title: Anodal iontophoresis of a soluble guanylate cyclase stimulator induces a sustained increase in skin blood flow in rats.
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.
authors.affiliation: INSERM U1042, Grenoble, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Kotzki
authors.forename: Matthieu
authors.initials: M
authors.lastname: Roustit
authors.forename: Claire
authors.initials: C
authors.lastname: Arnaud
authors.forename: Jean
authors.initials: J
authors.lastname: Boutonnat
authors.forename: Sophie
authors.initials: S
authors.lastname: Blaise
authors.forename: Diane
authors.initials: D
authors.lastname: Godin-Ribuot
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Cracowski
mesh_terms: D000085:Acetates / Q000009:adverse effects / Q000494:pharmacology; D000178:Acrylamides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D003627:Data Interpretation, Statistical; D004558:Electric Stimulation; D004566:Electrodes; D006162:Guanylate Cyclase / Q000187:drug effects*; D066298:In Vitro Techniques; D007478:Iontophoresis; D008297:Male; D009602:Nitrosamines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010080:Oxazoles / Q000009:adverse effects / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044006:Receptors, Epoprostenol / Q000819:agonists; D012039:Regional Blood Flow / Q000187:drug effects*; D012867:Skin / Q000098:blood supply* / Q000187:drug effects*
chemical_list: C470768:3-(2-(4-chlorophenylsulfanyl)phenyl)-N-(4-dimethylaminobutyl)acrylamide; D000085:Acetates; D000178:Acrylamides; D009602:Nitrosamines; D010080:Oxazoles; D010975:Platelet Aggregation Inhibitors; D011719:Pyrazines; D011720:Pyrazoles; D044006:Receptors, Epoprostenol; C084677:BMY 45778; C006006:N-nitrosomorpholinoaminoacetonitrile; C531934:(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid; D006162:Guanylate Cyclase; C419404:CFM 1571