Hypoxic Excitation

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In addition to the hypoxia-sensitive sympathoexcitatory region, the respiratory-related region located just rostral to the Cl sympathoexcitatory region, the pre-Botzinger complex, is also directly excited by local hypoxia (38). Analogous to the 

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Mazza E Jr, Edelman NH, Neubauer JA. 2000. Hypoxic excitation in neurons cultured from the rostral ventrolateral medulla of the neonatal rat. J Appl Physiol 88 2319-2329. 

However, some investigators have questioned the role of Kv or maxi-K charmels in the hypoxic excitation of glomus cells. The activation thresholds of these charmels are approximately —30 mV Therefore, most charmels would be closed at the normal resting membrane potential ( —50mV) (31). Hypoxic inhibition of... 

Mironov SL, Richter DW. Intracellular signalling pathways modulate K(ATP) channels in inspiratory brainstem neurones and their hypoxic activation involvement of metabotropic receptors, G-proteins and cytoskeleton. Brain Res 2000 853 60-67. Cummins TR, Jiang C, Haddad GG. Human neocortical excitability is decreased during anoxia via sodium channel modulation. J Clin Invest 1993 91 608-615. Mironov SL, Richter DW. Cytoskeleton mediates inhibition of the fast Na+ current in respiratory brainstem neurons during hypoxia. Eur J Neurosci 1999 11 1831-1834. Mironov SL, Richter DW. Oscillations and hypoxic changes of mitochondrial variables in neurons of the brainstem respiratory centre of mice. J Physiol 2001 533 227-236. Mazza E Jr, Edelman NH, Neubauer JA. Hypoxic excitation in neurons cultured fi om the rostral ventrolateral medulla of the neonatal rat. J Appl Physiol 2000 88 2319-2329. 

In the intact animal, there are a number of phenomena that are thought to represent either direct or indirect CNS-mediated hypoxic excitation of respiratory ouQ)ut. It has been shown in several species, although not in humans, that there is a full recovery of the ventilatory response to acute hypoxia following peripheral chemodenervation in about 21-90 days (41-46). This does not appear to refleet return of peripheral chemoreceptor function but, rather, a considerable reorganization of the central hypoxia chemoreflex pathways (46). 

It is our view that the most convineing examples of direct, i.e., chemoreceptor-like, hypoxic excitation of motor output mediated by discrete sites in the CNS are excitation of sympathetic discharge and gasping brought about by severe brain hypoxia. 

There is substantial evidence fi om studies in the intact animal that these neurons are directly stimulated by hypoxia. Sun and colleagues have shown that microinjection of cyanide into the RVLM of rats evokes a pressor response (68). The RVLM reticulospinal sympathoexcitatory vasomotor neurons, many of which exhibit pacemaker-hke activity, are rapidly and reversibly excited in a dose-dependent manner when the cyanide is delivered by either microinjection or microiontophoresis (63,66,68,69). This excitation is not altered by blockade of ionotropic excitatory amino acid (EAA) receptors in this region (70). Fiuiher, during hypoxic excitation of these RVLM reticulospinal sympathoexcitatory vasomotor neurons, their response to baroreceptor stimulation is preserved, suggesting that the... 

Ramirez et al. (82) produced bilateral synaptic blockade within the pre-BotC in pentobarbitone-anesthetized cats by injection of TTX and abolished eupneic ouQ)ut without eliminating the gasping response to severe hypoxia or asphyxia. It is important to note in this regard that Sun and Reis have shown that hypoxic excitation of reticulospinal sympathoexcitatory vasomotor neurons seems to be independent of synaptic transmission, or, at least, TTX-sensitive mechanisms (63,69,70 described above). If similar mechanisms exist in the pre-BotC, the inability of TTX to block hypoxia-induced gasping is not unexpected. 

Sun MK, Reis DJ. Hypoxic excitation of medullary vasomotor neurons in rats are not mediated by glutamate or nitric oxide. Neurosci Lett 1993 157 219-222. 

Less state-dependent, block inactivated channels—preference for tissues partly depolarized (slow conduction in hypoxic and ischemic tissues). This results in an increased threshold for excitation and less excitability of hypoxic heart musde. 

More recently, successful reinnervation of carotid body glomus cells, changes in the electrical properties, pharmacological sensitivity, and reappearance of hypoxic chemosensitivity in petrosal ganglion cells have been reported when explants of both organs are cultured together (31-35). Petrosal ganghon neurons acutely disconnected from the carotid body and superfused in vitro are not excited by hypoxic hypoxia (36). 

Figure 4 In situ recording of neural trafSc in the whole carotid sinus nerve. Cat carotid body is responding to a perfusion of hypoxic Krebs Ringer bicarbonate solution without (open bars) and with (hatched bars) 4 pM AFDX 116, an M2 receptor inhibitor (mean SEM). This neural response could be due to an increase in ACh release because glomus cell M2-inhibiting autoreceptors are inhibited, releasing a greater amount of ACh. Or the postsynaptic M2 receptors (responsible for the slow inhibitory postsynaptic potential) are inhibited, making the postsynaptic sensory afferent neuron more excitable, or both processes.

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