TY - JOUR T1 - Chronic Caffeine Intake in Adult Rat Inhibits Carotid Body Sensitization Produced by Chronic Sustained Hypoxia but Maintains Intact Chemoreflex Output JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.081216 SP - mol.112.081216 AU - Silvia Vilares Conde AU - Maria Joao Ribeiro AU - Ana Obeso AU - Ricardo Rigual AU - Emilia C Monteiro AU - Constancio Gonzalez Y1 - 2012/08/28 UR - http://molpharm.aspetjournals.org/content/early/2012/08/28/mol.112.081216.abstract N2 - Sustained hypoxia produces a carotid body (CB) sensitization, known as acclimatization, which leads to an increase in the carotid sinus nerve (CSN) activity and ensuing hyperventilation greater than expected from the prevailing PO2,. Whether sustained hypoxia is physiological (high altitude) or pathological (lung disease), acclimatization has a homeostatic implication as it tends to minimize hypoxia. Caffeine, the most commonly ingested psychoactive drug and a non-selective adenosine receptor antagonist, alters CB function and ventilatory responses when acutely administered. Our aim is to investigate the effect of chronic caffeine intake on CB function and acclimatization using four groups of rats: normoxic, caffeine-treated normoxic, chronic hypoxic (12%O2, 15 days) and caffeine-treated chronically hypoxic-rats. Caffeine was administered in drinking water (1mg/ml). Caffeine ameliorated ventilatory responses to acute hypoxia in normoxic animals without altering the output of the CB (CSN neural activity). Chronically hypoxic-caffeine-treated rats exhibited a decrease in the CSN response to acute hypoxic tests, but maintained ventilation when compared to chronic hypoxic animals. The findings related to CSN neural activity combined with the ventilatory responses indicate that caffeine alters central integration of the CB input to increase the gain of the chemoreflex, and indicate that caffeine abolishes CB acclimatization. The putative mechanisms involved in sensitization and its loss were investigated: expression of adenosine receptors in CB (A2B) were downregulated and petrosal ganglion (PG; A2A) were upregulated in caffeine treated-chronic hypoxic rats; both adenosine and dopamine release from CB chemoreceptor cells were increased in chronic hypoxia and in caffeine-treated chronic hypoxia groups. ER -