Purpose: In left ventricular dysfunction, shortterm A1 adenosine receptor blockade causes diuresis/natriuresis without altering potassium excretion and, in contrast to loop diuretics, improves renal function. Blockade of the A2b adenosine receptor has an antidiabetic effect. This study was done to examine the long-term efficacy and safety of BG9928, a novel, orally active, and highly potent A1 adenosine receptor antagonist with moderate activity at the A2b
receptor, in an animal system designed to model the complex pathology that characterizes, with increasing frequency, the modern cardiac patient Methods: The ZSF1 rat is a model of the metabolic syndrome that expresses obesity, hypertension, type 2 diabetes, dyslipidemia, dilated cardiomyopathy, and severe nephropathy. BG9928 (10 mg/kg/day), captopril
(100 mg/kg/day, orally), and furosemide (50 mg/kg/day, orally), alone or in combination, were administered for 24 weeks to ZSF1 rats (9 or 10 per group). An untreated control group was included. Results: BG9928 reduced urinary glucose excretion (from 823±179 to 196±80 mg/kg/day; P=0.004) and attenuated captopril-induced worsening of the oral glucose tolerance test as well as captopril-induced increases in fasting plasma glucose and insulin levels. Chronic captopril doubled the urinary excretion rate (P<0.001) and the renal interstitial
levels (P=0.008) of adenosine. Compared with control animals, BG9928 blocked the age-related increase in plasma triglycerides and significantly reduced focal segmental glomerulosclerosis and cardiac vasculitis, degenerative ischemic changes, and necrosis (P<0.05). At 12 weeks of treatment, BG9928 increased captopril- and furosemide-induced renin release, but this effect was lost by 24 weeks into treatment. Conclusion: In heart and renal disease chronic administration of BG9928 was safe as detected by renal and cardiac histopathology by inhibition of both A1 and A2b adenosine receptors.may improve type 2 diabetes, lower plasma triglycerides, and attenuaterenal and cardiac histopathology by inhibition of both A1 and A2b adenosine receptors