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ENVIRONMENTAL, EXERCISE AND RESPIRATORY PHYSIOLOGY

Disruption of adenosinergic modulation of ventilation at rest and during hypercapnia by neonatal caffeine in young rats: role of adenosine A₁ and A_2A receptors

¹Department of Pediatric, Laval University, Centre de Recherche Hôpital St-François d'Assise, Quebec, Canada

Submitted 19 July 2006 ; accepted in final form 20 November 2006

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 A₁- 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 (A₁ antagonist, 4 mg/kg), or ZM-241385 (A_2A antagonist, 1 mg/kg) before plethysmographic measurements of resting ventilation, hypercapnic ventilatory response (5% CO₂), and occurrence of apneas in freely behaving rats. In controls, data show that A_2A, but not A₁, antagonist decreased resting ventilation by 31% (P = 0.003). A₁ 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, A₁ antagonist increased resting ventilation by 27% (P = 0.02), but the increase of the hypercapnic response was blunted compared with controls. A₁ 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 CO₂ via A₁ receptors. NCT elicits developmental plasticity of adenosinergic modulation, since neonatal caffeine persistently decreases ventilatory sensitivity to adenosine blockers.

control of breathing; carbon dioxide chemosensitivity; ventilation; plasticity; hypercapnic ventilatory response

This article has been cited by other articles:

				G. Montandon, A. Bairam, and R. Kinkead Neonatal caffeine induces sex-specific developmental plasticity of the hypoxic respiratory chemoreflex in adult rats Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2008; 295(3): R922 - R934. [Abstract] [Full Text] [PDF]