

In a first series of experiments after the baseline, we switched the perfusion medium to CL (Sigma-Aldrich, Munich, Germany) dissolved in saline for a period of 30 min, at a concentration of 10–3 mol/l (total of n = 11 fibers), 5 x 10–4 mol/l (n = 11 fibers), or 10–4 mol/l (n = 11 fibers). Because local vasodilation occurred only with higher concentration of CL (see RESULTS), in a second series of experiments we applied NG-monomethyl-L-arginine 10–2 mol/l (L-NMMA; Sigma-Aldrich, Munich, Germany) or 10–2 mol/l acetylsalicylic acid (ASA; Bayer, Leverkusen, Germany) in saline for 30 min. Thereafter, in a third series of experiments, we mixed either L-NMMA or ASA with 10–3 mol/l CL (n = 11 each).

Laser-Doppler imaging.   Laser-Doppler imaging (LDI) technique (Moor Instruments, London, UK) was used to obtain pictures of skin perfusion. The distance between the LDI and the skin was 50 cm. A rectangular area covering the skin where the MD fibers were inserted was scanned. Each scan area was individually adjusted. Scans took 59.8 ± 2.1 s on average, and scan speed was 4 ms/pixel. LDI pictures were recorded every 15 min during the baseline period and every 4 min during the stimulation period.

On the basis of visual screening of LDI pictures, we made the decision to quantify skin blood flow in a rectangular area (2 x 10 mm) directly above the MD fiber. The mean blood flow in perfusion units was calculated using dedicated software offline (Moor LDI image processing, Moor Instruments). For statistical analysis, flux values were normalized and expressed as percent change of baseline (last picture before stimulation).

Data analysis.   For statistical evaluation, multivariate ANOVA for repeated measures (7 pictures during drug application) was calculated. Main factors were the course of vasoconstriction (subsequent pictures, within-subject factor), the different concentrations of CL (10–3, 5 x 10–4, 10–4 mol/l), and the effects of L-NMMA and ASA (between-subjects factors). To allocate significant differences, Scheffé's post hoc test was performed. For planned comparisons of single time points, one-way ANOVAs with Scheffé's post hoc tests were calculated. In the paper, all values are presented as means ± SE. Statistical significance is considered at P < 0.05.


   RESULTS
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 MATERIALS AND METHODS
 RESULTS
DISCUSSION
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CL-induced vascular effects.   Insertion of the MD fibers caused skin trauma, and related vasodilation was observed. During baseline perfusion with saline, this vasodilation steadily subsided and skin blood flow reached a plateau after 60 min, as has been described previously (38). Then, perfusion medium was switched to different CL solutions. CL at concentrations of 10–3, 5 x 10–4, and 10–4 mol/l initially (4-min picture) induced vasoconstriction, which did not differ between the different concentrations (n = 11; 10–3 mol/l: 39.5 ± 3.1%, 5 x 10–4 mol/l: 44.2 ± 3.6% and 10–4 mol/l: 34.3 ± 3.1%; F = 2.33, not significant).

Thereafter, blood flow curves diverge (F = 18.23, P < 0.001). CL at the higher concentrations (10–3, 5 x 10–4 mol/l) induced vasodilation (after 28 min: 10–3 mol/l, 76.2 ± 6.4%; 5 x 10–4 mol/l, 55.2 ± 5.7%; 10–4 mol/l, 29.7 ± 2.4%). Post hoc analysis of the whole curve revealed significant differences between 10–4 mol/l CL and both 10–3 mol/l CL (P < 0.001) and 5 x 10–4 mol/l CL (P < 0.005). Planned comparisons revealed that in addition there were significant differences between 10–3 and 5 x 10–4 mol/l CL from 20 min on (20 min, P < 0.03; 24 min, P < 0.05; 28 min, P < 0.03). For details, see Figs. 1 and 2.



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  		Fig. 1. Photograph of microdialysis fibers inserted in the skin (left) and the corresponding laser-Doppler picture (right) showing an increase of skin blood flow directly at the 10–3 mmol clonidine (CL) application site (bright pixels). Rectangle indicates area of skin blood flow quantification.

