To determine whether afferents in the middle cardiac nerves (MCN) contributied to extrapulmonary Paco mg/kg), and cannulated the cutaneous ulmar vein, and the carotid and brachial arteries. The thorax was opened and each lung unidirectionally ventilated from separate gas delivery systems. A ligature, which temporarily occluded blood flow, was placed around the right pulmonary artery. Both cardiac sympathetic nerves were cut, as well as the left vagus just above the level of the recurrent branch. We exposed the non-perfused right lung to 105 Torr Pco to silence intrapulmonary cemoreceptors (IPC). We measured blood pressure, heart rate and ventilatory movements while the denervated left lung was used to fix Paco at sevel levels ranging from 7-140 Torr. As arterial Pco increased, ventilatory amplitude increased from 0.3 mm to 3.6 mm, while frequency decreased from 140 to 24 per min. After cutting the MCN, ventilatory movements were less responsive to Paco changes. Ventilatory amplitude was 3.0 mm at the lowest Paco and increased to 4.0 at the highest Paco. We conclude that: 1) when IPC discharge is low, afferents in the MCN inhibit ventilatory movements during hypocapnia, and 2) these afferens may contribute to systemic CO2 sensitivity. © 1990.