Adenosinergic modulation of ventilation in obese zucker rats

Objectives: The goal of our study was to determine whether altered adenosinergic mechanisms contribute to the depressed ventilatory response observed in obese Zucker rats. Research Methods and Procedures: Eight lean and eight obese Zucker rats were studied at 7 to 8 weeks of age. Ventilation (V _E) during room air, during 5-minute hypercapnic (7% CO₂, balance O₂), and during 30-minute sustained hypoxic (10% O ₂) exposures were sequentially measured by the barometric method on three separate occasions after the randomized blinded administration of equal volumes of either saline (control), 8-(p-sulfophenyl)-theophylline (8-PST, 7 mg/kg, peripheral adenosine antagonist), or aminophylline (AMPH, 15 mg/kg, peripheral and central adenosine antagonist). Results: During room air and hypercapnic exposures, AMPH (but not 8-PST) significantly (p < 0.05) increased V_E in both lean and obese rats. During acute (2 minute) hypoxic exposure, 8-PST (but not AMPH) significantly depressed V_E in lean rats. In contrast, AMPH (but not 8-PST) selectively increased V_E in obese rats. During sustained (10 to 30 minutes) hypoxic exposure, neither AMPH nor 8-PST administration altered V_E in lean rats. In contrast, AMPH (but not 8-PST) selectively increased V_E during the late response in obese rats. Discussion: Our findings indicate that obese rats possess altered adenosinergic modulation of ventilatory responses to acute and sustained hypoxia in two opposite ways. We conclude that the reduced hypoxic ventilatory response observed in obese Zucker rats is attributed to depressed adenosinergic peripheral excitatory mechanisms and to enhanced adenosinergic central depression mechanisms, both of which contribute to the blunted ventilatory response in obesity.