 


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  		Fig. 2. Skin blood flow at skin overlying microdialysis membranes during 28 min of perfusion with CL. Flux values are expressed as mean percent change of baseline skin blood flow. Error bars represent SE. CL-induced vasoconstriction after 4 min did not differ between different concentrations of CL. Thereafter, however, curves differed significantly. Both 10–3 and 5 x 10–4 mol/l CL induced a significant vasodilation compared with CL 10–4 mol/l (ANOVA, brackets indicate main effects). *Post hoc analysis further revealed significant differences (P < 0.05) between 10–3 and 5 x 10–4 mol/l CL from 20 min on. NS, not significant.

 
L-NMMA- and ASA-induced vascular effects.   Both L-NMMA (51.6 ± 4.3% after 28 min) and ASA (53.9 ± 5.0% after 28 min; n = 11; F = 14.71, P < 0.001) significantly reduced skin blood flow compared with saline (Fig. 3). Post hoc tests revealed significant differences between saline and L-NMMA (P < 0.001) and saline and ASA (P < 0.005).



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  		Fig. 3. Both NG-monomethyl-l-arginine (L-NMMA) and acetylsalicylic acid (ASA) reduced skin blood flow. Flux values are expressed as mean percent change of baseline skin blood flow. Error bars represent SE. There was a significant difference between L-NMMA or ASA and saline as indicated by the brackets (ANOVA, main effect).

 
Inhibition of CL-induced vasodilation by L-NMMA and ASA.   For the investigation whether L-NMMA or ASA affects CL-induced vasodilation, we focused on 10–3 mol/l CL perfusion, because this concentration revealed greatest effects. Simultaneous perfusion of CL with ASA or L-NMMA partially prevented vasodilation (F = 9.31, P < 0.001; Fig. 4). After 28 min, the values were 76.2 ± 6.4% for CL, 53.3 ± 5.6% for CL + L-NMMA, and 67.0 ± 7.0% for CL + ASA. Post hoc test revealed significant differences between CL and CL + L-NMMA (P < 0.001) or CL + ASA (P < 0.05). There was, however, no significant difference between CL + L-NMMA and CL + ASA.



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  		Fig. 4. Coapplication of 10–3 mol/l CL and L-NMMA or ASA partially prevented vasodilation. For CL, same data are depicted as in Fig. 2. Flux values are expressed as mean percent change of baseline skin blood flow. Error bars represent SE. Statistical analysis revealed significant differences between CL and both CL + L-NMMA and CL + ASA (indicated by brackets, ANOVA, main effect). There was no difference between L-NMMA and ASA.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The present investigation shows that the {alpha}2-agonist clonidine (CL) not only induced vasoconstriction but also vasodilation in healthy human skin, in vivo. Vasodilation was dose dependent and restricted to skin areas with highest CL concentrations close to the MD membranes. Blocking NO synthase (NOS) by NMMA and cyclooxygenase (COX) by ASA suggested that both NO and prostaglandins contribute to CL-induced vasodilation in human skin.

CL-induced vasoconstriction.   Our results indicate that CL delivered to the interstitial space by dermal MD first induces vasoconstriction. This vasoconstriction is of the same intensity as when phenylephrine (an {alpha}1-receptor agonist) was delivered (38). That means that CL from MD fibers first binds to {alpha}2-receptors on smooth muscles of arterioles, which mediate vasoconstriction and skin blanching. This is in accordance with former in vitro studies on human subcutaneous resistance vessels showing that postsynaptic vasoconstrictive {alpha}2-receptors are present on arterioles (29). Although newer studies in general revealed a predominance of adrenergic {alpha}1-receptors compared with {alpha}2-receptors mediating vasoconstriction in humans, obviously the {alpha}2-receptor component crucially depends on the investigated vascular bed (16). In the skin, {alpha}2-mediated vasoconstriction is very important (7, 35), because temperature is able to modify the {alpha}2-receptor response. This is significant for thermoregulation. Therefore, we performed our experiments on acclimatized subjects and under constant temperature conditions.

CL-induced vasodilation.   After initial vasoconstriction, continuous delivery of CL then leads to vasodilation already after a few minutes in the present study. The switch from vasoconstriction to vasodilation strongly depends on CL concentration in the perfusate. The concentration of 10–4 mol/l CL did not induce vasodilation, 5 x 10–4 mol/l CL induced moderate, and 10–3 mol/l CL induced more pronounced vasodilation. This means the concentration range between very different reactions, maximum vasoconstriction and maximum vasodilation, is narrow. Clinically, CL is used as an antihypertensive drug. It is shown that CL preferentially activates central postsynaptic and peripheral presynaptic {alpha}2-receptors (22) and thereby reduces sympathetic activity (21). More recently, it has been demonstrated that by binding to endothelial {alpha}2-D receptors CL also induces vasodilation, and that this might amplify the antihypertensive action of CL (13). The vasodilatory effect of activation of endothelial {alpha}2-receptors has been demonstrated in rats (3) and pigs (2). The most important second messengers mediating vasodilation in humans might be NO (5) and prostaglandins (30) (28). The endothelial {alpha}2-receptor is a G protein-coupled receptor, which activates endothelial NOS, and NO is produced from L-arginine (12, 25). When NO is released from endothelium cells, it diffuses to the vascular smooth muscles and mediates vasodilation via cGMP, as has been shown for human skin (8). Consequently, intracellular Ca2+ and the sensitivity of the contractile system to Ca2+ decrease, leading to relaxation of the smooth muscle cells (6). The exact mechanism of {alpha}2-receptor coupling to prostaglandin synthesis is not clear. However, it is known that prostaglandins are produced in endothelial cells by activation of phospholipase A2, COX, and prostacyclin synthase. After diffusion, prostaglandins mediate relaxation of smooth muscle cells and thereby induce vasodilation, which again is Ca2+ dependent (37). According to our results, both mechanisms significantly contribute to vascular tone at rest. Otherwise, the significant reduction of skin blood flow during inhibition of endothelial NOS by L-NMMA and during inhibition of COX by ASA could not be explained. Moreover, NO and prostaglandins might also contribute to CL-induced and {alpha}2-receptor-mediated vasodilation. In our study, inhibition of NOS reduced CL-induced vasodilation by 22.9% and inhibition of COX by 9.2%. Although we found no statistically significant difference, it is likely that NO is more important. Unfortunately we did not simultaneously apply L-NMMA and ASA, because adding up both inhibitory effects (see Fig. 4) might theoretically explain CL-induced vasodilation. Therefore, we must discuss further mechanisms that could contribute to CL-induced vasodilation. First, CL binds not exclusively to {alpha}2-receptors but also to {alpha}1-receptors. Although {alpha}1-receptor-mediated vasodilation has not been shown in humans, more specific {alpha}2-receptor agonists like medotomidine or UK-14304 (17, 26) would have been advantageous. Second, high doses of CL, similar as it has been shown for high doses of phenylephrine (34), might exert some {beta}-receptor-mediated vasodilation. However, unlike phenylephrine CL is an imidazoline and usually has no pharmacologically relevant {beta}-adrenergic affinity. Third, CL binds to peripheral presynaptic {alpha}2-receptors and thereby might decrease the release of norepinephrine from peripheral sympathetic neurons (34). Because our investigations were performed under nerve trunk blockade, which outlasts the MD experiments, this explanation is also very unlikely to explain our results. Fourth, CL interacts not only with {alpha}-receptors but also with imidazoline receptors (9, 20, 31). Located in the rostral ventrolateral medulla, imidazoline-receptor binding contributes to the antihypertensive effect of CL (10). Interestingly, imidazoline-receptor subtypes were also found in peripheral blood vessels (32). However, the role of imidazoline receptors in regulation of local blood flow in human skin remains unclear (33). Fifth, a very different mechanism of vasodilation in the skin depends on the activation of primary afferent nociceptive fibers, which then release vasodilator neuropeptides: the flare response (24). In previous studies, it has been shown that C-fiber excitation might occur during catecholamine iontophoresis (11). Accordingly, one might speculate that CL binds to and stimulates {alpha}2-receptors on primary afferent neurons and thereby induces flare vasodilation. There are, however, some arguments against this hypothesis. The morphology of a flare would be quite different from the vasodilation observed in our study. Vasodilation in our study appeared as a reddish line (bright line in Fig. 1) corresponding to the highest CL concentration in the close vicinity of microdialysis membranes. In contrast, a flare would spread into the whole innervation territory of related axons (18). Furthermore, intradermal application of {alpha}-agonists into healthy human skin is not painful (38). After nerve injury, however, this might be basically different because in such patients sympathetically maintained pain has been demonstrated (19). Finally, we must consider that the attenuation of the CL response by L-NMMA or ASA could be simply the coincidence of vasodilation and vasoconstriction, which does not depend on a causal relationship. This, however, would be in contrast to previous animal and human data (13).

