Proceedings of The Physiological Society

University College Cork (2004) J Physiol 560P, C10



Kellett,Daniel ; Ramage,Andrew G; Jordan,David ;

1. Physiology, University College London, London, United Kingdom. 2. Pharmacology, University College London, London, United Kingdom.

  • Figure 1. Graph of mean (± s.e.m) effects of topical SB-269970 (100 µg kg-1) and saline (10 µl) on vagus-evoked NTS activity. *P<0.05 ** P<0.01 2-way ANOVA followed by least significant difference test.

In anaesthetised rats, intracisternal application of 5-HT7 receptor antagonists inhibits the bradycardias evoked during the cardiopulmonary, chemoreceptor and baroreflex (Kellett et al. 2003, 2004) This occurs within 5 min of administration, but the site of action is unknown. The present experiments investigate the effect of the 5-HT7 antagonist SB-269970 (Hagan et al., 2000), applied topically, and of the AMPA receptor antagonist DNQX, applied iontophoretically, on vagus-evoked NTS neuronal activity. Male Sprague-Dawley rats (280 - 380 g) were anaesthetised with pentobarbitone sodium (60 mg kg-1 I.P. followed by 20 mg kg-1 h-1 I.V), neuromuscularly blocked (gallamine 30 mg kg-1 I.V. followed by 6 mg kg-1 h-1), mechanically ventilated, and instrumented to record BP and HR. Depth of anaesthesia was assessed by the stability of BP and HR following a noxious stimulus. NTS and dorsal vagal nucleus (DVN) neurones that responded to stimulation of the ipsilateral vagus nerve (1 Hz, 1 ms pulse, 50 - 500 μA) were recorded extracellularly with single glass microelectrodes (impedance 5 - 15 MΩ) or compound recording/iontophoresis electrodes. At the end of experiments, animals were killed by an overdose of anaesthetic. Topical application of SB-269970 (100 μg kg-1; 10 μl) significantly reduced vagus-evoked NTS neuronal activity compared to topical saline (see Figure 1; 24 ± 8 vs. 47 ± 2 spikes (50 sweeps)-1 at 7 min; P < 0.01, 2-way ANOVA; n = 5). The time course of this inhibition was similar to the effect of intracisternal SB-269970 on reflex bradycardias. Furthermore, the same dose did not significantly affect ongoing discharge of DVN neurones (n = 6). Baseline BP and HR were unchanged. Iontophoretic application of DNQX (at currents selective for AMPA receptors: 30 - 100 nA) also significantly reduced vagus-evoked NTS neuronal activity (from 36 ± 8 to 15 ± 2 spikes (20 sweeps)-1; P < 0.01, Mann-Whitney test, n = 12). These data demonstrate that SB-269970 can act at the level of the NTS, where both 5-HT7 and AMPA receptors are activated by vagal afferents. The precise synaptic circuitry remains to be determined.

Where applicable, experiments conform with Society ethical requirements