The effect of glucose on endothelial function is a critical factor in the pathology of vascular disease in diabetes. Previous studies have yielded conflicting results with increases in glucose causing attenuated vasodilatation (Bohen & Lash 1993), enhanced vasodilatation (Cipolla et al 1997) or no change in vascular tone (Brands & Fitzgerald 1998). Indeed we have recently reported an enhanced vasodilatation in the presence of high glucose (Cooper et al 2006). One possible explanation for the contrasting results is that hyperglycaemia may have different effects in differing vascular beds. Here we examine the effects of high glucose on endothelial-dependent & –independent relaxation in two sets of human arteries. Mesenteric arteries (MA; 546+27μm, n>8) & subcutaneous arteries (SA; 643+67μm, n=7), obtained from patients undergoing elective abdominal (n=5) or breast reduction surgery (n=4) at the Glasgow Royal Infirmary, were dissected, mounted on a wire myograph, normalised & left to equilibrate (60mmHg, 37°C, 20mins). Endothelial-dependent relaxations induced by acetylcholine (ACh; 1nM-10mM) & bradykinin (Bk; 0.1nM-1mM), & endothelial-independent relaxations induced by the NO-donor glycerol trinitrate (GTN; 0.1nM-1mM) were assessed in precontracted vessels (EC₈₀ U46619) before and after incubation for 2h in either control (5mM glucose) or high glucose krebs (20mM glucose). Data is expressed as mean+sem & analysed using two way ANOVA or paired t-tests. Incubating vessels in 5 or 20mM glucose for 2 hours had no effect on basal vascular tone or vessel constriction to U46619 (EC₈₀=25+2 & 27+4kPa in 5mM glucose compared with 25+2 & 22+2kPa in 20mM glucose in MA & SA respectively, p>0.05). After incubation for 2h in 5mM glucose ACh, Bk & GTN all elicited dose dependant relaxations with maximums of 54+9, 75+8 & 71+6% respectively in MA & 75+9, 50+12 & 63+7% respectively in SA. When MA were incubated in high glucose (20mM) for 2h, relaxation to both ACh (maximum=72+9%, p=0.01) & Bk were enhanced (EC₅₀=7.8+0.3nM vs 85.1+0.4nM in 5mM glucose, p=0.01). In contrast, in SA, incubation in high glucose for 2h significantly attenuated relaxation in response to ACh (maximum=58+15%, p<0.01) & Bk (maximum=37+13%, p=0.05). GTN induced relaxations were unaffected by high glucose in both MA (maximum=75+6%) & SA (maximum=56+13%). These results demonstrate that high glucose has no effect on the basal release of endothelial relaxants or the ability of NO to induce smooth muscle relaxation. However the effects of high glucose on endothelial-dependent relaxations are clearly dependant on the vascular bed studied. These differences may be an adaptive response due to variations in the glucose requirements of the different vascular beds.