Short Title: Venous insufficiency and vasodilator function

2 Objectives: To assess the effects of posture, endothelial function and venous insufficiency on cutaneous microvascular vasodilator function in the gaiter area, in particular defining factors which may affect microangiopathy and ulcer formation. Methods: Endothelial-dependent and –independent vasodilator responses to incremental-doses of acetylcholine (Ach) and sodium nitroprusside (SNP) were evaluated in the perimalleolar region in the supine and standing positions in middle-aged patients with isolated superficial venous insufficiency (ISVI) (n=25) and health controls (n=28) using laser Doppler fluximetry (LDF) and iontophoresis of vasodilators. Results: The venoarteriolar reflex (vasoconstriction on standing) was equally present in both groups, and reduced the vasodilator responses to SNP in the upright position (e.g for patients with ISVI, peak SNP response was 82+11 PU [standing] vs 123+15 PU [supine]). The presence of ISVI had no effect on endothelial vasodilator function in the supine position, but on standing cutaneous reactivity to Ach was significantly reduced (e.g peak Ach response 69+8 PU [ISVI] vs 109+11 PU [controls], p<0.003). Conclusions: Upright posture impairs cutaneous endothelial-dependent vasodilation in the gaiter area of patients with ISVI. This may be of clinical and prognostic utility in identifying which patients with uncomplicated ISVI are at highest risk of tissue breakdown and ulcer formation in the gaiter area. Key Words: Endothelial function; microvascular; venous insufficiency; ulceration