DIURETIC AND RENAL PROTECTIVE EFFECTS OF 8-(NORADAMANTAN-3-YL)-1,3-DIPROPYLXANTHINE (KW-3902), A NOVEL ADENOSINE-A(1)-RECEPTOR ANTAGONIST, VIA PERTUSSIS TOXIN-INSENSITIVE MECHANISM

KW-3902 [8-(noradamantan-3-yl)-1,3-dipropylxanthine] is a novel potent and selective adenosine Al-receptor antagonist. In anesthetized rats, KW-3902 (0.1 and 1 mg/kg p.o.) antagonized the 5'-N-ethylcarboxamidoa denosine (NECA) induced bradycardic response, which is thought to be m ediated via adenosine Al-receptors. However, the hypotensive response to NECA, which is predominantly due to adenosine A2-receptor activatio n, was not affected by KW-3902. Diuretic and renal protective effects of KW-3902 were investigated in normal and pertussis toxin (IAP; 10 mu g/kg i. v.)-treated rats. KW-3902 (0.001 -1 mg/kg p.o.) caused signifi cant increases of urine volume and sodium excretion with little change of potassium excretion in saline-loaded normal rats. In anesthetized normal rats, KW-3902 (0.01 and 0.1 mg/kg i.v.) caused significant diur esis and natriuresis with no change in renal plasma flow and glomerula r filtration rate. These findings suggest that KW-3902 caused the diur etic effect not by the change in the renal hemodynamics, but by the in hibition of water and sodium reabsorption in tubular sites. KW-3902 (0 .01-1 mg/kg p.o.) significantly attenuated increases of serum creatini ne and urea nitrogen and renal tubular damage in glycerol-induced acut e renal failure rats. Neither diuretic nor renal protective effects of KW-3902 were affected by pretreatment of rats with IAP, which totally abolished the bradycardic response to NECA. These results are compati ble with the hypothesis that diuretic and renal protective effects by adenosine A1-receptor blockade are mediated via IAP-insensitive mechan ism.