Prevention of radiocontrast-induced nephropathy by adenosine antagonists in rats with chronic nitric oxide deficiency.
To evaluate therapeutic options for the prevention of radiocontrast media (RCM)-induced nephropathy, a model was developed in which rats received NG-nitro-L-arginine methyl ester (L-NAME) for 10 wk in order to inhibit nitric oxide (NO) synthetase. This study tests the hypothesis that infusion of an adenosine antagonist before RCM application may avoid the vasoconstrictive response in NO-depleted rats. Rats received L-NAME for 10 wk orally (50 mg/L drinking water) to achieve NO depletion. Renal function was determined by [3H]inulin clearance for analysis of the GFR and by flowmetry for assessing renal blood flow (RBF). After a control clearance period (baseline clearance period), the renal response to RCM application (sodium diatrizoate, 2 ml/kg body wt) was measured two times every 30 min starting 30 min after RCM application (clearance periods 1 and 2). L-NAME rats and control rats received two adenosine antagonists. The nonselective adenosine antagonist theophylline was given as an initial bolus of 50 mumol/kg body wt within 10 min, followed by continuous infusion of 100 mumol/kg body wt per h, and the specific adenosine A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was given as a bolus of 100 micrograms/kg body wt before RCM application. Results were compared with vehicle infusion. In the control group, no significant change of GFR or RBF could be detected after application of RCM with or without prior infusion of DPCPX or theophylline. In L-NAME rats, RBF decreased significantly after RCM application (baseline, 5.6 +/- 0.2 ml/min; first clearance period, 4.6 +/- 0.3 ml/min [P < 0.05]; second clearance period, 4.3 +/- 0.3 [P < 0.01]). GFR was also reduced in L-NAME rats without previous infusion of theophylline or DPCPX (baseline, 0.95 +/- 0.1 ml/min; first clearance period, 0.83 +/- 0.1 ml/min; second clearance period, 0.69 +/- 0.1 ml/min [P = 0.058]). Prior treatment with either theophylline or DPCPX resulted in complete protection against a decline of RBF and GFR induced by RCM in L-NAME rats. Rats with chronic NO blockade showed a significant increase of the renal vasoconstrictive effect of contrast media. Application of L-NAME in rats seems to constitute a suitable animal model to study the pathophysiology of radiocontrast media-induced nephropathy. In this animal model, administration of adenosine antagonists prevented the decline of GFR and RBF.
Erley
C M
CM
Department of Internal Medicine III, University of Tübingen, Germany.
Heyne
N
N
Burgert
K
K
Langanke
J
J
Risler
T
T
Osswald
H
H
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D000241:Adenosine / Q000037:antagonists & inhibitors; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003287:Contrast Media / Q000633:toxicity*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D013806:Theophylline / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014970:Xanthines / Q000494:pharmacology
D003287:Contrast Media; D004791:Enzyme Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; D009569:Nitric Oxide; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D019001:Nitric Oxide Synthase; D000241:Adenosine; D019331:NG-Nitroarginine Methyl Ester