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

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.

Cardiorenal effects of adenosine subtype 1 (A1) receptor inhibition in an experimental model of heart failure.

BACKGROUND: Elaboration of a number of bioactive substances, including adenosine, occurs in heart failure (HF). Adenosine, through the adenosine subtype 1 (A1) receptor, can reduce renal perfusion pressure and glomerular filtration rate and increase tubular sodium reabsorption, which can affect natriuresis and aquaresis. Accordingly, the present study examined the acute effects of selective A1 receptor blockade on hemodynamics and renal function in a model of HF. STUDY DESIGN: HF was induced in adult pigs (n = 19) by chronic pacing (240 beats/min for 3 weeks). The pigs were then instrumented for hemodynamic and renal function measurements. After baseline measurements were taken, pigs received either A1 block [ 1 mg/kg BG9719 (1,3-dipropyl-8-[2(5,6-epoxynorbornyl)]xanthine; n = 9)] or infusion of vehicle (n = 10), and measurements were repeated at intervals for up to 2 hours. Normal controls (n = 7) were included for comparison. RESULTS: Cardiac output remained unchanged between the A1 block and vehicle groups throughout the study. Pulmonary vascular resistance fell 38% from baseline at 10 minutes post-A1 block in the HF group (p < 0.05) with no change in the vehicle group. At 10 minutes post-A1 block, urine flow increased sixfold and sodium excretion increased over 10-fold (for both, p < 0.05) with no change in the vehicle group. At 10 minutes post-A1 block, creatinine clearance increased with no change in the vehicle group. At 10 minutes post-A1 block, plasma renin activity had increased over threefold (p <0.05), and it returned to baseline levels by 30 minutes post-A1 block. CONCLUSIONS: The unique findings from this study were threefold. First, increased A1 receptor activation contributes to renal mediated fluid retention in HF. Second, selective A1 blockade can induce diuresis without hemodynamic compromise and with possible benefit to pulmonary resistance in a model of HF. A1 blockade transiently increased plasma renin activity with no change in hemodynamics. These unique results suggest that selective A1 blockade can be a useful adjunctive diuretic in the setting of HF.