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Am J Physiol Heart Circ Physiol 288: H1668-H1673, 2005. First published November 24, 2004; doi:10.1152/ajpheart.00415.2004
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Early vasodilator response to anodal current application in human is not impaired by cyclooxygenase-2 blockade

Maylis Tartas,1 Philippe Bouyé,1 Audrey Koïtka,3 Sylvain Durand,1 Yves Gallois,2 Jean Louis Saumet,3 and Pierre Abraham1

1Laboratory for Vascular Investigations and 2Laboratory of Biochemistry, University Hospital, and 3Centre National de la Recherche Scientifique UMR 6188, Physiology, University of Medicine, Angers Cedex, France

Submitted 10 May 2004 ; accepted in final form 18 November 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
It is generally acknowledged that cutaneous vasodilatation in response to monopolar galvanic current application would result from an axon reflex in primary afferent fibers and the neurogenic inflammation resulting from neuropeptide release. Previous studies suggested participation of prostaglandin (PG) in anodal current-induced cutaneous vasodilatation. Thus the inducible cyclooxygenase (COX) isoform (COX-2), assumed to play a key role in inflammation, should be involved in the synthesis of the PG that is released. Skin blood flow (SkBF) variations induced by 5 min of 0.1-mA monopolar anodal current application were evaluated with laser-Doppler flowmetry on the forearm of healthy volunteers treated with indomethacin (COX-1 and COX-2 inhibitor), celecoxib (COX-2 inhibitor), or placebo. SkBF was indexed as cutaneous vascular conductance (CVC), expressed as percentage of heat-induced maximal CVC (%MVC). Urinalyses were performed to test celecoxib treatment efficiency. No difference was found in CVC values at rest: 14.3 ± 4.0, 11.9 ± 3.2, and 10.9 ± 2.0% MVC after indomethacin, celecoxib, and placebo treatment, respectively. At 10 min after the onset of anodal current application, CVC values were 22.2 ± 4.9% MVC (not significantly different from rest) with indomethacin, 85.7 ± 15.3% MVC (P < 0.001 vs. rest) with celecoxib, and 70.4 ± 13.1% MVC (P < 0.001 vs. rest) with placebo. Celecoxib significantly depressed the urinary prostacyclin metabolite 6-keto-PGF1{alpha} (P < 0.05 vs. placebo). Indomethacin, but not celecoxib, significantly inhibited the anodal current-induced vasodilatation. Thus, although they are assumed to result from an axon reflex in primary afferent fibers and neurogenic inflammation, these results suggest that the early anodal current-induced vasodilatation is mainly dependent on COX-1-induced PG synthesis.

neurogenic inflammation; neuropeptide release; skin blood flow

ABNORMALITIES OF THE MICROCIRCULATION play a major role in the complication of diabetes (44) and are also observed in coronary heart disease (32). Thus noninvasive methods for assessing peripheral microvascular function are of considerable clinical interest. Continuous monopolar galvanic current application can be used to facilitate the migration of charged molecule migration across the skin and, thus, allows for the study of endothelium-dependent and non-endothelium-dependent vasodilatation. However, in the human, current induces a cutaneous vasodilatation that could interfere with assessment of microvascular function. Therefore, the study of underlying mechanisms involved in the cutaneous current-induced vasodilatation deserves further investigation.

It is generally acknowledged that the cutaneous vasodilatation in response to monopolar galvanic current application would result from an axon reflex (3, 15) and neurogenic inflammation (3). Indeed, this cutaneous vasodilatation is abolished under local anesthesia and largely decreased after desensitization of C-nociceptive fibers by chronic application of capsaicin cream (8). The axon reflex-related cutaneous vasodilatation relies on the local release, from primary afferent fibers, of neural mediators such as calcitonin gene-related peptide, substance P (16), and prostaglandin (PG) (31). PGs are likely essential for the axon reflex-related cutaneous vasodilatation induced by anodal current application, because the current-induced cutaneous vasodilatation is almost abolished by aspirin treatment (7). Aspirin impairs PG biosynthesis through the irreversible blockade of cyclooxygenase (COX) (41). Two isoforms of COX have been identified: COX-1, a constitutive isoform expressed in most cells, present under physiological conditions, and COX-2, an inducible isoform arising in response to inflammatory stimuli (4). Constitutive COX-1 is the enzyme involved in the basal flow in the uninjured state. On the other hand, the available literature is consistent with the assumption that vasodilatation induced during neurogenic inflammation and/or neuropeptide release depends on the inducible COX-2 isoform (17, 31, 39). In parallel with its effects on COX, aspirin could also impair the anodal current-induced vasodilatation by blocking the vanilloid receptors (VR1) (38) and/or by interfering with the function of acid-sensing ion channels (ASICs) (45), which are possibly involved in the response.

