Characterization of the effects of adenosine receptor agonists on cerebral blood flow in uninjured and traumatically injured rat brain using continuous arterial spin-labeled magnetic resonance imaging.
Hypoperfusion after traumatic brain injury may exacerbate damage. Adenosine, a vasodilator, regulates cerebral blood flow (CBF). Treatment with adenosine receptor agonists has shown benefit in experimental CNS trauma; however, their effects on CBF after injury remain undefined. We used magnetic resonance imaging to assess CBF in uninjured rats both early and at 24 h after intrahippocampal administration of either the nonselective adenosine receptor agonist 2-chloroadenosine (2-CA, 12 nmol) or the A(2A)-receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarbox-amidoadenosine (CGS 21680, 6 nmol). We also assessed the effects of these agents on cerebral metabolic rate for glucose (CMRglu). We then assessed the effect of 2-CA on CBF at 3.5 to 5 h after controlled cortical impact (CCI). Injection of 2-CA into uninjured rat brain produced marked increases in CBF in ipsilateral hippocampus and cortex versus vehicle (P<0.05); CBF increases persisted even at 24 h. Measurement of hippocampal levels of 2-CA showed persistent increases to 24 h. CGS 21680 produced even more marked global increases in CBF than seen with 2-CA (2-6-fold versus vehicle, P<0.05 in 10/12 regions of interest (ROIs)). Neither agonist altered CMRglu versus vehicle. After CCI, 2-CA increased CBF in ipsilateral hippocampal and hemispheric ROIs (P<0.05 versus vehicle), but the response was attenuated at severe injury levels. We report marked increases in CBF after injection of adenosine receptor agonists into uninjured rat brain despite unaltered CMRglu. 2-Chloroadenosine produced enduring increases in CBF in uninjured brain and attenuated posttraumatic hypoperfusion. Future studies of adenosine-related therapies in CNS injury should address the role of CBF.
Kochanek
Patrick M
PM
Safar Center for Resuscitation Research, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA. Kochanekpm@ccm.upmc.edu
Hendrich
Kristy S
KS
Jackson
Edwin K
EK
Wisniewski
Stephen R
SR
Melick
John A
JA
Shore
Paul M
PM
Janesko
Keri L
KL
Zacharia
Lefteris
L
Ho
Chien
C
D015762:2-Chloroadenosine / Q000493:pharmacokinetics / Q000494:pharmacology*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D015599:Trauma Severity Indices
D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D000959:Antihypertensive Agents; D010627:Phenethylamines; D013113:Spin Labels; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D015762:2-Chloroadenosine; D000241:Adenosine