Adenosine inhibits L-type Ca2+ current and catecholamine release in the rabbit carotid body chemoreceptor cells.
In an in vitro preparation of the intact carotid body (CB) of the rabbit, adenosine (100 microM) inhibited hypoxia-induced catecholamine release by 25%. The specific A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 1 microM) prevented the inhibition and increased the response to hypoxia further. In isolated chemoreceptor cells from the same species, adenosine inhibited voltage-dependent Ca2+ currents by 29% at 1 microM (concentration producing half-maximal inhibition, IC50 = 50 nM). This inhibition was mimicked by R(-)N6-(2-phenylisopropyl)-adenosine and 2-chloroadenosine (1 microM), two purinergic agonists poorly active at the intracellular ('P') site, and persisted in the presence of dipyridamole (a blocker of adenosine uptake; 1 microM) and was fully inhibited by 8-phenyltheophylline (10 microM). The A1 antagonists DPCPX (10 microM) and 8-cyclopentyl-1,3-dimethylxantine (0.1 microM) inhibited the effect of adenosine by 93% (IC50 = 0.14 microM) and 59%, respectively. The inhibition of the Ca2+ current (I(Ca)) was reduced by nisoldipine (an L-type Ca2+ channel antagonist) by nearly 50%, and was unaltered by omega-conotoxin GVIA, a blocker of N-type Ca2+ channels. Adenosine did not affect the voltage-dependent Na+ current (I(Na)) or K+ current (I(K)). We conclude that adenosine A1 receptors are located in chemoreceptor cells and mediate the inhibition of L-type Ca2+ channels and thereby the release of catecholamines produced by hypoxia. The data also indicate that endogenous adenosine acts as a physiological negative modulator of the chemoreceptor cell function. The previously reported excitatory action of adenosine on the activity of the sensory nerve of the CB is discussed in terms of a balance between the inhibition mediated by A1 receptors and the excitation mediated by A2 receptors.
Department of Biochemistry and Molecular Biology and Physiology, CSIC, School of Medicine, University of Valladolid, Spain.
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Rocher
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Gonzalez
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Almaraz
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D020746:Calcium Channels, L-Type; D002344:Carotid Body / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D002395:Catecholamines / Q000493:pharmacokinetics*; D002628:Chemoreceptor Cells / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D000860:Hypoxia / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D012964:Sodium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014316:Tritium; D014970:Xanthines / Q000494:pharmacology; D020866:omega-Conotoxin GVIA
D000317:Adrenergic alpha-Antagonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002395:Catecholamines; D018696:Neuroprotective Agents; D010455:Peptides; D014970:Xanthines; D014316:Tritium; C047235:N-(1-methyl-2-phenylethyl)adenosine; C053907:8-cyclopentyl-1,3-dimethylxanthine; D013779:Tetrodotoxin; D020866:omega-Conotoxin GVIA; D012964:Sodium; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D000241:Adenosine; D011188:Potassium; D002118:Calcium