We aimed to confirm that cutaneous vasodilatation induced by anodal current application relies on PG. For this purpose, we studied the effects of the nonselective COX inhibitor indomethacin, which, in contrast to aspirin, has not been shown to have a direct effect on VR1 or ASICs. Then we aimed to test whether anodal current-induced vasodilatation relies on COX-2-dependent PG synthesis. For this purpose, we studied the effects of the COX-2-specific inhibitor celecoxib on anodal current-induced cutaneous vasodilatation.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects

Sixteen nonsmoking healthy volunteers with no clinical sign of, or risk factors for, vascular disease participated in the study. Anthropometric characteristics of subjects are summarized in Table 1. For 3 wk before each experiment, volunteers took no drugs other than those proposed in the protocols. This institutionally approved study was conducted in accordance with the Declaration of Helsinki. Before their participation, all subjects were informed of the methods and procedures and gave their written consent to participate.


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  		Table 1. Anthropometric data

 
Treatment

Treatment was started 3 days before each experiment to take into account the biological half-life of the drug, which was administered as nonidentifiable capsules, and was performed over 4 days. The last capsule was taken 2–2.5 h before the start of microvascular investigations. Treatment consisted of a single oral dose of 1) indomethacin (75 mg/day; Indocid, MSD), 2) celecoxib (200 mg/day; Celebrex, Monsanto), or 3) placebo (lactose, 0.21 mg/day; Chemistry of Angers Hospital). Previous studies showed that a single oral dose of 75 mg of indomethacin induced a significant suppression of urinary PGE2 excretion (10, 30), which is correlated with inhibition of PG synthesis. Furthermore, low oral doses of indomethacin reduce urinary excretion rates of thromboxane B2 and 6-keto-PGF1{alpha}, which are the stable urinary metabolites of thromboxane and prostacyclin, respectively, mainly synthesized through COX-1 and COX-2, respectively (13). Studies about COX-2-specific inhibitors have demonstrated a significant inhibition of PGE2 after a single oral dose of 100, 400, or 800 mg. Urinary excretion of 6-keto-PGF1{alpha} was depressed by celecoxib, whereas the excretion rate of thromboxane B2 was not statistically different from that of placebo (26).

The order of the treatments was chosen randomly, and subjects were blinded to the nature of the treatment proposed. To avoid any potential prolonged effects of previous experiments, experimental trials in the same subject were separated by ≥3 wk.

Protocols

Protocol 1. In protocol 1, subjects were treated with celecoxib, indomethacin, and placebo in a random order. The last capsule was taken at 7 AM on the day of microvascular investigation. All microvascular investigations were started between 9:00 and 9:30 AM.

Protocol 2. Because of the unexpected absence of effect of COX-2 inhibitor in protocol 1, protocol 2 was designed to confirm the efficiency of COX-2 inhibitor in PG synthesis at the dose used. In protocol 2, subjects were treated with celecoxib and placebo in a random order. The last capsule was taken at 9 AM on the day of microvascular investigation. Urinary collections were performed at 11 AM and 1 PM for urinalyses, and microvascular investigations were started between 11:15 and 11:30 AM.

Microvascular Investigations

We studied the effect on skin blood flow (SkBF) of anodal current application, through deionized water, on the volar aspect of the forearm. The technique has been extensively described elsewhere (7). Briefly, two laser-Doppler multifiber probes were connected to a laser-Doppler flowmeter (Periflux PF4001, Perimed). One ("active") probe (model PF481.1, Perimed) was specially designed to allow for SkBF measurements and local heating temperature through a regulated heating system (Peritemp PF4005, Perimed). The heating system allows for the heating of the active probe to 44°C to attain maximal cutaneous vasodilatation capacity (19, 33, 36, 40). The active probe has a circular chamber allowing for the positioning of an adhesive patch designed with an ~1.2-cm2 sponge (model PF383, Perimed). Before each experiment, the sponge was moistened with 0.2 ml of deionized water, and the patch with the active probe was fixed to the skin. The patch allowed for current application through the anodal terminal of a 9-V current intensity-regulated supplier (Periiont, Micropharmacology System, model PF382, Perimed). The cathodal terminal was connected to an Ag/AgCl disposable electrode (Care 610, Kendall, Neustadt, Germany) fixed 5 cm from the active probe. A schematic representation of the active probe is shown in Fig. 1. The second laser-Doppler ("reference") probe (model PF408, Perimed), positioned on the same volar aspect of the skin of the forearm, was used to control the stability of SkBF at an adjacent unstimulated site. Local cutaneous temperature was measured using a surface thermocouple probe connected to an electronic thermometer (model BAT-12, Physitemp Instruments, Clifton, NJ). The thermocouple was positioned 6 cm from the laser probes. Systemic arterial blood pressure was monitored using a Finapres 2350 (Ohmeda) positioned on the second or third finger of the hand contralateral to the sites of SkBF measurements.



