Caffeine inhibition of rat carotid body chemoreceptors is mediated by A2A and A2B adenosine receptors.
Caffeine, an unspecific antagonist of adenosine receptors, is commonly used to treat the apnea of prematurity. We have defined the effects of caffeine on the carotid body (CB) chemoreceptors, the main peripheral controllers of breathing, and identified the adenosine receptors involved. Caffeine inhibited basal (IC50, 210 microm) and low intensity (PO2 approximately 66 mm Hg/30 mm K+) stimulation-induced release of catecholamines from chemoreceptor cells in intact preparations of rat CB in vitro. Opposite to caffeine, 5'-(N-ethylcarboxamido)adenosine (NECA; an A2 agonist) augmented basal and low-intensity hypoxia-induced release. 2-p-(2-Carboxyethyl)phenethyl-amino-5'-N-ethylcaboxamido-adenosine hydrochloride (CGS21680), 2-hexynyl-NECA (HE-NECA) and SCH58621 (A2A receptors agents) neither affected catecholamine release nor altered the caffeine effects. The 8-cycle-1,3-dipropylxanthine (DPCPX; an A1/A2B antagonist) and 8-(4-{[(4-cyanophenyl)carbamoylmethyl]-oxy}phenyl)-1,3-di(n-propyl)xanthine (MRS1754; an A2B antagonist) mimicking of caffeine indicated that caffeine effects are mediated by A2B receptors. Immunocytochemical A2B receptors were located in tyrosine hydroxylase positive chemoreceptor cells. Caffeine reduced by 52% the chemosensory discharges elicited by hypoxia in the carotid sinus nerve. Inhibition had two components with pharmacological analysis indicating that A2A and A2B receptors mediate, respectively, the low (17 x 10(-9) m) and high (160 x 10(-6) m) IC50 effects. It is concluded that endogenous adenosine, via presynaptic A2B and postsynaptic A2A receptors, can exert excitatory effects on the overall output of the rat CB chemoreceptors.
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Departamento de Bioquímica y Biología Molecular y Fisiología/Instituto de Biología y Genética Molecular, Universidad de Valladolid/Consejo Superior de Investigaciones Científicas, Facultad de Medicina, Valladolid, Spain.
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Rocher
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Gonzalez
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D000241:Adenosine / Q000502:physiology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002344:Carotid Body / Q000187:drug effects*; D002395:Catecholamines / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002628:Chemoreceptor Cells / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000187:drug effects*; D043704:Receptor, Adenosine A2B / Q000187:drug effects*; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000502:physiology; D015656:Respiratory Mechanics / Q000502:physiology; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D002395:Catecholamines; D000697:Central Nervous System Stimulants; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D017661:Receptors, Presynaptic; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; D002110:Caffeine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D011188:Potassium