Differential effects of carbon dioxide and pH on central chemoreceptors in the rat in vitro.

SUMMARY1. Experiments were performed on the brain stem-spinal cord preparation of newborn rats, in which the phrenic and hypoglossal nerves continue to show rhythmic respiratory activity in vitro, in order to compare the effects of serotonin (5-HT) on both activities and to analyse the mechanisms responsible for the depression by 5-HT of the hypoglossal activity.2. Under control conditions, simultaneous recordings of the inspiratory discharges of hypoglossal and cervical roots showed that the two bursts did not start simultaneously and had different patterns (time-to-peak and peak values); this suggests that both pools of motoneurons did not share the same central drive(s).3. Adding 5-HT and related agents to the bathing medium delayed and depressed the hypoglossal inspiratory discharge via activation of 5-HT2 receptors since these effects were elicited by 5-HT2 agonists (a-methyl-5-HT and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-HCl (DOI)) but not by 5-HT1 agonists (RU 24969 and (± )-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide (8-OH-DPAT)). The 5-HT depression of the hypoglossal discharge was prevented by applying a pretreatment with a specific 5-HT2 antagonist (ketanserin). Parallel to the hypoglossal discharge decrease, 5-HT elicited a permanent cervical root discharge along with a persistent inspiratory bursting. Adding the 5-HT precursor L-tryptophan to the bathing medium depressed the hypoglossal (XII) discharge without affecting the cervical one.4. Local application of 5-HT within the hypoglossal motor nucleus decreased the hypoglossal output, revealing that the 5-HT depression of the hypoglossal discharge was at least partly mediated by the 5-HT effects at the level of the motoneurons. Local application of 5-HT within the cervical motor nucleus elicited a permanent firing in the cervical root with a persistent inspiratory bursting.5. Intracellular analysis confirmed the existence of differences in central respiratory drive between cervical and hypoglossal motoneurons under control conditions, as well as differences in response to 5-HT. All the hypoglossal motoneurons became silent under 5-HT bathing, and showed no change in the input membrane resistance, a moderate depolarization, and a delayed central respiratory MS 9503 D. MORIN, R. MONTEA U AND 0. HILAIRE drive with a decreased amplitude. The cervical motoneurons became more active during inspiration, despite a decrease in the amplitude of the central respiratory drive, which was compensated for by a large depolarization and an increased input membrane resistance. Some cervical motoneurons even fired at a low rate during expiration.6. Taken as a whole, these results suggest that the hypoglossal depression induced by 5-HT was due to the activation of 5-HT2 receptors located within the hypoglossal nucleus but the exact mechanisms whereby 5-HT modulates the hypoglossal outputs are still open to debate. The functional significance of the effects of 5-HT on hypoglossal inspiratory activity is discussed with reference to the obstructive apno...

Section: Introductionmentioning

confidence: 87%

Compared effects of serotonin on cervical and hypoglossal inspiratory activities: an in vitro study in the newborn rat.

Morin

Monteau

Hilaire

1992

“…The in vitro brainstem-spinal cord preparation from newborn rat is known to respond to hypercapnia mainly by an increase in respiratory frequency (Issa & Remmers, 1992;Okada et al 1993b;Kawai et al 1996); however, it has also been suggested that the amplitude of phrenic nerve activity could increase independently in response to hypercapnia (Harada et al 1985). In the awake adult rat preparation, hypercapnia increases both respiratory frequency and tidal volume .…”

mentioning

confidence: 99%

Mechanisms of CO₂/H⁺ chemoreception by respiratory rhythm generator neurons in the medulla from newborn rats in vitro

Kawai

Onimaru

Homma

2006

We investigated mechanisms of CO 2 /H + chemoreception in the respiratory centre of the medulla by measuring membrane potentials of pre-inspiratory neurons, which are putative respiratory rhythm generators, in the brainstem-spinal cord preparation of the neonatal rat. Neuronal response was tested by changing superfusate CO 2 concentration from 2% to 8% at constant HCO 3 -concentration (26 mM) or by changing pH from 7.8 to 7.2 by reducing HCO 3 -concentration at constant CO 2 (5%). Both respiratory and metabolic acidosis lead to depolarization of neurons with increased excitatory synaptic input and increased burst rate. Respiratory acidosis potentiated the amplitude of the neuronal drive potential. In the presence of tetrodotoxin (TTX), membrane depolarization persisted during respiratory and metabolic acidosis. However, the depolarization was smaller than that before application of TTX, which suggests that some neurons are intrinsically, and others synaptically, chemosensitive to CO 2 /H + . Application of Ba 2+ blocked membrane depolarization by respiratory acidosis, whereas significant depolarization in response to metabolic acidosis still remained after application of Cd 2+ and Ba 2+ . We concluded that the intrinsic responses to CO 2 /H + changes were mediated by potassium channels during respiratory acidosis, and that some other mechanisms operate during metabolic acidosis. In low-Ca 2+ , high-Mg 2+ solution, an increased CO 2 concentration induced a membrane depolarization with a simultaneous increase of the burst rate. Pre-inspiratory neurons could adapt their baseline membrane potential to external CO 2 /H + changes by integration of these mechanisms to modulate their burst rates. Thus, pre-inspiratory neurons might play an important role in modulation of respiratory rhythm by central chemoreception in the brainstem-spinal cord preparation.

“…An increase in respiratory burst frequency after basilar artery perfusion or bath superfusion of an acidic Krebs solution is also observed in the isolated newborn brainstem preparation (Harada et al 1985;Tarasiuk & Grossman, 1991;Issa & Remmers, 1992 (Murakoshi, Suzue & Tamai, 1985;Greer, Smith & Feldman, 1991;Di Pascale, Morin, Monteau & Hilaire, 1992) (Neubauer et al 1991) but exists to a large degree in glia and in the endothelium of blood vessels (Pan, Nauss, Bernard, Douglas & Trouth, 1991), confirming the extra neuronal space for the chemotransduction mechanisms. The classical view is that the chemosensitive stimulus is the hydrogen ion (Loeschke, 1982).…”

Section: Discussionmentioning

confidence: 96%

“…Recent evidence, however, indicates that C02 plays an independent role. Using the isolated brainstem preparation of the newborn rat, Harada, Kuno & Wang (1985) …”

mentioning

confidence: 99%

Localization of chemosensitive structures in the isolated brainstem of adult guinea‐pig.

Morin-Surun

Boudinot

Schäfer

et al. 1995

amplitude with no effect on respiratory burst frequency. 5. Bath superfusion with hypercapnic non-acidic Krebs solution increased the inspiratory burst amplitude and decreased the respiratory frequency, while normocapnic acidic Krebs solution increased the respiratory frequency with no change in burst amplitude. 6. These results show that respiratory responses to changes in CO2 and pH depend upon the sites of action. While a CO2 increase or a pH decrease affected the respiratory frequency in the deep brainstem structures (perfused through the basilar artery), CO2 respiratory chemosensitivity at the ventral surface could be differentiated from the hydrogen ion chemosensitivity. This suggests that different mechanisms mediated respiratory responses when deep versus superficial brainstem structures were stimulated.