PW293 Impact of upregulated O-GlcNAcylation on left ventricular (LV) inotropic responsiveness in diabetic heart

Introduction: Increased hexosamine biosythesis and downstream upregulated protein OGlcNAcylation has been linked to diabetic complications in many tissues; its impact on LV contractile responsiveness is not well understood. Objectives: To determine the impact of acute and chronic upregulated O-GlcNAcylation on LV inotropic responsiveness. Methods: Hearts isolated from anaesthetised adult male rats (ketamine:xylazine, 100:20mg/kg i.p.) were Langendorff-perfused (Krebs’ at constant flow, 10ml/min). Baseline and phenylephrine-stimulated (PE, 10mmol/L) LV function was determined in response to acute (5mmol/L glucosamine, 30mins pretreatment) versus chronic upregulation of O-GlcNAcylation (8 weeks post-streptozotocin diabetes, 55mg/kg i.v.). Results were compared to untreated control or non-diabetic sham hearts, respectively. Results: Chronic diabetes inhibited PE-induced inotropic responsiveness (Table, *P<0.05 vs control; P<0.05 vs non-diabetic sham; peak at 6 mins); preliminary results also suggested a trend for diabetes-upregulated LV O-GlcNAc content (not shown). In contrast, acute O-GlcNAcylation with glucosamine did not fully reproduce the impaired PE inotropic response (Table), although baseline LV function was transiently reduced (not shown).