title: Dual A1/A2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction.
abstract: Heart failure with preserved ejection fraction (HFpEF) is prevalent and often accompanied by metabolic syndrome. Current treatment options are limited. Here, we test the hypothesis that combined A1/A2B adenosine receptor blockade is beneficial in obese ZSF1 rats, an animal model of HFpEF with metabolic syndrome. The combined A1/A2B receptor antagonist 3-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)-1-bicyclo[2.2.2]octanyl]propanoic acid (BG9928) was administered orally (10 mg/kg/day) to obese ZSF1 rats (n = 10) for 24 weeks (from 20 to 44 weeks of age). Untreated ZSF1 rats (n = 9) served as controls. After 24 weeks of administration, BG9928 significantly lowered plasma triglycerides (in mg/dl: control group, 4351 ± 550; BG9928 group, 2900 ± 551) without adversely affecting plasma cholesterol or activating renin release. BG9928 significantly decreased 24-hour urinary glucose excretion (in mg/kg/day: control group, 823 ± 179; BG9928 group, 196 ± 80) and improved oral glucose tolerance, polydipsia, and polyuria. BG9928 significantly augmented left ventricular diastolic function in association with a reduction in cardiac vasculitis and cardiac necrosis. BG9928 significantly reduced 24-hour urinary protein excretion (in mg/kg/day: control group, 1702 ± 263; BG9928 group, 1076 ± 238), and this was associated with a reduction in focal segmental glomerulosclerosis, tubular atrophy, tubular dilation, and deposition of proteinaceous material in the tubules. These findings show that, in a model of HFpEF with metabolic syndrome, A1/A2B receptor inhibition improves hyperlipidemia, exerts antidiabetic actions, reduces HFpEF, improves cardiac histopathology, and affords renal protection. We conclude that chronic administration of combined A1/A2B receptor antagonists could be beneficial in patients with HFpEF, in particular those with comorbidities such as obesity, diabetes, and dyslipidemias.
authors.affiliation: Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.).
authors.forename: Stevan P
authors.initials: SP
authors.lastname: Tofovic
authors.affiliation: Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.).
authors.forename: Eman M
authors.initials: EM
authors.lastname: Salah
authors.affiliation: Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.).
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Smits
authors.affiliation: Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.).
authors.forename: Eric T
authors.initials: ET
authors.lastname: Whalley
authors.affiliation: Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.).
authors.forename: Barry
authors.initials: B
authors.lastname: Ticho
authors.affiliation: Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.).
authors.forename: Aaron
authors.initials: A
authors.lastname: Deykin
authors.affiliation: Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.) edj@pitt.edu.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000008:administration & dosage*; D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage*; D000818:Animals; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats; D011924:Rats, Zucker; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects* / Q000502:physiology; D016896:Treatment Outcome; D014970:Xanthines / Q000008:administration & dosage*
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; C505954:BG 9928; D043682:Receptor, Adenosine A1; D043704:Receptor, Adenosine A2B; D014970:Xanthines