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  		Fig. 1. Section view of the "active" probe used in experiments designed to allow simultaneous skin blood flow recording and local heating. Current is applied through a patch inserted in a circular chamber below the probe.

 
Microvascular investigations were performed in a quiet air-conditioned room with ambient temperature set at 24 ± 1°C. To avoid side effects, position of the probes on the forearm and arm (right or left) was chosen randomly for each microvascular investigation (14). The subjects were placed in a supine position and rested for 15 min before data collection. A resting period of 2 min was recorded at the beginning of each experiment before the start of current application. The current application consisted of transcutaneous delivery of a 0.1-mA anodal current for 5 min. After current application, a 20-min period was recorded. Thereafter, the skin under the active probe was warmed to 44°C for 24 min to attain maximal vasodilatation and limit the total duration of each experiment to <1 h.

Measurement

The laser-Doppler flowmeter technique has been shown to accurately monitor SkBF continuously (18, 34) and is not influenced by underlying muscle blood flow (35). Data were recorded on a computer via an analog-to-digital converter (Biopac System) with a sample frequency of 3 Hz. Because of instantaneous variability of vasomotion, individual laser-Doppler flowmeter signals were averaged over 15-s intervals throughout each experiment. To take into account possible changes in systemic hemodynamic conditions, SkBF was indexed as cutaneous vascular conductance (CVC) calculated as the ratio of SkBF expressed in arbitrary units to mean arterial blood pressure over the same 15-s interval. Maximal CVC in response to local heating represented the mean CVC values observed over the last minute of the heating period. Then CVC was normalized for each subject, with maximal CVC equal to 100% to better reflect changes in SkBF (20, 29), and results are expressed as percentage of heat-induced maximal CVC (%MVC).

To compare short- and long-term components of the response to current application, four points were analyzed: CVC at rest and at 5, 10, and 25 min, corresponding to the time before current application, the end of current application, and 5 and 20 min after the end of current application, respectively.

Urinalyses

A few milliliters of fresh urine were used to assess urinary density and creatine concentration, and 10 ml of urine were stored at –80°C for later urinalyses. We measured 11-dehydrothromboxane (Tx-M) and 6-keto-PGF1{alpha}, urinary metabolites of thromboxane and prostacyclin, respectively (12). Urine samples were assayed for specific PG with the use of enzyme immunoassay kits (Cayman Chemicals). Values from 11 AM and 1 PM and duplicate enzyme immunoassay analysis for each sample were averaged.

Statistical Analyses

SkBF is expressed in arbitrary units, and CVC values are means ± SE expressed as %MVC. CVC comparisons for indomethacin or celecoxib treatment vs. placebo treatment were performed with Student's unpaired t-test. Comparisons of CVC values at 5, 10, and 25 min with resting values were analyzed with a one-way ANOVA followed by a Newman-Keuls test. Results for urinalyses are presented as means ± SE and expressed as nanograms per millimole creatinine. Statistical comparisons of urinary results between placebo and celecoxib were made by using one-tailed paired t-test, with 95% confidence intervals.

Statistical analyses were performed with Prism (Prism 2.01, Graphpad). P ≤ 0.05 was considered significant in all statistical analyses.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Microvascular Investigations

Compared with resting values, no significant changes were observed for control SkBF at the reference probe, mean arterial blood pressure, and local skin temperature during each experiment.

Protocol 1

A typical recording of the vascular responses to 5 min of anodal current application with indomethacin or celecoxib or placebo treatment in the same subject is presented in Fig. 2. No significant vasodilatation was noted during current application with any treatment (Fig. 2).



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  		Fig. 2. Typical skin blood flow (SkBF) laser-Doppler recordings from 3 experiments [with indomethacin (A), celecoxib (B), and placebo (C)] in the same subject at rest (2 min) and during and 20 min after 5 min of 0.10-mA anodal current application (area between dashed vertical lines, Stim) and during local heating. AU, arbitrary units.

 
After the end of the 5-min anodal current application, a progressive vasodilatation appeared with placebo or celecoxib treatment (Fig. 2, B and C). This vasodilatation lasted throughout the recovery period. In contrast, indomethacin treatment (Fig. 2A) did not allow for development of the vasodilatation.

