The effect of dipyridamole and theophylline on hypercapnic ventilatory responses: The role of adenosine

The purine nucleoside, adenosine, has been implicated as a neuromodulator in central respiratory depression during prolonged exposure to hypoxia. It may also be a mediator of hypoxic hyperpnoea, actin on the carotid bodies. As there may be adenosine-sensitive mechanisms of hypoxic respiratory control, we sought to determine whether adenosine might be involved as a respiratory modulator in another central but non-oxygen-related control mechanism, the ventilatory response to hyperoxic hypercapnia. Twelve normal subjects were studied following 3 days of oral treatment with placebo, dipyridamole (which potentiates adenosine effects by inhibiting cellular uptake), and theophylline (a specific adenosine antagonist of cell surface receptors). The drugs were given in random order, double-blind fashion. Resting end-tidal carbon dioxide tension (PeT,CO2) and the maximum rate of isometric inspiratory pressure change at the mouth ((dP/dt)max), an index of respiratory drive, were determined in all subjects on each treatment. Hyperoxic, hypercapnic ventilatory responses were determined in seven of these subjects using a rebreathing technique. For each hypercapnic response, minute ventilation (V'E) and (dP/dt)max were plotted against PET,CO2 breath-by-breath. Resting PET,CO2 breathing room air was lower with theophylline (5.47 (SD 0.21) kPa) than with placebo (5.74 (0.26) kPa) or dipyridamole (5.86 (0.34) kPa), with no significant drug differences in resting (dP/dt)max. However, neither the slope nor the PET,CO2 intercept of the relationship between ventilation or respiratory drive and PET,CO2 were altered by the study drugs under hyperoxic conditions. We conclude that endogeneous adenosine-related mechanisms are unlikely to be involved in determining either the sensitivity or the threshold of the ventilatory response to carbon dioxide under hyperoxic conditions. However, in normoxia, a centrally-acting, tonic adenosine-mediated, respiratory modulation is not ruled out.