Adenosine A2A-receptor blockade abolishes the roll-off respiratory response to hypoxia in awake lambs

Nicholas S. Assali Perinatal Research Laboratory, Department of Obstetrics and Gynecology, and Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, California Submitted 25 October 2004 ; accepted in final form 21 December 2004 Adenosine (ADO) receptor antagonists (aminophylline, caffeine) blunt the respiratory roll-off response to hypoxia in the newborn. This study was designed to determine the ADO receptor subtype involved in the respiratory depression. Chronically catheterized lambs of 7–16 days of age breathed via face mask a gas mixture with a fraction of inspired O 2 of 0.21 (normoxia) or 0.07 (hypoxia), while being infused intravascularly with 9-cyclopentyl-1,3-dipropylxanthine (DPCPX; ADO A 1 -receptor antagonist, n = 8), ZM-241385 (ADO A 2A -receptor antagonist, n = 7), or vehicle. Ventilation was measured at 20°C by a turbine transducer flowmeter. In normoxia [arterial P O 2 (Pa O 2 ) of 83 Torr], infusion of vehicle did not alter cardiorespiratory measurements, whereas hypoxia (Pa O 2 of 31 Torr, 15 min) elicited biphasic effects on mean arterial pressure (transient increase), heart rate (HR; diminishing tachycardia), and minute ventilation. In the latter, hypoxia increased ventilation to a peak value of 2.5 times control within the first 3 min, which was followed by a significant ( P < 0.05) decline to 50% of the maximum increment over the subsequent 7 min. ZM-241385 abolished the hypoxic ventilatory roll-off and blunted the rate of rise in HR without affecting mean arterial pressure or rectal temperature responses. In normoxia, DPCPX increased ventilation and mean arterial pressure but did not change HR. Compared with vehicle, DPCPX did not significantly affect cardiorespiratory responses to hypoxemia (Pa O 2 of 31 Torr, 10 min). It is concluded that 1 ) ADO A 2A receptors are critically involved in the ventilatory roll-off and HR responses to hypoxia, and 2 ) ADO A 1 receptors, which are tonically active in cardiorespiratory control in normoxia, appear to have little impact on hypoxic ventilatory depression. brain; newborn; respiration; caffeine; thermoregulation Address for reprint requests and other correspondence: B. J. Koos, 22-128 CHS, Dept. of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1740 (E-mail address: bkoos{at}mednet.ucla.edu )