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)) and two nonprostanoid prostaglandin I2 (prostacyclin) receptor agonists (1-methylethyl)amino]butoxy]-acetic acid] and BMY 45778 [[3-(4,5-diphenyl[2,49-bioxazol]-59-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 5 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.

Effect of continuous vs pulsed iontophoresis of treprostinil on skin blood flow

“…Rats were kept in a day/ night cycle of 12 h/12 h with food and water at will. Thirty minutes before iontophoresis, rats were shaved as previously described (Blaise et al, 2011;Roustit et al, 2012;Kotzki et al, 2013).…”

Cutaneous Iontophoresis of Vasoactive Medications in Patients with Scleroderma- Associated Pulmonary Arterial Hypertension

“…A350619 is an activator of sGC that had been previously shown to increase cutaneous perfusion in rats using anodal iontophoresis (37,38). This sGC activator works in a dose-dependent fashion with maximum e cacy in an NO rich environment (37).…”

Cutaneous iontophoresis of vasoactive medications in patients with scleroderma‐associated pulmonary arterial hypertension

“…9,23 A350619 hydrochloride (Santa Cruz, Dallas, Texas, USA) 7.5 mM solution was delivered using positive polarity and a current of 100 mA for 20 min followed by 10 min of observation. 24,25 Acetylcholine (Sigma-Aldrich, St. Louis, Missouri, USA) 1% solution was delivered using positive polarity at a current of 40 mA for 5 min. 22,25 Sodium nitroprusside (Marathon Pharmaceuticals, Northbrook, Illinois, USA) 1% solution was delivered using negative polarity at a current of 40 mA for 5 min.…”

“…A350619 is an activator of sGC that had been previously shown to increase cutaneous perfusion in rats using anodal iontophoresis. 24,40 This sGC activator works in a dose-dependent fashion with maximum efficacy in an NO-rich environment. 40 The failure of We did not find a difference among groups in the microvascular response to local thermal stimulation or PORH.…”