title: Enhanced adenosine A2b receptor signaling facilitates stimulus-induced catecholamine secretion in chronically hypoxic carotid body type I cells.
abstract: Chronic hypoxia (CHox) augments chemoafferent activity in sensory fibers innervating carotid body (CB) chemoreceptor type I cells; however, the underlying mechanisms are poorly understood. We tested the hypothesis that enhanced paracrine signaling via adenosine (Ado) A2b receptors is involved. Dissociated rat CB cultures were exposed for 24 h to normoxia (Nox, 21% O2) or CHox (2% O2) or treated with the hypoxia mimetic deferoxamine mesylate (DFX), and catecholamine secretion from type I cells was monitored by amperometry. Catecholamine secretion was more robust in CHox and DFX type I cells than Nox controls after acute exposure to acid hypercapnia (10% CO2, pH 7.1) and high K(+) (75 mM). Exogenous Ado increased catecholamine secretion in a dose-dependent manner, and the EC50 was shifted to the right from ∼21 μM Ado in Nox cells to ∼78 μM in CHox cells. Ado-evoked secretion in Nox and CHox cells was markedly inhibited by MRS-1754, an A2b receptor blocker, but was unaffected by SCH-58261, an A2a receptor blocker. Similarly, MRS-1754, but not SCH-58261, partially inhibited high-K(+)-evoked catecholamine secretion, suggesting a contribution from paracrine activation of A2b receptors by endogenous Ado. CB chemostimuli, acid hypercapnia, and hypoxia elicited a MRS-1754-sensitive rise in intracellular Ca(2+) that was more robust in CHox and DFX than Nox cells. Taken together, these data suggest that paracrine Ado A2b receptor signaling contributes to stimulus-evoked catecholamine secretion in Nox and CHox CB chemoreceptors; however, the effects of Ado are more robust after CHox.
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Livermore
authors.forename: Colin A
authors.initials: CA
authors.lastname: Nurse
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002344:Carotid Body / Q000187:drug effects / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008564:Membrane Potentials; D019899:Paracrine Communication / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D002395:Catecholamines; D043704:Receptor, Adenosine A2B; D003676:Deferoxamine; D000241:Adenosine
keywords: A2 receptors; acid hypercapnia; adenosine; carotid body chemoreceptor; hypoxia