Dual A1/A2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction.

Autor:	Tofovic SP; 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.)., Salah EM; 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.)., Smits GJ; 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.)., Whalley ET; 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.)., Ticho B; 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.)., Deykin A; 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.)., Jackson EK; 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.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2016 Feb; Vol. 356 (2), pp. 333-40. Date of Electronic Publication: 2015 Nov 19.
DOI:	10.1124/jpet.115.228841
Abstrakt:	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. (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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