The nucleoside adenosine has been implicated in the regulation of respiration especially in during hypoxia. In this study we examined respiration of unrestrained adult adenosine A1 receptor knockout mice (A1R-/-) and wildtype mice (A1R+/+) in a plethysmographic device. Under control conditions (21% O2) and mild hypoxia (15% O2) no difference in respiration patterns was observed between A1R+/+- and A1R-/- mice. Under more severe hypoxia (6–10% O2) A1R+/+-mice showed after a transient increase of respiration a slight decrease of respiration frequency

(f) and tidal volume (Vt) leading to a decrease of minute volume (MV). In contrast to this, A1R-/- mice exhibited not a decreased respiration under severe hypoxia but a stimulated one: f, Vt, and MV were enhanced by some 30–40%. The difference in hypoxia-induced breathing patterns between the genotypes could be abolished by theophylline (50 mg/g i.p.) injection: Under hypoxic conditions, theophylline led to an increase of MV in wildtype mice but had virtually no effect in A1R-/-. These data suggest that the theophylline-induced increase of respiration during hypoxia is mainly mediated via blockade of adenosine A1 receptors. Interestingly, no differences in respiration of A1R-/- and A1R+/+ were observed during hypercapnia (3–5% CO2). This is the first in vivo study clearly demonstrating that the adenosine A1 receptor is a critical determinant of the down-regulation of respiration under hypoxia in mice.