Diuretic and renal protective effects of 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902), a novel adenosine A1-receptor antagonist, via pertussis toxin insensitive mechanism.
KW-3902 [8-(noradamantan-3-yl)-1,3-dipropylxanthine] is a novel potent and selective adenosine A1-receptor antagonist. In anesthetized rats, KW-3902 (0.1 and 1 mg/kg p.o.) antagonized the 5'-N-ethylcarboxamidoadenosine (NECA) induced bradycardic response, which is thought to be mediated via adenosine A1-receptors. However, the hypotensive response to NECA, which is predominantly due to adenosine A2-receptor activation, was not affected by KW-3902. Diuretic and renal protective effects of KW-3902 were investigated in normal and pertussis toxin (IAP; 10 micrograms/kg i.v.)-treated rats. KW-3902 (0.001-1 mg/kg p.o.) caused significant 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 diuresis and natriuresis with no change in renal plasma flow and glomerular filtration rate. These findings suggest that KW-3902 caused the diuretic effect not by the change in the renal hemodynamics, but by the inhibition of water and sodium reabsorption in tubular sites. KW-3902 (0.01-1 mg/kg p.o.) significantly attenuated increases of serum creatinine and urea nitrogen and renal tubular damage in glycerol-induced acute 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 compatible with the hypothesis that diuretic and renal protective effects by adenosine A1-receptor blockade are mediated via IAP-insensitive mechanism.
Mizumoto
H
H
Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka-ken, Japan.
Karasawa
A
A
Kubo
K
K
D000042:Absorption; D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood / Q000652:urine; D004232:Diuretics / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005990:Glycerol; D007668:Kidney / Q000187:drug effects*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008297:Male; D037342:Pertussis Toxin; D058914:Purinergic Antagonists; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D012964:Sodium / Q000493:pharmacokinetics; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*; D014867:Water / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology*; D010130:p-Aminohippuric Acid / Q000652:urine
D004232:Diuretics; D058914:Purinergic Antagonists; D010566:Virulence Factors, Bordetella; D014970:Xanthines; D014867:Water; D019830:Adenosine-5'-(N-ethylcarboxamide); C073525:rolofylline; D012964:Sodium; D003404:Creatinine; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000241:Adenosine; D005990:Glycerol; D010130:p-Aminohippuric Acid