In the whole group, no difference was found in CVC values at rest: 14.3 ± 4.0, 11.9 ± 3.2, and 10.9 ± 2.0% MVC with indomethacin, celecoxib, and placebo, respectively. At 5 min after the onset of anodal current application, CVC values were 14.5 ± 3.1% MVC [P = not significant (NS) vs. rest] with indomethacin, 21.6 ± 7.3% MVC (P = NS vs. rest) with celecoxib, and 19.7 ± 3.8% MVC (P = NS vs. rest) with placebo. At 10 min after the onset of anodal current application, CVC values were 22.2 ± 4.9% MVC (P = NS vs. rest) with indomethacin, 85.7 ± 15.3% MVC (P < 0.001 vs. rest) with celecoxib, and 70.4 ± 13.1% MVC (P < 0.001 vs. rest) with placebo. At 25 min after the onset of anodal current application, CVC values were 18.9 ± 5.6% MVC (P = NS vs. rest) with indomethacin, 64.5 ± 17.7% MVC (P < 0.001 vs. rest) with celecoxib, and 73.0 ± 15.0% MVC (P < 0.001 vs. rest) with placebo. CVC values recorded with celecoxib or indomethacin treatment compared with placebo treatment at rest and at 5, 10 and 25 min after onset of current application are summarized in Fig. 3.



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  		Fig. 3. Cutaneous vascular response to 5 min of monopolar anodal current application with indomethacin, celecoxib, and placebo treatment. Response was studied at rest and 5, 10, and 25 min after the start of current application. Values are means ± SE, expressed as percentage of heat-induced maximal cutaneous vascular conductance (%MVC).

 
Protocol 2

As observed in protocol 1, after anodal current application, placebo and celecoxib produced a progressive vasodilatation that lasted throughout the recovery period. In the whole group, no differences were found in CVC values at rest: 12.5 ± 7.0 and 17.7 ± 9.0% MVC with celecoxib and placebo treatment, respectively. At 5 min after the onset of anodal current application, CVC values were 32.3 ± 7.9% MVC (P = NS vs. rest) with celecoxib and 30.7 ± 9.9% MVC (P = NS vs. rest) with placebo. At 10 min after the onset of anodal current application, CVC values were 63.3 ± 10.3% MVC (P < 0.001 vs. rest) with celecoxib and 69.2 ± 11.6% MVC (P < 0.01 vs. rest) with placebo. At 25 min after the onset of anodal current application, CVC values were 67.7 ± 10.5% MVC (P < 0.001 vs. rest) with celecoxib and 81.2 ± 8.8% MVC (P < 0.001 vs. rest) with placebo. After anodal current application, the vascular responses observed with celecoxib and placebo treatment in protocol 2 were comparable to those observed in protocol 1.

Concentration of Tx-M, reflecting COX-1-dependent PG synthesis, was not statistically different between celecoxib (65.2 ± 5.9 ng/mmol) and placebo (69.6 ± 5.9 ng/mmol) groups, whereas urinary 6-keto-PGF1{alpha} concentration was decreased with celecoxib compared with placebo: 61.6 ± 8.3 vs. 73.2 ± 7.8 ng/mmol (P < 0.05).


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The major finding of the present study is that the COX-2-specific inhibitor (celecoxib) resulted in no apparent inhibition of the cutaneous vasodilatation observed within 20 min after anodal current application, whereas nonspecific COX blockade with indomethacin significantly decreased this response, compared with placebo.

Durand et al. (7) showed that a single oral dose of 1 g of aspirin abolished the cutaneous vasodilatation induced by 5 min of anodal current application. This suggested a role for PG in the cutaneous vasodilatation induced by anodal current application, but the irreversible blockade of COX is not the sole action of aspirin. Aspirin is also able to block VR1 (38) and interfere with the function of ASICs, such as ASIC3 or ASIC2b/3 (45). Protons are known to be powerful activators of primary afferent fibers through VR1 and could also activate ASICs. Indeed, protons that could possibly be locally produced through water electrolysis by anodal current application have been proposed as candidates for primary afferent fiber excitation during anodal galvanic current application (9). Therefore, it could be proposed that blockade of anodal current-induced cutaneous vasodilatation by aspirin relies on VR1/ASIC impairment during the eventual excitation of primary afferent fibers by protons, rather than on COX blockade. In contrast to aspirin, indomethacin has not been reported as a potent direct VR1 blocker. In contrast to many nonsteroidal anti-inflammatory drugs, indomethacin has been shown to have no effect on ASICs (45). Therefore, we assume that the impairment of cutaneous vasodilatation induced by 5 min of anodal current application, observed with aspirin treatment in a previous study (9) and with indomethacin treatment in the present study, likely results from COX, rather than VR1 or ASIC, blockade.