In a companion study, we investigated the role of adrenoreceptors in the flare response, and consistent with the present investigation we also did not detect adrenoreceptor-induced flare responses (38). In this previous investigation using comparable methods, we applied different doses of epinephrine, phenylephrine, and CL. In that study, we also measured adrenoreceptor-induced vasoconstriction but did not detect vasodilation after the application of 10–3 mol/l CL. At the first glance, this might be a contradiction. There are, however, good arguments to rebut this contradiction. The vascular reaction induced by CL obviously depends on the amount of CL that is delivered to the tissue. Both studies were performed under similar conditions, but we used differentially prepared (e.g., sterilized) MD membranes. This suffices to slightly affect CL tissue concentrations. As explained above, concentration range inducing vasoconstriction or vasodilation is narrow. Therefore, both studies are not really comparable, which is not a drawback because we never intended to compare both investigations.

Independent of the exact mechanisms, it is remarkable that CL is able to induce vasodilation in human skin at all. Our data suggest a possible interaction of sympathetic vasoconstrictor mechanisms and endothelium-related vasodilation. In rats, coupling of sympathetic excitation and NO release from endothelial cells has been described for mesenteric (4) and skeletal muscle arterioles but not for skin vessels (14). Obviously, skin perfusion in hairy rodents is differently organized from skin perfusion in more or less hairless humans. One main question remains: whether or not sympathetic activation also leads to (probably less pronounced) endothelial vasodilation, as high doses of CL did in our study. We cannot answer this question with our data. However, if there would be really dual responses, it offers an explanation for vasodilation, which is sometimes observed in neuropathic pain despite an obvious increase in sympathetic outlflow.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This work was supported by Deutsche Forschungsgemeinschaft Grants Bi 579-1 and Bi 579-4.


   ACKNOWLEDGMENTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank Stuart Turner for help with the manuscript preparation.

This study contains parts of the MD thesis of D. Hermann, which will be submitted to the Faculty of Medicine, Johannes Gutenberg-University, Mainz, Germany.


   FOOTNOTES
 

Address for reprint requests and other correspondence: F. Birklein, Neurologische Klinik, Universität Mainz, Langenbeckstrasse 1, D-55101 Mainz, Germany (e-mail: birklein{at}neurologie.klinik.uni-mainz.de)

