Abstract 14965: Pharmacological Targeting of the Hexosamine Biosynthesis Pathway (HBP) Overcomes Diabetes-Induced Impaired Myocardial Inotropic Responsiveness to α1-Adrenoceptor (α1-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 with Tukey’s). Inhibition of glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme of HBP, via co-infusion of 100μM diazo-5-oxo-L-norleucine (starting 30mins prior to PE), restored myocardial inotropic responsiveness to PE across all parameters of LV function in the diabetic rat heart. Similar protective actions were observed with co-infusion of 5mM alloxan (a putative inhibitor of the downstream HBP enzyme, O-linked β-N-acetylglucosamine transferase, OGT) commencing 30mins prior to PE. Neither pretreatment alone affected baseline LV function at these concentrations. In contrast, inotropic responsiveness to the β-AR agonist isoproterenol (1μM) was preserved across each of LVSP, LVDP, LV+dP/dt and RPP in diabetic compared to sham hearts (n=5-6, P=NS). These results suggest that acute pharmacological targeting of HBP restores myocardial inotropic responsiveness to α1-AR stimulation in the diabetic heart.
Author Disclosures: R.H. Ritchie: None. C. Qin: None. R.S. Sleaby: None. L.M. Delbridge: None. S. Rosli: None. A.J. Davidoff: None. S.A. Marsh: None. J.C. Chatham: None.
- © 2014 by American Heart Association, Inc.