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

Abstract

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, acting 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 a random order, double-blind fashion. Resting endtidal carbon dioxide tension (PET,CO 2 ) 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,CO 2 breath-by-breath.Resting PET,CO 2 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,CO 2 intercept of the relationship between ventilation or respiratory drive and PET,CO 2 were altered by the study drugs under hyperoxic conditions. We conclude that endogenous 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.

Plasma Adenosine during Investigation of Hypoxic Ventilatory Response

“…But as mentioned before it is known that exogenous adenosine stimulates ventilation by activating the carotid bodies. [8][9][10]30,32,34 Considering the results of this study it seems possible that endogenous adenosine influences the HVR and the ventilatory drive. This reaction could help the organism to fight against hypoxia as adenosine is released within tissues under hypoxic conditions, because of increased tissue-ATP-depletion as a consequence of reduced oxygen delivery.…”

Effects of Theophylline on Ventilatory Poststimulus Potentiation in Patients with Brain Damage

“…Indeed, it has been demonstrated that theophylline did not however, posthypoxic hyperoxic ventilation did not differ with affect either the intercept of the extrapolation of hypercapnic and without theophylline. In addition, we have shown that almiventilatory response to zero ventilation (an index of apneic trine, a drug that is associated with a comparable increase in threshold) or the slope of the hypercapnic ventilatory response resting ventilation did not affect the posthypoxic hyperoxic venti- (34). Notwithstanding the uncertainty of extrapolation the ventilation (19).…”

“…Notwithstanding the uncertainty of extrapolation the ventilation (19). These data indicate that changes in resting ventilalatory response to CO 2 to below eupnea and that normal subjects tion, at least in the range observed in our study, may not be an were studied (34), these findings indicate that theophylline does important determinant of ventilatory poststimulus potentiation. not alter the CO 2 -mediated ventilatory control, rendering the Previous studies have shown that patients with periodic breathlikelihood of a selective action of theophylline on apneic threshing such as those with sleep apnea syndrome or brain damage old rather unlikely.…”

Protective role of neuronal KATP channels in brain hypoxia

“…theophylline (Hedner et al, 1982;Eldridge et al, 1985). On the other hand, adenosine stimulates breathing in conscious, unanesthetised humans (Fuller et al, 1987;Griffith et al, 1997). The depressant effect of adenosine on breathing in vivo is more potent during the time period around birth and/or is also more severe in anesthetised animals (Herlenius et al, 2002).…”