Valsartan improves resting skin blood flow in type 2 diabetic patients and reduces poly(adenosine diphosphate-ribose) polymerase activation Gautam Shrikhande,

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Valsartan improves resting skin blood flow in type 2 diabetic patients and reduces poly(adenosine diphosphate-ribose) polymerase activation Gautam Shrikhande, MD, Lalita Khaodhiar, MD, Salvatore Scali, MD, Christina Lima, BA, Matthew Hubbard, BS, Katherine Dudley, BS, Om Ganda, MD, Christiane Ferran, MD, PhD, Aristidis Veves, MD, DSc Journal of Vascular Surgery Volume 43, Issue 4, Pages 760-770 (April 2006) DOI: 10.1016/j.jvs.2005.12.059 Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 1 Scheme of the clinical trial. Journal of Vascular Surgery 2006 43, 760-770DOI: (10.1016/j.jvs.2005.12.059) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 2 A, Changes in the resting and acetylcholine postiontophoresis blood flow between the beginning and the end of the treatment period either with valsartan or placebo in the type 2 diabetic patient (T2DM) group. The increase in the resting blood flow was higher during the period of valsartan treatment (first column) compared with placebo (third column) (*P < 0.05). No differences were observed in the changes of the postiontophoresis blood flow (second and fourth columns) (P = not significant). Data are presented as median and confidence interval box. B, Changes in the resting and sodium nitroprusside postiontophoresis blood flow between the beginning and the end of the treatment period either with valsartan or placebo in the T2DM group. The skin area that was selected for this test was different from the area chosen for the acetylcholine iontophoresis. The increase in the resting blood flow was higher during the period of valsartan treatment (first column) compared with placebo (third column) (*P < .05). No differences were observed in the changes of the postiontophoresis blood flow (second and fourth columns) (P = not significant). Data are presented as median and confidence interval box. Journal of Vascular Surgery 2006 43, 760-770DOI: (10.1016/j.jvs.2005.12.059) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 3 Representative skin biopsy samples from two type 2 diabetic patients before and after treatment with either placebo or valsartan and stained for poly(adenosine diphosphate [ADP]-ribose) (PAR), the product of the PAR polymerase (PARP) enzyme and, therefore, a surrogate measurement of PARP activity (A) and CD31 (B) immunoreactivity. A, Results demonstrate intense staining (arrows) in both patients before treatment for PAR. PAR immunoreactivity remained as intense after treatment with placebo but significantly decreased after treatment with valsartan (original magnification, ×200). B, CD31 immunoreactivity (arrows), indicative of endothelial cells and small dermal capillaries, was sparse before treatment in both patients and remained so after treatment in the patient receiving placebo. In contrast, significantly more CD31 staining was detected after treatment with valsartan (original magnification, ×100). Journal of Vascular Surgery 2006 43, 760-770DOI: (10.1016/j.jvs.2005.12.059) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 4 A, Differences in the PARP activity in forearm skin biopsy samples taken before treatment initiation and after completion of a 12-week period of treatment either with valsartan (black columns) or placebo (gray columns). Staining for poly(adenosine diphosphate-ribose) (PAR, the product of the PAR polymerase [PARP] enzyme and, therefore, a surrogate measurement of PARP activity) was characterized as reduced when the exit visit staining intensity was scored as less than that of the initial visit, unchanged when the intensity was similar in both visits, and increased when the intensity was higher at the exit visit. The PAR staining was reduced in six (50%) valsartan-treated subjects, whereas no reduction was observed in none (0%) placebo-treated patients (P < .02). B, Differences in the CD31 staining in biopsy samples that were taken before initiation of treatment and after completion of a 12-week treatment period. Valsartan treatment (black columns) increased the staining in four (33%) subjects as compared with no (0%) placebo-treated subjects (gray columns), thus resulting in marginal statistical significance (P = .057). Journal of Vascular Surgery 2006 43, 760-770DOI: (10.1016/j.jvs.2005.12.059) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions