The mechanism of inhibition by xanthine of adenosine A1-receptor responses in rat hippocampus.
We have recently observed that the free radical-generating mixture of xanthine and xanthine oxidase (X/XO) can suppress the inhibitory effects of adenosine on synaptic transmission in the hippocampus, but that this action can be mimicked by xanthine alone. We have now clarified the mechanism of these interactions by using the new, potent and highly selective inhibitor of xanthine oxidase, 1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid (Y-700). Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region of rat hippocampal slices. X/XO induced a long-lasting increase of fEPSP slope and significantly reduced the presynaptic inhibitory effect of adenosine. Both these actions were prevented by Y-700 at a concentration of only 200nM. Similarly the superfusion of xanthine alone increased fEPSP slope and reduced sensitivity to adenosine but these effects were also prevented by Y-700. The results indicate that the antagonism of adenosine responses by X/XO or by xanthine alone are entirely attributable to the activity of the added or endogenous XO activity, probably generating free radicals, and are not likely to be caused by a direct antagonistic action at the xanthine-sensitive site on the adenosine receptor.
Shahraki
Ali
A
Institute of Biomedical and Life Sciences, University of Glasgow, West Medical Building, Glasgow G12 8QQ, Scotland, UK.
Fukunari
Atsushi
A
Stone
Trevor W
TW
D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000502:physiology; D019820:Xanthine / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
C433950:1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid; D058916:Adenosine A1 Receptor Antagonists; D011720:Pyrazoles; D043682:Receptor, Adenosine A1; D019820:Xanthine; D014969:Xanthine Oxidase