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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 MATERIALS AND METHODS
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  1. Bergersen TK, Hisdal J, and Walloe L. Perfusion of the human finger during cold-induced vasodilatation. Am J Physiol Regul Integr Comp Physiol 276: R731–R737, 1999.[Abstract/Free Full Text]
  2. Bockman CS, Gonzalez-Cabrera I, and Abel PW. Alpha-2 adrenoceptor subtype causing nitric oxide-mediated vascular relaxation in rats. J Pharmacol Exp Ther 278: 1235–1243, 1996.[Abstract/Free Full Text]
  3. Bockman CS, Jeffries WB, and Abel PW. Binding and functional characterization of alpha-2 adrenergic receptor subtypes on pig vascular endothelium. J Pharmacol Exp Ther 267: 1126–1133, 1993.[Abstract/Free Full Text]
  4. Boric MP, Figueroa XF, Donoso MV, Paredes A, Poblete I, and Huidobro-Toro JP. Rise in endothelium-derived NO after stimulation of rat perivascular sympathetic mesenteric nerves. Am J Physiol Heart Circ Physiol 277: H1027–H1035, 1999.[Abstract/Free Full Text]
  5. Bruck H, Gossl M, Spitthover R, Schafers RF, Kohnle M, Philipp T, and Wenzel RR. The nitric oxide synthase inhibitor L-NMMA potentiates noradrenaline-induced vasoconstriction: effects of the alpha2-receptor antagonist yohimbine. J Hypertens 19: 907–911, 2001.[CrossRef][ISI][Medline]
  6. Carvajal JA, Germain AM, Huidobro-Toro JP, and Weiner CP. Molecular mechanism of cGMP-mediated smooth muscle relaxation. J Cell Physiol 184: 409–420, 2000.[CrossRef][ISI][Medline]
  7. Chotani MA, Flavahan S, Mitra S, Daunt D, and Flavahan NA. Silent alpha(2C)-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am J Physiol Heart Circ Physiol 278: H1075–H1083, 2000.[Abstract/Free Full Text]
  8. Clough GF. Role of nitric oxide in the regulation of microvascular perfusion in human skin in vivo. J Physiol 516: 549–557, 1999.[Abstract/Free Full Text]
  9. Coupry I, Lachaud V, Podevin RA, Koenig E, and Parini A. Different affinities of alpha 2-agonists for imidazoline and alpha 2-adrenergic receptors. Am J Hypertens 2: 468–470, 1989.[ISI][Medline]
  10. Dominiak P. Historic aspects in the identification of the I1 receptor and the pharmacology of imidazolines. Cardiovasc Drugs Ther 8, Suppl 1: 21–26, 1994.
  11. Drummond PD. Prior iontophoresis of saline enhances vasoconstriction to phenylephrine and clonidine in the skin of the human forearm. Br J Clin Pharmacol 54: 45–50, 2002.[CrossRef][ISI][Medline]
  12. Duran WN, Seyama A, Yoshimura K, Gonzalez DR, Jara PI, Figueroa XF, and Boric MP. Stimulation of NO production and of eNOS phosphorylation in the microcirculation in vivo. Microvasc Res 60: 104–111, 2000.[CrossRef][ISI][Medline]
  13. Figueroa XF, Poblete MI, Boric MP, Mendizabal VE, Adler-Graschinsky E, and Huidobro-Toro JP. Clonidine-induced nitric oxide-dependent vasorelaxation mediated by endothelial alpha(2)-adrenoceptor activation. Br J Pharmacol 134: 957–968, 2001.[CrossRef][ISI][Medline]
  14. Habler HJ, Wasner G, and Janig W. Attenuation of neurogenic vasoconstriction by nitric oxide in hindlimb microvascular beds of the rat in vivo. Hypertension 30: 957–961, 1997.[Abstract/Free Full Text]
  15. Henriksen O. Sympathetic reflex control of blood flow in human peripheral tissues. Acta Physiol Scand Suppl 603: 33–39, 1991.[Medline]
  16. Jarajapu YP, Johnston F, Berry C, Renwick A, McGrath JC, MacDonald A, and Hillier C. Functional characterization of alpha1-adrenoceptor subtypes in human subcutaneous resistance arteries. J Pharmacol Exp Ther 299: 729–734, 2001.[Abstract/Free Full Text]
  17. Jie K, van Brummelen P, Vermey P, Timmermans PB, and van Zwieten PA. Identification of vascular postsynaptic alpha 1- and alpha 2-adrenoceptors in man. Circ Res 54: 447–452, 1984.[Abstract/Free Full Text]
  18. Kramer HH, Schmelz M, Birklein F, and Bickel A. Electrically stimulated axon reflexes are diminished in diabetic small fiber neuropathies. Diabetes 53: 769–774, 2004.[Abstract/Free Full Text]
