Carotid body overactivity induces respiratory neurone channelopathy contributing to neurogenic hypertension

Abstract

Why sympathetic activity rises in neurogenic hypertension remains unknown. It has been postulated that changes in the electrical excitability of medullary pre-sympathetic neurones are the main causal mechanism for the development of sympathetic overactivity in experimental hypertension. Here we review recent data suggesting that enhanced sympathetic activity in neurogenic hypertension is, at least in part, dependent on alterations in the electrical excitability of medullary respiratory neurones and their central modulation of sympatho-excitatory networks. We also present results showing a critical role for carotid body tonicity in the aetiology of enhanced central respiratory modulation of sympathetic activity in neurogenic hypertension. We propose a novel hypothesis of respiratory neurone channelopathy induced by carotid body overactivity in neurogenic hypertension that may contribute to sympathetic excess. Moreover, our data support the notion of targeting the carotid body as a potential novel therapeutic approach for reducing sympathetic vasomotor tone in neurogenic hypertension.

Figure 1

Schematic representation of ventral approach of in situ perfused preparation of rats The brainstem was adequately oxygenated by perfusing carbogenated Ringer solution at 31°C via descending aorta. Perfusion pressure was recorded via the catheter inside the aorta. A eupnoeic respiratory motor pattern was recorded from phrenic (PN), abdominal (AbN), hypoglossal (HN) and cervical vagus (cVN) nerves, which showed three respiratory phases (inspiration (I), post-inspiration (PI) and second half of expiration (E2). The sympathetic outflow was recorded from thoracic sympathetic nerve (tSN). Note the respiratory modulation of sympathetic activity starting during I with the peak at PI. The trachea, oesophagus, all muscles and connective tissues covering the basilar surface of occipital bone were removed. The basilar portion of the atlantooccipital membrane was also cut and the bone carefully removed to expose the ventral surface of the medulla in the anteroposterior extension from the vertebral arteries to the pontine nuclei. Blind whole cell patch clamp recordings were made from pre-sympathetic and respiratory neurones located within ventrolateral medulla (Moraes et al. a). Recordings of ventral medullary expiratory (upper) and inspiratory (lower) neurones are shown in the upper right corner.

Figure 2

Inspiratory-modulated RVLM pre-sympathetic neurones from Wistar and SH rats Raw records of phrenic nerve (PN) and whole cell patch clamp of RVLM pre-sympathetic neurones with inspiratory modulation in Wistar (Ai) and SH (Aii) rats. All RVLM pre-sympathetic neurones were barosensitive and spinal stimulation (T8–T12) evoked constant latency antidromic action potentials. SH rats showed higher firing frequency because of the additional action potentials during the pre-inspiratory phase (Moraes et al. c). B, reduced spike discharge frequency with a small continuous hyperpolarizing current revealed spontaneous excitatory postsynaptic potentials (sEPSPs) during inspiration (I) in RVLM pre-sympathetic neurones from Wistar and SH rats. Additional sEPSPs were also observed at the end of second half of expiration (E2) or pre-inspiratory phase only in RVLM pre-sympathetic neurones from SH rat. C, photomicrographs of one representative RVLM pre-sympathetic neurone with inspiratory modulation labelled with biocytin (i), tyrosine hydroxylase (TH) immunohistochemical staining (ii) and its co-localization (iii). Note that this RVLM pre-sympathetic neurone is a positive TH cell as shown in a previous study (Moraes et al. a). PI: post-inspiratory phase. Scale bar, 20 μm.

Figure 3

Post-inspiratory-modulated RVLM pre-sympathetic neurones from Wistar and SH rats Raw records of phrenic nerve (PN) and whole cell patch clamp of RVLM pre-sympathetic neurones with post-inspiratory modulation in Wistar (Ai) and SH (Aii) rats. All RVLM pre-sympathetic neurones were barosensitive and spinal stimulation (T8–T12) evoked constant latency antidromic action potentials. SH rats showed increased firing frequency because of the additional action potentials during the post-inspiratory phase (Moraes et al. c). B, reduced spike discharge frequency with a small continuous hyperpolarizing current revealed sEPSPs during post-inspiration (PI) in RVLM pre-sympathetic neurones from Wistar and SH rats. Increases in frequency and amplitude of sEPSPs were also observed during PI in RVLM pre-sympathetic neurones from SH rat. C, photomicrographs of one representative RVLM pre-sympathetic neurone with post-inspiratory modulation labelled with biocytin (i), tyrosine hydroxylase (TH) immunohistochemical staining (ii) and its overlay (iii). Note that this RVLM pre-sympathetic neurone is a negative TH cell as shown in a previous study (Moraes et al. a). I: inspiration; E2: second half of expiration. Scale bar, 20 μm.