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.
Rocher
A
A
Department of Biochemistry and Molecular Biology and Physiology, CSIC, School of Medicine, University of Valladolid, Spain.
Gonzalez
C
C
Almaraz
L
L
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