Adenosine receptor blockade augments interstitial fluid levels of excitatory amino acids during cerebral ischemia.
The excitotoxic hypothesis suggests that cerebral ischemic damage results in part from the accumulation of the excitatory and potentially toxic neurotransmitters glutamate and aspartate. Adenosine, which also increases during cerebral ischemia, is proposed to inhibit neurotransmitter release. The purpose of this study was to determine if adenosine receptor blockade exacerbates the accumulation of glutamate and aspartate during cerebral ischemia. Microdialysis probes, implanted bilaterally in the caudate nucleus of halothane-anesthetized rats, were used to (1) assess changes in interstitial fluid (ISF) glutamate, aspartate, adenosine, and adenosine metabolites; (2) measure local cerebral blood flow (H2 clearance); and (3) deliver 8-(p-sulfophenyl)theophylline (SPT), an adenosine receptor antagonist, locally to the brain. The probe on one side of the brain was perfused with artificial cerebrospinal fluid (CSF) containing 10(-3) M SPT, while the probe on the opposite side received only artificial CSF. Animals were exposed to 20 min of ischemia (carotid occlusion+arterial blood pressure = 50 mm Hg) followed by 60 min of reperfusion. Dialysate glutamate and aspartate increased during and after cerebral ischemia, but were increased to a greater extent in the presence of adenosine receptor blockade. Likewise, the increase in dialysate adenosine and adenosine metabolites was enhanced on the side of locally administered SPT. These data suggest that endogenous adenosine attenuates the accumulation of glutamate and aspartate during cerebral ischemia.
Department of Physiology, School of Medicine and Biomedical Sciences, State University of New York, Buffalo 14215.
V M
VM
Sciotti
F M
FM
Roche
M C
MC
Grabb
D G
DG
Van Wylen
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000378:metabolism; D008297:Male; D009498:Neurotoxins / Q000378:metabolism; D058914:Purinergic Antagonists; D051381:Rats; D011919:Rats, Inbred Strains; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D019820:Xanthine; D014970:Xanthines / Q000378:metabolism
D005971:Glutamates; D007042:Hypoxanthines; D009498:Neurotoxins; D058914:Purinergic Antagonists; D014970:Xanthines; D019820:Xanthine; D019271:Hypoxanthine; D001224:Aspartic Acid; D018698:Glutamic Acid; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline