Adenosine can mediate its actions through generation of reactive oxygen species.
Adenosine is an important cerebral vasodilator, but mediating mechanisms are not understood. We investigated the expression of adenosine receptor subtypes in isolated cerebral arterial muscle cells (CAMCs), and their role in adenosine-induced superoxide (O(2)(-)) generation and reduction in cerebral arterial tone. Reverse transcriptase-PCR, western blotting, and immunofluorescence studies have shown that CAMCs express transcript and protein for A1, A(2A), A(2B), and A(3) adenosine receptors. Stimulation of CAMCs with adenosine or the A(2A) agonist CGS-21680 increased the generation of O(2)(-) that was attenuated by the inhibition of A(2A) and A(2B) adenosine receptor subtypes, or by the peptide inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase gp91ds-tat, or by the mitochondria uncoupler 2,4-dinitrophenol. Application of adenosine or CGS-21680 dilated pressure-constricted cerebral arterial segments that were prevented by the antioxidants superoxide dismutase (SOD) conjugated to polyethylene glycol (PEG) and PEG-catalase or by the A(2B) adenosine receptor antagonist MRS-1754, or by the mixed A(2A) and A(2B) antagonist ZM-241385. Antagonism of the A(2A) and A(2B) adenosine receptors had no effect on cerebral vasodilatation induced by nifedipine. These findings indicate that adenosine reduces pressure-induced cerebral arterial tone through stimulation of A(2A) and A(2B) adenosine receptors and generation of O(2)(-) from NADPH oxidase and mitochondrial sources. This signaling pathway could be one of the mediators of the cerebral vasodilatory actions of adenosine.
Gebremedhin
Debebe
D
Department of Physiology, Medical College of Wisconsin, Milwaukee, 53226, USA. mariyei@mcw.edu
Weinberger
Brian
B
Lourim
David
D
Harder
David R
DR
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression; D008297:Male; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000032:analysis / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
D000959:Antihypertensive Agents; D016166:Free Radical Scavengers; D010627:Phenethylamines; D018047:Receptors, Purinergic P1; C070295:catalase-polyethylene glycol; D013481:Superoxides; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D011092:Polyethylene Glycols; D002374:Catalase; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase; D000241:Adenosine