Ventilatory effects of gap junction blockade in the RTN in awake rats

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Abstract
We tested the hypothesis that carbenoxolone, a pharmacological inhibitor of gap junctions, would reduce the ventilatory response to CO2 when focally perfused within the retrotrapezoid nucleus (RTN). We tested this hypothesis by measuring minute ventilation (VE), tidal volume (VT), and respiratory frequency (FR) responses to increasing concentrations of inspired CO2 (FiCO2 = 0–8%) in rats during wakefulness. We confirmed that the RTN was chemosensitive by perfusing the RTN unilaterally with either acetazolamide (AZ; 10 μM) or hypercapnic artificial cerebrospinal fluid equilibrated with 50% CO2 (pH ∼6.5). Focal perfusion of AZ or hypercapnic aCSF increased VE, VT, and FR during exposure to room air. Carbenoxolone (300 μM) focally perfused into the RTN decreased VE and VT in animals 12 wk of age. Glyzyrrhizic acid, a congener of carbenoxolone, did not change VE, VT, or FR when focally perfused into the RTN. Carbenoxolone binds to the mineralocorticoid receptor, but spironolactone (10 μM) did not block the disinhibition of VE or VT in older animals when combined with carbenoxolone. Thus the RTN is a CO2 chemosensory site in all ages tested, but the function of gap junctions in the chemosensory process varies substantially among animals of different ages: gap junctions amplify the ventilatory response to CO2 in younger animals, but appear to inhibit the ventilatory response to CO2 in older animals.