Pharmacological Targeting of the Hexosamine Biosynthesis Pathway (HBP) Overcomes Diabetes-Induced Impaired Myocardial Inotropic Responsiveness to alpha 1-Adrenoceptor (alpha 1-AR) Stimulation

Acute HBP upregulation is a cytoprotective mechanism in many tissues. In contrast, persistent unchecked HBP upregulation in the context of diabetes has emerged as a contributing factor to diabetic complications. Regulation of myocardial function by HBP in this context remains poorly understood. We tested the hypothesis that targeting HBP overcomes impaired inotropic responsiveness to α1-AR stimulation in chronically diabetic myocardium (evaluated in isolated adult Sprague-Dawley male rat hearts ex vivo). Positive inotropic responsiveness to the α1-AR agonist phenylephrine (PE 10μM, in the presence of 0.1μM propranolol) 8wks after citrate vehicle was no longer evident after 8wks of streptozotocin-induced diabetes (55mg/kg iv). Indices included left ventricular systolic pressure (LVSP), LV developed pressure (LVDP), LV+dP/dt and rate-pressure product (RPP, see Figure). Dashed line indicates baseline LV function prior to PE (n/group on bars, *P<0.05 vs sham alone; ***P<0.001 vs diabetes alone, one-way ANOVA ...