Reduced adenosine uptake accelerates ischaemic block of population spikes in hippocampal slices from streptozotocin-treated diabetic rats.
We have used rats with streptozotocin-induced diabetes to investigate the effects of hyperglycaemia-mediated impaired nucleoside uptake on the actions of endogenous adenosine in hippocampal slices. In control tissue under conditions of anoxia and aglycaemia the rise in the extracellular adenosine concentration resulted in complete inhibition of synaptic activity in about 2 min. In slices from previously hyperglycaemic rats the inhibition of synaptically mediated responses occurred significantly faster, although this change could be prevented by insulin treatment. Application of the selective adenosine A1 receptor antagonist [8-cyclopentyl-1,3-dipropylxanthine (DPCPX)] prevented the anoxia/aglycaemia-mediated inhibition and, furthermore, abolished the differences in the electrophysiological responses between control and diabetic tissue. The effects of impaired nucleoside uptake could be mimicked in control slices by applying the nucleoside uptake blocker hydroxynitrobenzylthioinosine (HNBTI). This had the effect of speeding up the rate of anoxia/aglycaemia-induced synaptic inhibition in control tissue to that seen in diabetic tissue. However, such treatment had no effect on the responses in diabetic tissue as expected if the HNBTI-sensitive uptake process was already inhibited by the chronic hyperglycaemia. The impairment of nucleoside uptake by chronic hyperglycaemia results in the potentiation of the modulatory actions of endogenous adenosine in the central nervous system. Such an alteration in adenosine function may be important in explaining behavioural and pathological changes associated with diabetes mellitus.
Cassar
M
M
Department of Physiology & Biophysics, Imperial College School of Medicine at St. Mary's, London, UK.
Jones
M G
MG
Szatkowski
M
M
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000241:Adenosine / Q000493:pharmacokinetics*; D000345:Affinity Labels; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D007003:Hypoglycemia / Q000378:metabolism; D002534:Hypoxia, Brain / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013868:Thioinosine / Q000031:analogs & derivatives; D014970:Xanthines / Q000494:pharmacology
D000345:Affinity Labels; D014970:Xanthines; D013868:Thioinosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; C001789:4-nitrobenzylthioinosine; D000241:Adenosine