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Research ArticleDrug Discovery and Translational Medicine

Anodal Iontophoresis of a Soluble Guanylate Cyclase Stimulator Induces a Sustained Increase in Skin Blood Flow in Rats

Sylvain Kotzki, Matthieu Roustit, Claire Arnaud, Jean Boutonnat, Sophie Blaise, Diane Godin-Ribuot and Jean-Luc Cracowski
Journal of Pharmacology and Experimental Therapeutics September 2013, 346 (3) 424-431; DOI: https://doi.org/10.1124/jpet.113.205484
Sylvain Kotzki
INSERM U1042, Grenoble, France (S.K., M.R., C.A., S.B., D.G.-R., J.-L.C.); Université Joseph Fourier, CNRS UMR 5525, Grenoble, France (J.B.); Université Joseph Fourier, Clinical Pharmacology Unit–INSERM CIC03, Grenoble, France (S.K., M.R., J.-L.C.); and Vascular Medicine Department, Grenoble University Hospital, Grenoble, France (S.B.)
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Matthieu Roustit
INSERM U1042, Grenoble, France (S.K., M.R., C.A., S.B., D.G.-R., J.-L.C.); Université Joseph Fourier, CNRS UMR 5525, Grenoble, France (J.B.); Université Joseph Fourier, Clinical Pharmacology Unit–INSERM CIC03, Grenoble, France (S.K., M.R., J.-L.C.); and Vascular Medicine Department, Grenoble University Hospital, Grenoble, France (S.B.)
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Claire Arnaud
INSERM U1042, Grenoble, France (S.K., M.R., C.A., S.B., D.G.-R., J.-L.C.); Université Joseph Fourier, CNRS UMR 5525, Grenoble, France (J.B.); Université Joseph Fourier, Clinical Pharmacology Unit–INSERM CIC03, Grenoble, France (S.K., M.R., J.-L.C.); and Vascular Medicine Department, Grenoble University Hospital, Grenoble, France (S.B.)
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Jean Boutonnat
INSERM U1042, Grenoble, France (S.K., M.R., C.A., S.B., D.G.-R., J.-L.C.); Université Joseph Fourier, CNRS UMR 5525, Grenoble, France (J.B.); Université Joseph Fourier, Clinical Pharmacology Unit–INSERM CIC03, Grenoble, France (S.K., M.R., J.-L.C.); and Vascular Medicine Department, Grenoble University Hospital, Grenoble, France (S.B.)
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Sophie Blaise
INSERM U1042, Grenoble, France (S.K., M.R., C.A., S.B., D.G.-R., J.-L.C.); Université Joseph Fourier, CNRS UMR 5525, Grenoble, France (J.B.); Université Joseph Fourier, Clinical Pharmacology Unit–INSERM CIC03, Grenoble, France (S.K., M.R., J.-L.C.); and Vascular Medicine Department, Grenoble University Hospital, Grenoble, France (S.B.)
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Diane Godin-Ribuot
INSERM U1042, Grenoble, France (S.K., M.R., C.A., S.B., D.G.-R., J.-L.C.); Université Joseph Fourier, CNRS UMR 5525, Grenoble, France (J.B.); Université Joseph Fourier, Clinical Pharmacology Unit–INSERM CIC03, Grenoble, France (S.K., M.R., J.-L.C.); and Vascular Medicine Department, Grenoble University Hospital, Grenoble, France (S.B.)
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Jean-Luc Cracowski
INSERM U1042, Grenoble, France (S.K., M.R., C.A., S.B., D.G.-R., J.-L.C.); Université Joseph Fourier, CNRS UMR 5525, Grenoble, France (J.B.); Université Joseph Fourier, Clinical Pharmacology Unit–INSERM CIC03, Grenoble, France (S.K., M.R., J.-L.C.); and Vascular Medicine Department, Grenoble University Hospital, Grenoble, France (S.B.)
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Abstract

The treatment of systemic sclerosis–related digital ulcers is challenging. Although the only effective drugs are prostacyclin analogs, their use is limited by vasodilation-related adverse reactions. In this study, we assessed the local iontophoresis administration of three soluble guanylate cyclase (A-350619 [3-[2-[(4-chlorophenyl)thiophenyl]-N-[4-(dimethylamino)butyl]-2-propenamide hydrochloride], SIN-1 [amino-3-morpholinyl-1,2,3-oxadiazolium chloride], and CFM 1571 [3-[3-(dimethylamino)propoxy]-N-(4-methoxyphenyl)-1-(phenylmethyl)-1H-pyrazole-5-carboxamide hydrochloride]) and two nonprostanoid prostaglandin I2 (prostacyclin) receptor agonists (MRE-269 [[4-​[(5,​6-​diphenylpyrazinyl)(1-​methylethyl)amino]butoxy]-​acetic acid] and BMY 45778 [[3-(4,5-diphenyl[2,4′-bioxazol]-5′-yl)phenoxy]acetic acid]) to induce vasodilation onto the hindquarters of anesthetized rats. Skin blood flow was quantified using laser Doppler imaging during the whole experience, and safety was assessed by continuous recording of blood pressure and histopathological examination. Anodal iontophoresis of A-350619 (7.54 mM) induced a sustained increase in cutaneous blood flow (P = 0.008 vs. control). All other drugs exhibited poor or no effect on skin blood flow. Vasodilation with A-350619 iontophoresis was concentration-dependent (7.5, 0.75, and 0.075 mM; P < 0.001, Jonckheere-Terpstra trend test), and repeated administrations do not suggest any risk of tolerance. This study also compared continuous versus intermittent iontophoresis protocols. Continuous anodal iontophoresis of A-350619 at 7.5 mM increases cutaneous blood flow with good local tolerance. Iontophoresis of soluble guanylate cyclase stimulators should be investigated as potential local therapy for digital ulceration in patients with scleroderma.

Footnotes

    • Received April 26, 2013.
    • Accepted July 8, 2013.
  • This research was supported by a grant from the patients’ association “Association des Sclérodermiques de France.”

  • dx.doi.org/10.1124/jpet.113.205484.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 346 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 346, Issue 3
1 Sep 2013
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Research ArticleDrug Discovery and Translational Medicine

Iontophoresis of a Soluble Guanylate Cyclase Stimulator

Sylvain Kotzki, Matthieu Roustit, Claire Arnaud, Jean Boutonnat, Sophie Blaise, Diane Godin-Ribuot and Jean-Luc Cracowski
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 424-431; DOI: https://doi.org/10.1124/jpet.113.205484

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Research ArticleDrug Discovery and Translational Medicine

Iontophoresis of a Soluble Guanylate Cyclase Stimulator

Sylvain Kotzki, Matthieu Roustit, Claire Arnaud, Jean Boutonnat, Sophie Blaise, Diane Godin-Ribuot and Jean-Luc Cracowski
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 424-431; DOI: https://doi.org/10.1124/jpet.113.205484
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