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

Am J Physiol Regul Integr Comp Physiol. 2007 Apr;292(4):R1621-31. doi: 10.1152/ajpregu.00514.2006. Epub 2006 Nov 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Antagonists
  • Animals
  • Caffeine / administration & dosage
  • Caffeine / blood
  • Caffeine / pharmacology*
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / blood
  • Central Nervous System Stimulants / pharmacology*
  • Hypercapnia*
  • Injections, Intraperitoneal
  • Male
  • Plethysmography / drug effects
  • Pulmonary Ventilation / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Adenosine A1 / metabolism*
  • Receptor, Adenosine A2A / metabolism*
  • Rest
  • Time Factors
  • Triazines / administration & dosage
  • Triazines / pharmacology
  • Triazoles / administration & dosage
  • Triazoles / pharmacology
  • Xanthines / administration & dosage
  • Xanthines / pharmacology


  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Antagonists
  • Central Nervous System Stimulants
  • Receptor, Adenosine A1
  • Receptor, Adenosine A2A
  • Triazines
  • Triazoles
  • Xanthines
  • ZM 241385
  • Caffeine
  • 1,3-dipropyl-8-cyclopentylxanthine