title: Disruption of adenosinergic modulation of ventilation at rest and during hypercapnia by neonatal caffeine in young rats: role of adenosine A(1) and A(2A) receptors.
abstract: Caffeine is commonly used to treat respiratory instabilities related to prematurity. However, the role of adenosinergic modulation and the potential long-term effects of neonatal caffeine treatment (NCT) on respiratory control are poorly understood. To address these shortcomings, we tested the following hypotheses: 1) adenosine A(1)- and A(2A)-receptor antagonists modulate respiratory activity at rest and during hypercapnia; 2) NCT has long-term consequences on adenosinergic modulation of respiratory control. Rat pups received by gavage either caffeine (15 mg/kg) or water (control) once a day from postnatal days 3 to 12. At day 20, rats received intraperitoneal injection with vehicle, DPCPX (A(1) antagonist, 4 mg/kg), or ZM-241385 (A(2A) antagonist, 1 mg/kg) before plethysmographic measurements of resting ventilation, hypercapnic ventilatory response (5% CO(2)), and occurrence of apneas in freely behaving rats. In controls, data show that A(2A), but not A(1), antagonist decreased resting ventilation by 31% (P = 0.003). A(1) antagonist increased the hypercapnic response by 60% (P < 0.001), whereas A(2A) antagonist increased the hypercapnic response by 42% (P = 0.033). In NCT rats, A(1) antagonist increased resting ventilation by 27% (P = 0.02), but the increase of the hypercapnic response was blunted compared with controls. A(1) antagonist enhanced the occurrence of spontaneous apneas in NCT rats only (P = 0.005). Finally, A(2A) antagonist injected in NCT rats had no effect on ventilation. These data show that hypercapnia activates adenosinergic pathways, which attenuate responsiveness (and/or sensitivity) to CO(2) via A(1) receptors. NCT elicits developmental plasticity of adenosinergic modulation, since neonatal caffeine persistently decreases ventilatory sensitivity to adenosine blockers.
authors.affiliation: Department of Pediatric, Laval University, Centre de Recherche Hôpital St-François d'Assise (D0-711 10 rue de l'Espinay, Québec, QC, Canada G1L 3L5. gaspard.montandon.1@ulaval.ca
authors.forename: Gaspard
authors.initials: G
authors.lastname: Montandon
authors.forename: Richard
authors.initials: R
authors.lastname: Kinkead
authors.forename: Aida
authors.initials: A
authors.lastname: Bairam
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002110:Caffeine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D006935:Hypercapnia; D007274:Injections, Intraperitoneal; D008297:Male; D010991:Plethysmography / Q000187:drug effects; D012123:Pulmonary Ventilation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D012146:Rest; D013997:Time Factors; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology; D014970:Xanthines / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000697:Central Nervous System Stimulants; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; D002110:Caffeine; C051360:1,3-dipropyl-8-cyclopentylxanthine