The selective adenosine A1 receptor antagonist KW-3902 prevents radiocontrast media-induced nephropathy in rats with chronic nitric oxide deficiency.
Several studies have recently suggested a principal role of adenosine in the pathogenesis of radiocontrast media-induced nephropathy. In the present experiments, we therefore investigated the renal protective effects of 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902), a potent and selective adenosine A1 receptor antagonist, on radiocontrast media-induced nephropathy in the model of the N-pi-nitro-L-arginine methyl ester (L-NAME) hypertensive, chronic nitric oxide (NO)-depleted rat. Chronic NO depletion was induced by pretreatment with L-NAME, 50 mg/ml, added to drinking water for 8 weeks. Clearance experiments were performed in anesthetized rats and glomerular filtration rate was assessed prior to and following the application of high osmolar radiocontrast media (sodium diatrizoate, 3 ml/kg, i.v.) or an equivalent volume of isoosmolar mannitol to examine the role of hyperosmolarity in radiocontrast media-induced nephropathy. Subgroups received KW-3902 (0.1 mg/kg, i.v.), 20 min prior to radiocontrast media administration. Age-matched, untreated rats served as controls. Radiocontrast media application induced a significant decline in glomerular filtration rate in L-NAME hypertensive animals, whereas no effects were observed in control rats. KW-3902 fully prevented the drop in glomerular filtration rate in response to radiocontrast media in L-NAME hypertensive rats. No renal hemodynamic alterations were observed in mannitol-infused animals. The present experiments demonstrate that the decrease in glomerular filtration rate following radiocontrast media occurred independently of the osmotic load, and that KW-3902 effectively prevented the radiocontrast media-induced deterioration in renal function. KW-3902 may be especially beneficial in patients at high risk for developing acute renal failure following radiocontrast media application or in patients in which extracellular fluid volume expansion is limited by clinical conditions such as congestive heart failure.
Centre of Clinical Pharmacology and Department of Pharmacology, University of Tübingen, Wilhelmstr. 56, 72074, Tübingen, Germany. kozo.yao@kyowa.co.jp
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D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D003287:Contrast Media / Q000009:adverse effects; D003973:Diatrizoate / Q000009:adverse effects; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology* / Q000627:therapeutic use; D004234:Diuretics, Osmotic / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009402:Nephrosis, Lipoid / Q000139:chemically induced / Q000188:drug therapy; D009569:Nitric Oxide / Q000172:deficiency*; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000502:physiology; D012964:Sodium / Q000652:urine; D014970:Xanthines / Q000494:pharmacology* / Q000627:therapeutic use
D003287:Contrast Media; D004232:Diuretics; D004234:Diuretics, Osmotic; D004791:Enzyme Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; D003973:Diatrizoate; D009569:Nitric Oxide; D008353:Mannitol; C073525:rolofylline; D012964:Sodium; D019331:NG-Nitroarginine Methyl Ester