Chronic intermittent hypoxia alters glutamatergic control of sympathetic and respiratory activities in the commissural NTS of rats

Abstract

Costa-Silva JH, Zoccal DB, Machado BH. Chronic intermittent hypoxia alters glutamatergic control of sympathetic and respiratory activities in the commissural NTS of rats. Am J Physiol Regul Integr Comp Physiol 302: R785-R793, 2012. First published December 28, 2011 doi:10.1152/ajpregu.00363.2011.-Sympathetic overactivity and altered respiratory control are commonly observed after chronic intermittent hypoxia (CIH) exposure. However, the central mechanisms underlying such neurovegetative dysfunctions remain unclear. Herein, we hypothesized that CIH (6% O2 every 9 min, 8 h/day, 10 days) in juvenile rats alters glutamatergic transmission in the commissural nucleus tractus solitarius (cNTS), a pivotal site for integration of peripheral chemoreceptor inputs. Using an in situ working heart-brain stem preparation, we found that L-glutamate microinjections (1, 3, and 10 mM) into the cNTS of control rats (n ϭ 8) evoked increases in thoracic sympathetic nerve (tSN) and central vagus nerve (cVN) activities combined with inhibition of phrenic nerve (PN) activity. Besides, the ionotropic glutamatergic receptor antagonism with kynurenic acid (KYN; 250 mM) in the cNTS of control group (n ϭ 7) increased PN burst duration and frequency. In the CIH group (n ϭ 10), the magnitude of L-glutamate-induced cVN excitation was smaller, and the PN inhibitory response was blunted (P Ͻ 0.05). In addition, KYN microinjections into the cNTS of CIH rats (n ϭ 9) did not alter PN burst duration and produced smaller increases in its frequency compared with controls. Moreover, KYN microinjections into the cNTS attenuated the sympathoexcitatory response to peripheral chemoreflex activation in control but not in CIH rats (P Ͻ 0.05). These functional CIH-induced alterations were accompanied by a significant 10% increase of N-methyl-D-aspartate receptor 1 (NMDAR1) and glutamate receptor 2/3 (GluR2/3) receptor subunit density in the cNTS (n ϭ 3-8, P Ͻ 0.05), evaluated by Western blot analysis. These data indicate that glutamatergic transmission is altered in the cNTS of CIH rats and may contribute to the sympathetic and respiratory changes observed in this experimental model. nucleus tractus solitarius; glutamatergic neurotransmission; chemoreception ACTIVATION OF PERIPHERAL CHEMORECEPTORS during acute hypoxia provides a powerful excitatory drive to respiratory and sympathetic networks resulting in coordinated respiratory and sympathetic reflex responses (17,21,39). Clinical and experimental studies reported that in conditions of chronic intermittent hypoxia (CIH), such as that observed in patients suffering from obstructive sleep apnea, the long-term and repetitive activation of peripheral chemoreceptors may evoke changes in the control of respiratory activity, excessive sympathetic outflow, and hypertension (24,34,40,45,56). Previously, we demonstrated that rats submitted to CIH exhibited reduction of central vagal postinspiratory activity and enhanced late-expiratory abdominal motor activity, indicating that the central control of expiratory activ...

Medullary GABAergic mechanisms contribute to electroacupuncture modulation of cardiovascular depressor responses during gastric distention in rats

“…The GABAA antagonist gabazine (27 mM) and the glutamatergic antagonist kynurenic acid (100 nM) were dissolved in normal saline (20,27,42). Similar concentrations of kynurenic acid have been used by others investigating cardiovascular and respiratory responses (7,35). We microinjected 50 nl of gabazine, kynurenic acid, or saline unilaterally into the NAmb, rVLM, or cVLM.…”

Medullary Respiratory Network Drives Sympathetic Overactivity and Hypertension in Rats Submitted to Chronic Intermittent Hypoxia

“…At the peripheral level, it was demonstrated that CIH produces a sensitization of chemosensitive glomus cells by mechanisms dependent on the generation of reactive oxygen species 39,40 and changes in angiotensin II transmission. 41 At the central nervous system level, important alterations in mechanisms of neurotransmission in neuronal groups critically involved with the processing of sympathetic chemoreflex response, such as in the nucleus tractus solitarius, 42,43 the hypothalamus, 44,45 and the ventral medulla, have been reported. [46][47][48] These peripheral and central alterations of chemoreflex pathways induced by CIH contribute to the facilitation of sympathetic chemoreflex response, and it represents an important mechanism of long-lasting excitation of medullary presympathetic neurons in response to new episodes of hypoxia and sustained increase of baseline sympathetic outflow after CIH.…”

“…This hypothesis is supported by the fact that CIH produce substantial changes in the mechanisms controlling baseline respiratory activity. 18,28,29,43,49 Therefore, in our view, changes in the mechanisms of interaction between respiratory and sympathetic networks should be considered as a novel mechanism contributing to the development of sympathetic overactivity and hypertension in CIH rats.…”

Leptin dependent changes in the expression of tropomyosin receptor kinase B protein in nucleus of the solitary tract to acute intermittent hypoxia

“…Cardiovascular afferent fibers have previously been shown to release glutamate in responses to activation of their peripheral receptors [5]. Recent findings have shown that the caudal medial NTS, which is believed to be the primary area to receive peripheral chemoreceptor afferents [10,38], displays increased glutamatergic responsiveness following IH [15].…”