Natriuretic and diuretic actions of a highly selective adenosine A(1) receptor antagonist

The natriuretic and diuretic action of a highly selective adenosine A(1) re ceptor (A(1)AdoR) antagonist, 1,3-dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthi ne (CVT-124), was investigated in anesthetized rats. CVT-124 (0.1 to 1 mg/k g) caused dose-dependent increases in urine flow and fractional and absolut e sodium excretion of by six- to 10-fold and, at 0.1 mg/kg, increased the G FR (1.6 +/- 0.1 to 2.5 +/- 0.2 ml/min; P < 0.01). There were no changes in BP or heart rate. CVT-124 reduced absolute proximal reabsorption (26 +/- 3 to 20 +/- 2 nl/min; P < 0.05) despite unchanged proximally measured, single -nephron GFR (SNGFR) (42 +/- 5 to 44 +/- 4 nl/min; NS) and thereby decrease d fractional proximal reabsorption (60 +/- 3 to 46 +/- 4%; P < 0.05). Despi te increasing distal tubular fluid flow rate (5.4 +/- 0.7 to 9.7 +/- 0.9 nl /min; P < 0.001), it reduced the proximal-distal difference in SNGFR (befor e: 9.4 +/- 1.0 versus during CVT-124: 4.6 +/- 1.5 nl/min; P < 0.01), sugges ting that it had blunted the effects of the macula densa on SNGFR. Direct m easurements of maximal tubuloglomerular feedback (TGF) responses were made from proximal stop flow pressure (PSF) during orthograde loop perfusion fro m the proximal tubule with artificial tubular fluid at 40 nl/min. TGF was b lunted by intravenous CVT-124 (0.5 mg/kg; Delta PSF with vehicle: 8.3 +/- 0 .6 versus CVT-124: 6.5 +/- 0.3 mmHg; n = 9; P < 0.01). In conclusion, A(1)A doR blockade reduces proximal reabsorption and uncouples it from glomerular filtration. It increases distal delivery of fluid yet does not activate a macula densa-dependent fall in SNGFR because it blunts the TGF response. Na triuresis accompanied by blockade of proximal glomerulotubular balance and TGF characterizes a new class of diuretic drugs.