Abstract
Sustained hypoxia produces a carotid body (CB) sensitization, known as acclimatization, which leads to an increase in carotid sinus nerve (CSN) activity and ensuing hyperventilation greater than expected from the prevailing partial pressure of oxygen. Whether sustained hypoxia is physiological (high altitude) or pathological (lung disease), acclimatization has a homeostatic implication because it tends to minimize hypoxia. Caffeine, the most commonly ingested psychoactive drug and a nonselective adenosine receptor antagonist, alters CB function and ventilatory responses when administered acutely. Our aim was to investigate the effect of chronic caffeine intake on CB function and acclimatization using four groups of rats: normoxic, caffeine-treated normoxic, chronically hypoxic (12% O2, 15 days), and caffeine-treated chronically hypoxic rats. Caffeine was administered in drinking water (1 mg/ml). Caffeine ameliorated ventilatory responses to acute hypoxia in normoxic animals without altering the output of the CB (CSN neural activity). Caffeine-treated chronically hypoxic rats exhibited a decrease in the CSN response to acute hypoxia tests but maintained ventilation compared with chronically 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 that caffeine abolishes CB acclimatization. The putative mechanisms involved in sensitization and its loss were investigated: expression of adenosine receptors in CB (A2B) was down-regulated and that in petrosal ganglion (A2A) was up-regulated in caffeine-treated chronically hypoxic rats; both adenosine and dopamine release from CB chemoreceptor cells was increased in chronic hypoxia and in caffeine-treated chronic hypoxia groups.
Footnotes
The work was supported by Junta de Castilla y Leon [GR242]; Ciber de Enfermedades Respiratorias [CB06/06/0050 (FISS-ICiii)]; Dirección General de Investigación Científica y Tecnológica [BFU2007-61848]; Spanish Micinn/Portugal CRUP [2009-0172]; and Portuguese Foundation for Science and Technology [PTDC/SAU-ORG/111417/2009].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- CB
- carotid body
- CSN
- carotid sinus nerve
- PG
- petrosal ganglion
- DA
- dopamine
- ACh
- acetylcholine
- VE
- minute ventilation
- PO2
- partial pressure of oxygen
- N
- normoxic
- CafN
- caffeine-treated normoxic
- CH
- chronically hypoxic
- CafH
- caffeine-treated chronically hypoxic
- PCA
- perchloric acid
- HPLC
- high-performance liquid chromatography
- ANOVA
- analysis of variance.
- Received July 13, 2012.
- Accepted August 28, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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