Respiratory effects of a long-acting analog of adenosine

The effect on respiration, measured as integrated phrenic nerve activity, of an analog of adenosine, N6(L-2-phenylisopropyl)adenosine (PIA), was determined in 26 paralyzed, vagotomized and glomectomized cats whose end-tidal pCO2 was kept constant by means of a servocontrolled ventilator. Whether given intravenously or into the third cerebral ventricle, PIA caused a dose-related depression of respiration, involving both tidal activity and respiratory frequency. In a group of 6 cats, the effects of intraventricular PIA or its vehicle alone on medullary extracellular fluid (ECF) pH were also determined. Vehicle alone had no effect on either ECF pH or respiratory activity. PIA was associated with the development over 10-20 min of a metabolic acidosis in the medulla, but still led to marked depression of respiration, thus ruling out an increase of medullary blood flow as cause of the decreased respiration. We conclude that the adenosine analog, PIA, acts to inhibit directly neurons in the brain that are involved in the control of respiration, and we suggest that adenosine may act as a tonic modulator of respiration.