NMDA receptors play a crucial role in mediating central inspiratory off-switch independent of the sensory feedback from pulmonary stretch receptors (PSR). In vagotomised animals, blockade of NMDA receptors either systemically or locally within the dorsal pons, prevents inspiratory termination and causes apneusis (see St John, 1998). However, apneustic breathing should be compensated by PSR input providing afferent inspiratory off-switch. In this study we investigated the afferent mediated inspiratory termination before and after NMDA-receptor blockade.

The working heart-brainstem preparation (WHBP, full details in Paton, 1996) of juvenile rat (age 27-30 days) was employed. Animals were deeply anaesthetised in a saturated atmosphere of halothane. To evoke fictive feedback from PSR, we stimulated repetitively the cervical vagal nerve with stimulus trains (200-300 ms, 20 Hz, 0.5-2 mA) applied at 1 Hz for a minute at 2 min intervals over seven trials. Respiratory cycle length (CL) and inspiratory time (T_i), as calculated from phrenic nerve activity, was measured for all seven trials as well as 1 min before and after stimulation. NMDA receptors were blocked systemically with MK-801 (2-3 µM). All data are expressed as means ± S.E.M., n = number of WHBP.

Vagal stimulation (n = 5) decreased baseline CL from 2.64 ± 0.4 to 1.58 ± 0.2 s and T_i (from 0.56 ± 0.4 to 0.33 ± 0.2 s) during the first trial. However, following the 7th trial, repetitive stimulation progressively decreased CL and T_i to 1.2 ± 0.2 and 0.28 ± 0.02 s, respectively. During this trial repetitive stimulation clearly produced a better entrainment of the respiratory rhythm. This might indicate a learning process of plasticity associated with the integration of fictive PSR input.

Systemic application of MK801 (n = 6) increased baseline T_i (from 0.8 ± 0.05 to 1.72 ± 0.08 s), indicative of blockade of the centrally mediated inspiratory off-switch mechanism. CL increased from 2.23 ± 0.4 to 8.04 ± 1.2 s. After MK-801, repetitive vagal stimulation (n = 5) caused a reduction of T_i (1.64 ± 0.09 to 0.8 ± 0.1 s) and cycle length (6.18 ± 1.3 to 4.6 ± 0.5 s, 1st trial). In contrast to control, a progressive decrease of the CL and T_i following repetitive stimulation was not observed even at the 7th trial (i.e. 7.8 ± 1.9 and 1 ± 0.1 s, respectively).

These data suggest that NMDA receptor-induced apneusis and decreased respiratory frequency could only be partially compensated for by afferent vagal feedback. Furthermore, the entrainment of respiratory frequency by vagal nerve stimulation is dependent upon NMDA receptors and may reflect a ‘learning process’.

This work was funded by Deutsche Forschungsgemeinschaft, SFB430/C9.