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BACKGROUND AND PURPOSE The treatment of scleroderma-related digital ulcers is still a therapeutic challenge. The most effective drugs are prostacyclin analogues. However, their usage is limited to an intravenous route of administration and by their frequent side effects. The objective of this study was to test whether treprostinil, iloprost and epoprostenol can induce sustained vasodilatation in rats when delivered locally using cutaneous iontophoresis. EXPERIMENTAL APPROACH Treprostinil, iloprost and epoprostenol were delivered by cathodal and anodal iontophoresis onto the hindquarters of anaesthesized rats (n= 8 for each group). Skin blood flow was quantified using laser Doppler imaging and cutaneous tolerance was assessed from day 0 to day 3. KEY RESULTS Cathodal but not anodal iontophoresis of treprostinil (6.4 mM), iloprost (0.2 mM) and epoprostenol (1.4 mM) induced a significant and sustained increase in cutaneous blood flow. The effects of treprostinil and iloprost were significantly different from those of treprostinil vehicle. Only weak effects were observed when both drugs were applied locally without current. Skin resistance was unchanged in areas treated with prostacyclin analogues. Finally, skin tolerance was good, with no evidence of epidermal damage. CONCLUSIONS AND IMPLICATIONS Cathodal iontophoresis of treprostinil and iloprost increases cutaneous blood flow with a good local tolerance. The effects of cathodal iontophoresis of these drugs should be investigated in humans, as they could have potential as new local therapies for digital ulcers in patients with scleroderma.

Background and purpose: Sildenafil, a specific inhibitor of phosphodiesterase 5A (PDE5A), is currently tested as a treatment for severe Raynaud's phenomenon. Here, we tested whether sildenafil, alone or combined with local sodium nitroprusside (SNP) delivered through skin iontophoresis, increased forearm cutaneous blood conductance in healthy volunteers, and to assess how well this combination was tolerated. Experimental approach: Ten healthy volunteers were enrolled. Variations in cutaneous vascular conductance (CVC) following oral administration of 50 or 100 mg of sildenafil with or without SNP iontophoresis were expressed as a percentage of maximal CVC, and were monitored using laser Doppler imaging. SNP iontophoresis was performed on the ventral surface of the forearm, 1 h after application of lidocaine/prilocaine cream. Key results: Sildenafil at 100 mg, but not 50 mg, increased overall responses (area under the curve) (44%) and peak responses (29%) to SNP iontophoresis. Sildenafil at 100 mg, but not 50 mg, increased baseline CVC (75%). Incidence of headache was not changed when SNP iontophoresis was combined with sildenafil. One episode of symptomatic arterial hypotension occurred in a volunteer given 50 mg sildenafil, 30 min after the beginning of SNP iontophoresis. Conclusions and implications: Oral sildenafil at 100 mg potentiated local skin hyperaemia induced by SNP iontophoresis, with no increased incidence of headaches. The combination of oral specific PDE5A inhibitor and nitrates administered through skin iontophoresis deserves further investigation in diseases such as severe Raynaud's phenomenon, with particular attention to the incidence of arterial hypotension.

Long-term treatment of rats with Nω-nitro-L-arginine methyl ester (L-NAME) induces hypertension associated with inflammatory and vascular changes. Leukotrienes are proinflammatory vasoactive products that are suspected to be involved in the pathogenesis of hypertension. We investigated, in rats chronically treated with L-NAME, the involvement of leukotrienes in the in vivo regulation of blood pressure and the in vitro contraction elicited by noradrenaline in isolated aorta. Rats were randomly assigned to four groups and orally treated for 3 weeks with L-NAME (1 mg ml−1), L-NAME (1 mg ml−1) plus the leukotriene biosynthesis inhibitor MK-886 (0.1 mg ml−1), MK-886 (0.1 mg ml−1) alone or vehicle (Methocel, 0.1%). All the drugs were added to the drinking fluid. The mean arterial blood pressure (MABP) increased significantly in L-NAME-treated rats (173.3±9.4 mmHg (n=25)) vs Methocel-treated rats (110.7±4.8 mmHg (n=11), P

Among the F2-isoprostanes, the 15- and the 5-series are currently used as markers of lipid peroxidation in vascular diseases. 15-F2t-IsoP (also named iPF2α-III) exerts a vasoconstriction in most vessels, whereas no data is available concerning 5-F2t-IsoP (also named iPF2α-VI), which is more abundant in plasma. The aim of this study was to determine whether 5-F2t-IsoP possess any vascular effects on various vessels including the isolated rat thoracic aorta, the human internal mammary artery and the saphenous vein. In organ baths, 5-F2t-IsoP and its 5-epimer did not affect the basal tone of any vessel, unlike 15-F2t-IsoP. These compounds possessed no antagonist effects on 15-F2t-IsoP-induced contractions, No dilator effect was observed in comparison with sodium nitroprusside and acetylcholine on the rat aorta. In conclusion, we show that unlike 15-F2t-IsoP, 5-F2t-IsoP and its 5-epimer possess no vasomotor effects and as such are unlikely to be involved in the pathogenesis of vascular diseases. Further studies are required to test whether these mediators may have effects on systems not being measured in the current study. British Journal of Pharmacology (2002) 135, 1276–1280; doi:10.1038/sj.bjp.0704558

1. Among the F(2)-isoprostanes, the 15- and the 5-series are currently used as markers of lipid peroxidation in vascular diseases. 15-F(2t)-IsoP (also named iPF(2 alpha)-III) exerts a vasoconstriction in most vessels, whereas no data is available concerning 5-F(2t)-IsoP (also named iPF(2 alpha)-VI), which is more abundant in plasma. 2. The aim of this study was to determine whether 5-F(2t)-IsoP possess any vascular effects on various vessels including the isolated rat thoracic aorta, the human internal mammary artery and the saphenous vein. 3. In organ baths, 5-F(2t)-IsoP and its 5-epimer did not affect the basal tone of any vessel, unlike 15-F(2t)-IsoP. These compounds possessed no antagonist effects on 15-F(2t)-IsoP-induced contractions, No dilator effect was observed in comparison with sodium nitroprusside and acetylcholine on the rat aorta. 4. In conclusion, we show that unlike 15-F(2t)-IsoP, 5-F(2t)-IsoP and its 5-epimer possess no vasomotor effects and as such are unlikely to be involved in the pathogenesis of vascular diseases. Further studies are required to test whether these mediators may have effects on systems not being measured in the current study.