EFFECTS OF REPEATED ADMINISTRATION OF KW-3902, A NOVEL ADENOSINE A(1)-RECEPTOR ANTAGONIST, ON ITS PHARMACOLOGICAL ACTIONS

Effects of repeated administration of KW-3902, a novel adenosine Al-receptor antagonist, on its pharmacological actions were studied with regards to: 1) in vivo adenosine A(1)-antagonism, 2) diuretic effects and 3) renal protective effects against glycerol-induced acute renal failure (ARF). After repeated oral administration of KW-3902 (0.1 mg/kg/day) for 24 days, neither enhancement of the sensitivity to 5'-N-ethylcarboxamidoadenosine (NECA) nor reduction of the inhibitory effect of KW-3902 on the NECA-induced bradycardic response were observed. After repeated oral administration of KW-3902 (0.01 and 0.1 mg/kg/day) for 20 days, the diuretic effects of KW-3902 did not change. Renal protective effects against glycerol-induced ARF were not reduced by repeated oral administration of KW-3902 (0.01 and 0.1 mg/kg/ day) for 23 days. These results suggest that repeated oral administration of KW-3902 has no effect on its pharmacological actions. Additionally, changes in serum parameters, which occurred after repeated administration of furosemide or trichlormethiazide, were minimal after repeated oral administration of KW3902 (0.001-1mg/kg/day) for 27 days. From these results, KW-3902 proved to be a diuretic which has renal protective effects with less side effects.