Attenuation of experimental subarachnoid hemorrhage--induced cerebral vasospasm by the adenosine A2A receptor agonist CGS 21680.
OBJECTIVE
Impaired endothelium-dependent relaxation is present in vasospastic cerebral vessels after subarachnoid hemorrhage (SAH) and may result from deficient production of endothelial nitric oxide synthase (eNOS) or increased production and/or activity of inducible NOS (iNOS). Accumulating evidence demonstrates that adenosine A2A receptors increase the production of NO by human and porcine arterial endothelial cells, which in turn leads to vasodilation. This study was designed to examine the effects of an adenosine A2A receptor agonist, (2(4-[2-carboxyethyl]phenyl)ethylamino)-5'-N-ethylcarboxamidoadenosine (CGS 21680), in the prevention of SAH-induced vasospasm.


METHODS
. Experimental SAH was induced in Sprague-Dawley rats by injecting 0.3 ml of autologous blood into the cisterna magna of each animal. Intraperitoneal injections of CGS 21680 or vehicle were administered 5 minutes and 24 hours after induction of SAH. The degree of vasospasm was determined by averaging measurements of cross-sectional areas of the basilar artery (BA) 48 hours after SAH. Expression of eNOS and iNOS in the BA was also evaluated. Prior to perfusion-fixation, there were no significant differences among animals in the control and treated groups in any physiological parameter that was recorded. The CGS 21680 treatment significantly attenuated SAH-induced vasospasm. Induction of iNOS mRNA and protein in the BA by the SAH was significantly diminished by administration of CGS 21680. The SAH-induced suppression of eNOS mRNA and protein was also relieved by the CGS 21680 treatment.


CONCLUSIONS
This is the first evidence that adenosine A2A receptor agonism is effective in preventing SAH-induced vasospasm without significant complications. The beneficial effect of adenosine A2A receptor agonists may be, at least in part, related to the prevention of augmented expression of iNOS and the preservation of normal eNOS expression following SAH. Adenosine A2A receptor agonism holds promise in the treatment of cerebral vasospasm following SAH and merits further investigation.
Lin
Chih-Lung
CL
Department of Neurosurgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Shih
Huei-Chuan
HC
Lieu
Ann-Shung
AS
Lee
Kung-Shing
KS
Dumont
Aaron S
AS
Kassell
Neal F
NF
Howng
Shen-Long
SL
Kwan
Aij-Lie
AL
D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010627:Phenethylamines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D020301:Vasospasm, Intracranial / Q000209:etiology* / Q000517:prevention & control*
D058908:Adenosine A2 Receptor Agonists; D000959:Antihypertensive Agents; D010627:Phenethylamines; D012333:RNA, Messenger; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D000241:Adenosine