EFFECTS OF HALOPERIDOL AND DOMPERIDONE ON VENTILATORY ROLL OFF DURING SUSTAINED HYPOXIA IN CATS

In a previous work, we showed that the adult cat demonstrates a ventilatory decline during sustained hypoxia (the "roll off" phenomenon) and that the mechanism responsible for this secondary decrease in ventilation lies within the central nervous system (J. Appl. Physiol. 63: 1658-1664, 1987). In this study, we sought to determine whether central dopaminergic mechanisms could have a role in the roll off. We studied the effects of haloperidol, a peripheral and centrally acting dopamine receptor antagonist, on the ventilatory response to sustained isocapnic hypoxia (end-tidal PO2 40-50 Torr, 20-25 min) in awake cats. In vehicle control cats (n = 5), sustained hypoxia elicited a biphasic respiratory response, during which an initial ventilatory stimulation is followed by a 24 +/- 6% (P < 0.01) reduction. In contrast, in haloperidol- (0.1 mg/kg) treated cats (n = 5) the ventilatory roll off was virtually abolished (-1 +/- 1%; P = NS). We also measured ventilatory, carotid sinus nerve (CSN) and phrenic nerve (PhN) responses to sustained isocapnic hypoxia in anesthetized animals (n = 6) to explore the influence of haloperidol on peripheral and central response during the roll off. Control responses to hypoxia showed an initial increase in ventilation, PhN, and CSN activity, followed by a subsequent decline in ventilation and PhN activity of 17 +/- 3 and 17 +/- 5%, respectively (P < 0.05). In contrast, CSN activity remained unchanged during the roll off. Administration of haloperidol (1 mg/kg) reduced the initial increment in ventilation, while the initial increase in CSN activity was augmented. After peak values were obtained the ventilatory roll off was abolished, and PhN and CSN activity also remained constant. We further examined the effects of domperidone, a selective peripheral dopamine receptor blocking agent, on ventilatory response to sustained hypoxia in awake cats (n = 5). Administration of domperidone (700-mu-g/kg), however, produced no significant change in ventilatory roll off. Thus the ventilatory roll off in sustained hypoxia was abolished by haloperidol of centrally acting dopamine blocker but not by the peripheral acting antagonist, domperidone. These results suggest that central dopaminergic mechanisms may have an inhibitory role in the late phase of sustained hypoxia.