Elevated extracellular glucose potentiates vasoconstrictor signalling in vascular smooth muscle. We have previously demonstrated that elevating bathing glucose from 5 to 20mM causes a marked increase in contractile responses, recorded using wire myography, to angiotensin II (ATII), UTP, U46619 in mesenteric(1), and U46619 in coronary arterioles that is PKC-dependent in mechanism(1,2). We hypothesised that 20mM glucose reduced receptor desensitisation in a PKC-dependent manner so providing a mechanism to explain the increased vasoconstriction in elevated bathing glucose.Rat mesenteric arterioles (200-400μm in diameter) were mounted in a Mulvany-Halpern myograph (Danish Myo Technology, Aarhus, Denmark) and maintained at a constant temperature of 37°C. Arteries were held under a tension equivalent to 90% of the diameter of the vessel at a pressure of 100 mmHg in 1.8 mM Ca2+ recording solution containing 5 or 20mM glucose for 30 minutes prior to experimentation. The myograph chamber was continuously perfused throughout the recording. 60mM potassium was applied to cause a depolarisation-induced contraction and all data was normalised to the peak contraction. 100nM ATII was perfused for 45 seconds followed by 100 (approximate EC50 value), 300 (maximal) and then a second 100μM addition of UTP to measure desensitisation for 5 minutes each, with a 5 minute wash between applications. Finally, 100nM ATII was reapplied at the end of the recording. In 5mM glucose, the second submaximal UTP response was reduced to 54.2±5.3% (n=10) of the first response and was unaffected by inclusion of 20μM L-NAME to inhibit eNOS (61.6±3.9%, n=20). In 20mM glucose this desensitisation was reduced to 76.4±4.2% (82.4±6.5% with L-NAME, P<0.01 compared to 5mM glucose control for both with and without L-NAME, t-test). Similarly, ATII desensitisation was reduced by 20mM glucose (5.1±2.4% vs 34.6±8.6%, 5 and 20mM glucose respectively, 20 vessels in each concentration, P<0.01, t-test). Inhibition of PKCα and β with 300nM Gö6976 in 20mM glucose attenuated the reduction of desensitisation to the same level as in 5 mM glucose control (54.2±5.3%, 76.4±4.2%** to 48.4±3.3%, in 5mM, 20mM glucose and with Gö6976 respectively, **P<0.01, ANOVA with Bonferroni’s post-hoc test), and reversed the ATII reduction in desensitisation ( 5.1±2.4%, 34.6±8.6% to 4.0±2.7% in 5mM, 20mM glucose and with Gö6976 respectively, **P<0.01, ANOVA with Bonferroni’s post-hoc test). In this study we demonstrate that receptor desensitisation is markedly reduced by increasing bathing glucose from 5 to 20mM, but that this can be attenuated using conventional PKC inhibition. This data support our hypothesis that glucose-mediated PKC activation reduces receptor desensitisation and enhancing vasoconstrictor responses in elevated glucose.