Natriuretic and diuretic actions of a highly selective adenosine A1 receptor antagonist.
The natriuretic and diuretic action of a highly selective adenosine A1 receptor (A1AdoR) antagonist, 1,3-dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine (CVT-124), was investigated in anesthetized rats. CVT-124 (0.1 to 1 mg/kg) caused dose-dependent increases in urine flow and fractional and absolute sodium excretion of by six- to 10-fold and, at 0.1 mg/kg, increased the GFR (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 decreased fractional proximal reabsorption (60+/-3 to 46+/-4%; P<0.05). Despite 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 (before: 9.4+/-1.0 versus during CVT-124: 4.6+/-1.5 nl/min; P<0.01), suggesting that it had blunted the effects of the macula densa on SNGFR. Direct measurements of maximal tubuloglomerular feedback (TGF) responses were made from proximal stop flow pressure (PSF) during orthograde loop perfusion from the proximal tubule with artificial tubular fluid at 40 nl/min. TGF was blunted by intravenous CVT-124 (0.5 mg/kg; deltaPSF with vehicle: 8.3+/-0.6 versus CVT-124: 6.5+/-0.3 mm Hg; n = 9; P<0.01). In conclusion, A1AdoR 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. Natriuresis accompanied by blockade of proximal glomerulotubular balance and TGF characterizes a new class of diuretic drugs.
Wilcox
C S
CS
Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, DC 20007, USA. wilcoxch@gunet.georgetown.edu
Welch
W J
WJ
Schreiner
G F
GF
Belardinelli
L
L
D000704:Analysis of Variance; D000818:Animals; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005246:Feedback / Q000502:physiology; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007275:Injections, Intravenous; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009399:Nephrons / Q000187:drug effects* / Q000502:physiology; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012964:Sodium / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology*
C097280:1,3-dipropyl-8-(2-(5,6-epoxy)norbornyl)xanthine; D004232:Diuretics; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; D012964:Sodium