Protective Effects of KW-3902, an Adenosine A1-Receptor Antagonist, against Cisplatin-Induced Acute Renal Failure in Rats

Abstract

ABSTRACT-We investigated possible renal protective and therapeutic effects of KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine), a novel and potent adenosine A,-receptor antagonist, on cisplatin-induced acute renal failure (ARF). ARF was induced in rats by a single injection of cisplatin (5 mg/kg, i.v.). Prophylactic treatment with KW-3902 (0.01-1 mg/kg, p.o., twice a day) significantly attenuated the increases of serum creatinine (S-CRE) and urea nitrogen (S-UN) induced by cisplatin. On the other hand, neither furosemide nor trichlormethiazide showed any ameliorating effects against the cisplatin-induced ARF. In the clearance study, the cisplatin-treatment induced marked decreases of glomerular filtration rate (GFR), renal plasma flow (RPF), and reabsorptions of water, sodium and potassium at tubular sites, in comparison with those in untreated normal rats. KW-3902 (0.1 mg/kg, p.o., twice a day) significantly improved these deteriorated glomerular and tubular functions. In the rats with established cisplatin-induced ARF, KW-3902 ameliorated the cisplatin-induced reductions of GFR, RPF, and reabsorptions of water, sodium and potassium at tubular sites. These results suggest that activation of adenosine A,-receptors is involved in the pathogenesis of cisplatin-induced ARF. The adenosine A,-receptor antagonist may be useful for the treatment of cisplatin-induced ARF.

Protective Effect of Tonapofylline (BG9928), an Adenosine A₁ Receptor Antagonist, against Cisplatin-Induced Acute Kidney Injury in Rats

“…In support of this is the observation by Jackson et al [33], that despite significant changes in GFR and RVR with the low dose (4 mg/kg) of CIS used, and the lack of efficacy of DPCPX, they saw no difference in the renal cortical interstitial levels of adenosine compared with control rats. In contrast, Nagashima et al [18], documented increased serum adenosine in the renal vein following 5 mg/kg CIS which gave marked renal injury with rolofylline being highly effective. Further studies are required to investigate these apparent correlations.…”

“…The reduction in tubular fluid flow appears to be associated with reduced renal plasma flow and effective filtration as a result of renal vasoconstriction [18] due partly to the release of adenosine [8,26]. …”

Role of the Lipid Emulsion on an Injectable Formulation of Lipophilic KW-3902, a Newly Synthesized Adenosine A1-Receptor Antagonist.

“…3) and it would be considered as a intrinsic pharmacokinetics of KW-3902 after injection in rats at 0.1 and 1 mg/kg, which are considered effective doses of KW-3902. 20,21) The amount of KW-3902 taken up by liver was about 8% of the dose at 10 min after injection irrespective of the dosage form (Figs. 4, 5).…”

“…15,16) Recently, it was reported that KW-3902 has potent diuretic and renal protective activities in rats and dogs. [17][18][19] Additionally, KW-3902 induces a diuretic effect in various models of acute renal failure in rats 20,21) and would be expected to have therapeutic value. In a previous study, 22) we developed a lipid emulsion of KW-3902 as an injectable formulation, because KW-3902 has a solubility of less than 1 mg/ml in water.…”

Theophylline Improves Early Allograft Function in Rat Kidney Transplantation

“…Adenosine-mediated afferent arteriolar vasoconstriction and a subsequent decrease in glomerular filtration pressure have been identified as a key hemodynamic mechanism, which contributes to acute renal failure following renal ischemia or administration of nephrotoxic substances (Osswald and Vallon, 1998). Theophylline or other adenosine receptor antagonists have been found to improve renal function in the following models of acute renal failure in laboratory animals: 1-h renal artery clamping (Lin et al, 1986;Gouyon and Guignard, 1988), administration of glycerol (Bidani and Churchill, 1983;Yates et al, 1987), uranyl nitrate (Osswald et al, 1979), radio contrast media (Arend et al, 1987;Erley et al, 1997), am-photericin B (Heidemann et al, 1983), and cisplatin (Heidemann et al, 1989;Nagashima et al, 1995). In humans, theophylline prevented renal functional deterioration following application of radio contrast media (Erley et al, 1994;Ix et al, 2004) and cisplatin-containing chemotherapy (Benoehr et al, 2005).…”