Several studies have contributed to identification of COX isoforms and their roles. The constitutive isoform COX-1 is reported to be responsible for PG production in basal conditions and in the regulation of basal flow in physiological conditions (2, 6, 42). In contrast, COX-2 is the inducible isoform involved in inflammation (4, 5), notably neurogenic inflammation (17, 43). Although the cutaneous vasodilatation in response to anodal current application is assumed to result from a neurogenic inflammation (3), our results suggest that COX-2 is not essential for this vascular response, at least within 20 min after anodal current application. Because of the time required for synthesis of the inducible enzyme, whether COX-2 may participate later is undetermined and remains to be studied.

It could be suggested that the absence of significant reduction of anodal current-induced cutaneous vasodilatation by the COX-2-specific inhibitor could be due to an insufficient COX blockade. However, the dose used in the present study (200 mg) was in the range used to significantly inhibit COX-2 activity (11, 26). Furthermore, treatment started 3 days before the experiment allowed for a significant decrease in urinary excretion of 6-keto-PGF1{alpha}, whereas Tx-M excretion was unchanged. This result confirmed the efficiency of COX-2 inhibition. The early cutaneous vasodilatation induced by anodal current application observed with celecoxib does not exclude the possibility that COX-2 may participate in the underlying mechanisms of this response but suggested that it is mainly a COX-1-dependent phenomenon. This is consistent with recent clinical studies suggesting an important COX-1 contribution to inflammation and pain, showing that inhibition of both COX isoforms is more efficient in achieving an effective analgesia in inflammation than COX-2 blockade alone (24, 25). Although the current delivery was never reported to be painful by any of the subjects, it is well known that stimulation of C-nociceptive fibers in the range of the nociceptive threshold may induce a vascular response, even in the absence of pain perception (23). Whether, during C-nociceptive fiber excitation, COX contribution is different after painful or nonpainful stimulation remains to be confirmed. This would require further experiments.

A specific COX-1 inhibitor is available for in vitro or animal studies (37, 46) but not for oral use in humans. Although our results suggest COX-1 involvement in cutaneous vasodilatation induced by anodal current application, we cannot prove that the response results solely from COX-1 participation.

The unexpected physiological observation that indomethacin, but not celecoxib, interferes with the anodal current-induced cutaneous vasodilatation could be important for clinicians and researchers. To investigate microvascular function, iontophoresis coupled with laser-Doppler flowmetry is largely used. With the use of anodal current application, iontophoresis allows for delivery of positively charged drugs (e.g., acetylcholine) through the skin (1, 22, 27). Unfortunately, anodal iontophoresis through vehicles devoid of vasoactive properties results in a cutaneous vasodilatation. This so-called "nonspecific" current-induced cutaneous vasodilatation could interfere with the study of the microvascular response specifically due to the drug delivered. Indeed, Hamdy et al. (15) showed that the axon reflex-related vasodilatation significantly participates in the total response to acetylcholine delivered through anodal iontophoresis. Thus the exact part of the microvascular response specifically due to acetylcholine in the total microvascular response after acetylcholine iontophoresis remains difficult to assess. Results of the present study show a difference in sensitivity of anodal current-induced vasodilatation to COX-2-specific and COX-nonspecific inhibitors. This difference should likely be taken into account in the interpretation of studies using anodal iontophoresis for drug delivery.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This project was supported by region Pays de la Loire and Centre National de la Recherche Scientifique (UMR 6188) and by grants from Direction Regionale et Departementale de la Jeunesse et des Sport and Projet Hospitalier de Recherche Clinique 2001. The experiments were performed at the University Hospital in Angers. S. Durand is the recipient of a grant from Fondation Electricite de France.


   ACKNOWLEDGMENTS
 
The authors gratefully acknowledge Dr. Scott Davis for review of the English and Claire Demiot (Pharmacie d'Angers) for technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: P. Abraham, Laboratory of Vascular Investigations, Univ. Hospital, 49033 Angers Cedex, France (E-mail: piabraham{at}chu-angers.fr)

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
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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P. Rousseau, M. Tartas, B. Fromy, A. Godon, M.-A. Custaud, J. L. Saumet, and P. Abraham
Platelet inhibition by low-dose aspirin but not by clopidogrel reduces the axon-reflex current-induced vasodilation in humans
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2008; 294(5): R1420 - R1426.
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