  19. Kress M and Fickenscher H. Infection by human varicella-zoster virus confers norepinephrine sensitivity to sensory neurons from rat dorsal root ganglia. FASEB J 15: 1037–1043, 2001.[Abstract/Free Full Text]
  20. Lachaud V, Coupry I, Podevin RA, Dausse JP, Koenig E, and Parini A. Interaction of clonidine and rilmenidine with imidazoline-preferring receptors. J Hypertens Suppl 6: S511–S513, 1988.[CrossRef][Medline]
  21. Langer SZ. 25 years since the discovery of presynaptic receptors: present knowledge and future perspectives. Trends Pharmacol Sci 18: 95–99, 1997.[CrossRef][Medline]
  22. Langer SZ, Cavero I, and Massingham R. Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents. Hypertension 2: 372–382, 1980.[Abstract/Free Full Text]
  23. Langer SZ and Hicks PE. Alpha-adrenoreceptor subtypes in blood vessels: physiology and pharmacology. J Cardiovasc Pharmacol 6, Suppl 4: S547–S558, 1984.[ISI][Medline]
  24. Lewis T. The nocifensor system of nerves and its reactions. Br Med J 1: 431–437, 1937.[ISI]
  25. Liao JK and Homey CJ. The release of endothelium-derived relaxing factor via alpha 2-adrenergic receptor activation is specifically mediated by Gi alpha 2. J Biol Chem 268: 19528–19533, 1993.[Abstract/Free Full Text]
  26. MacDonald E, Kobilka BK, and Scheinin M. Gene targeting–homing in on alpha 2-adrenoceptor-subtype function. Trends Pharmacol Sci 18: 211–219, 1997.[Medline]
  27. Moncada S and Vane JR. The role of prostacyclin in vascular tissue. Fed Proc 38: 66–71, 1979.[ISI][Medline]
  28. Neisius U, Olsson R, Rukwied R, Lischetzki G, and Schmelz M. Prostaglandin E2 induces vasodilation and pruritus, but no protein extravasation in atopic dermatitis and controls. J Am Acad Dermatol 47: 28–32, 2002.[CrossRef][ISI][Medline]
  29. Nielsen H, Thom SM, Hughes AD, Martin GN, Mulvany MJ, and Sever PS. Postjunctional alpha 2-adrenoceptors mediate vasoconstriction in human subcutaneous resistance vessels. Br J Pharmacol 97: 829–834, 1989.[ISI][Medline]
  30. Noon JP, Walker BR, Hand MF, and Webb DJ. Studies with iontophoretic administration of drugs to human dermal vessels in vivo: cholinergic vasodilatation is mediated by dilator prostanoids rather than nitric oxide. Br J Clin Pharmacol 45: 545–550, 1998.[CrossRef][ISI][Medline]
  31. Piletz JE, Zhu H, and Chikkala DN. Comparison of ligand binding affinities at human I1-imidazoline binding sites and the high affinity state of alpha-2 adrenoceptor subtypes. J Pharmacol Exp Ther 279: 694–702, 1996.[Abstract/Free Full Text]
  32. Regunathan S, Youngson C, Wang H, and Reis DJ. Imidazoline receptors in vascular smooth muscle and endothelial cells. Ann NY Acad Sci 763: 580–590, 1995.[Abstract]
  33. Serban DN, Nechifor M, and Slatineanu SM. Implications of imidazolines and imidazoline receptors role at the vascular level. Rev Med Chir Soc Med Nat Iasi 104: 37–44, 2000.[Medline]
  34. Torp KD, Tschakovsky ME, Halliwill JR, Minson CT, and Joyner MJ. {beta}-Receptor agonist activity of phenylephrine in the human forearm. J Appl Physiol 90: 1855–1859, 2001.[Abstract/Free Full Text]
  35. Vanhoutte PM and Flavahan NA. Effects of temperature on alpha adrenoceptors in limb veins: role of receptor reserve. Fed Proc 45: 2347–2354, 1986.[ISI][Medline]
  36. Weisbrod CJ, Minson CT, Joyner MJ, and Halliwill JR. Effects of regional phentolamine on hypoxic vasodilatation in healthy humans. J Physiol 537: 613–621, 2001.[Abstract/Free Full Text]
  37. White DG and Martin W. Differential control and calcium-dependence of production of endothelium-derived relaxing factor and prostacyclin by pig aortic endothelial cells. Br J Pharmacol 97: 683–690, 1989.[ISI][Medline]
  38. Zahn S, Leis S, Schick C, Schmelz M, and Birklein F. No {alpha}-adrenoreceptor-induced C-fiber activation in healthy human skin. J Appl Physiol 96: 1380–1384, 2004.[Abstract/Free Full Text]




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