ABSTRACT
AIM: Central chemoreceptors are important to detect changes of CO2/H(+), and the Locus coeruleus (LC) is one of the many putative central chemoreceptor sites. Here, we studied the contribution of LC glutamatergic receptors on ventilatory, cardiovascular and thermal responses to hypercapnia. METHODS: To this end, we determined pulmonary ventilation (V(E)), body temperatures (T(b)), mean arterial pressure (MAP) and heart rate (HR) of male Wistar rats before and after unilateral microinjection of kynurenic acid (KY, an ionotropic glutamate receptor antagonist, 10 nmol/0.1 µL) or α-methyl-4-carboxyphenylglycine (MCPG, a metabotropic glutamate receptor antagonist, 10 nmol/0.1 µL) into the LC, followed by 60 min of air breathing or hypercapnia exposure (7% CO2). RESULTS: Ventilatory response to hypercapnia was higher in animals treated with KY intra-LC (1918.7 ± 275.4) compared with the control group (1057.8 ± 213.9, P < 0.01). However, the MCPG treatment within the LC had no effect on the hypercapnia-induced hyperpnea. The cardiovascular and thermal controls were not affected by hypercapnia or by the injection of KY and MCPG in the LC. CONCLUSION: These data suggest that glutamate acting on ionotropic, but not metabotropic, receptors in the LC exerts an inhibitory modulation of hypercapnia-induced hyperpnea.
Subject(s)
Consciousness , Hypercapnia/metabolism , Locus Coeruleus/metabolism , Pulmonary Ventilation , Receptors, Ionotropic Glutamate/metabolism , Receptors, Metabotropic Glutamate/metabolism , Animals , Arterial Pressure , Body Temperature , Disease Models, Animal , Excitatory Amino Acid Antagonists/administration & dosage , Heart Rate , Hypercapnia/physiopathology , Locus Coeruleus/drug effects , Locus Coeruleus/physiopathology , Male , Microinjections , Pulmonary Ventilation/drug effects , Rats , Rats, Wistar , Receptors, Ionotropic Glutamate/antagonists & inhibitors , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Signal Transduction , Time FactorsABSTRACT
Central chemoreflex stimulation produces an increase in phrenic nerve activity (PNA) and sympathetic nerve activity (SNA). The A5 noradrenergic region projects to several brainstem areas involved in autonomic regulation and contributes to the increase in SNA elicited by peripheral chemoreflex activation. The aim of the present study was to further test the hypothesis that the A5 noradrenergic region could contribute to central chemoreflex activation. In urethane-anesthetized, sino-aortic denervated, and vagotomized male Wistar rats (n=6-8/group), hypercapnia (end-expiratory CO2 from 5% to 10%) increased mean arterial pressure (MAP; Δ=+33±4 mmHg, P<0.05), splanchnic SNA (sSNA; Δ=+97±13%, P<0.05), and PNA frequency and amplitude. Bilateral injection of muscimol (GABA-A agonist; 2 mM) into the A5 noradrenergic region reduced the rise in MAP (Δ=+19±3 mmHg, P<0.05), sSNA (Δ=+63±5%, P<0.05), and PNA frequency and amplitude produced by hypercapnia. Injections of the immunotoxin anti-dopamine ß-hydroxylase-saporin (anti-DßH-SAP) into the A5 region destroyed TH⺠neurons but spared facial motoneurons and the chemosensitive neurons in the retrotrapezoid nucleus that express the transcription factor Phox2b and that are non-catecholaminergic (THâ»Phox2bâº). Two weeks after selective destruction of the A5 region with the anti-DßH-SAP toxin, the increase in MAP (Δ=+22±5 mmHg, P<0.05), sSNA (Δ=+68±9%, P<0.05), and PNA amplitude was reduced after central chemoreflex activation. These results suggest that A5 noradrenergic neurons contribute to the increase in MAP, sSNA, and PNA activation during central chemoreflex stimulation.
