Intermittent hypoxia-induced sensitization of central chemoreceptors contributes to sympathetic nerve activity during late expiration in rats

Abstract

Molkov YI, Zoccal DB, Moraes DJ, Paton JF, Machado BH, Rybak IA. Intermittent hypoxia-induced sensitization of central chemoreceptors contributes to sympathetic nerve activity during late expiration in rats. J Neurophysiol 105: 3080 -3091, 2011. First published April 6, 2011 doi:10.1152/jn.00070.2011.-Hypertension elicited by chronic intermittent hypoxia (CIH) is associated with elevated activity of the thoracic sympathetic nerve (tSN) that exhibits an enhanced respiratory modulation reflecting a strengthened interaction between respiratory and sympathetic networks within the brain stem. Expiration is a passive process except for special metabolic conditions such as hypercapnia, when it becomes active through phasic excitation of abdominal motor nerves (AbN) in late expiration. An increase in CO 2 evokes late-expiratory (late-E) discharges phase-locked to phrenic bursts with the frequency increasing quantally as hypercapnia increases. In rats exposed to CIH, the late-E discharges synchronized in AbN and tSN emerge in normocapnia. To elucidate the possible neural mechanisms underlying these phenomena, we extended our computational model of the brain stem respiratory network by incorporating a population of presympathetic neurons in the rostral ventrolateral medulla that received inputs from the pons, medullary respiratory compartments, and retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG). Our simulations proposed that CIH conditioning increases the CO 2 sensitivity of RTN/pFRG neurons, causing a reduction in both the CO 2 threshold for emerging the late-E activity in AbN and tSN and the hypocapnic threshold for apnea. Using the in situ rat preparation, we have confirmed that CIHconditioned rats under normal conditions exhibit synchronized late-E discharges in AbN and tSN similar to those observed in control rats during hypercapnia. Moreover, the hypocapnic threshold for apnea was significantly lowered in CIH-conditioned rats relative to that in control rats. We conclude that CIH may sensitize central chemoreception and that this significantly contributes to the neural impetus for generation of sympathetic activity and hypertension.

Chronic intermittent hypoxia increases sympathetic control of blood pressure: role of neuronal activity in the hypothalamic paraventricular nucleus

“…Expression is also observed in downstream sympathetic regulatory cell groups, including neurons in the hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (8,27). Importantly, full expression of hypertension in our 7-day CIH model critically depends on activator protein-1 transcriptional regulation of MnPO neurons by FosB/⌬FosB (8).These and other observations (7,9,40,41,46,70) indicate that exaggerated SNA and the neurogenic component of CIHinduced hypertension are complex and might not arise solely from the sensitization of arterial chemoreceptors. In the present study, we sought to determine the early contribution of forebrain/hypothalamic neural mechanisms in hypertension induced by 7 days of CIH.…”

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

“…The altered control of expiratory activity of CIH rats seems to contribute significantly to increase baseline sympathetic activity in these animals (58). This is supported by our findings obtained in in situ preparations showing that the higher levels of sympathetic activity of CIH-treated rats are, in part, entrained with the emergence of high-amplitude bursts in abdominal expiratory motor activity (43,57,60). Furthermore, it has been reported that CIH rats exhibited exaggerated sympathoexcitatory and phrenic responses to a new hypoxic challenge (14,26,38,42), indicating a facilitation of the processing of hypoxic reflex responses.…”

“…Accumulating evidence suggests that the central mechanisms underpinning sympathetic overactivity associated with CIH exposure involve plastic changes in the neuronal circuitries modulating both sympathetic and respiratory functions (43,57,60). The present study provides neurochemical evidence that glutamatergic neurotransmission is increased in the cNTS of rats submitted to CIH.…”

Sympathoexcitation during chemoreflex active expiration is mediated byl-glutamate in the RVLM/Bötzinger complex of rats

“…Considering the increase in the respiratory frequency after KYN microinjected into the RVLM/BötC, we suggest that bilateral microinjections of KYN into the BötC decreased pontine/RTN excitatory inputs to post-I and aug-E BötC neurons, changing the basal respiratory pattern to the observed abnormal pattern characterized by an increase in the respiratory frequency due to a decrease in the duration of inspiration and expiration. This change probably occurred because the pre-I neurons received inhibitory inputs from aug-E neurons (controlling the pre-I activity), whereas ramp-I received inhibitory inputs from post-I (controlling the duration of inspiration and expiration) (Hayashi et al 1996;Molkov et al 2011;Rybak et al 2008). Microinjections of KYN into the RVLM/BötC decreased the inhibitory tonus from BötC post-I and aug-E neurons to preBötC inspiratory neurons, allowing a decrease in the duration of expiration and an increase in the activities of pre-I neurons.…”

“…On the other hand, the expiratory activity during baseline seems to be generated mainly by expiratory neurons of BötC (Ezure et al 2003a,b,c;Tian et al 1999) while during high respiratory drive, such as in conditions of hypercapnia/hypoxia, a distinct expiratory generator located at the retrotrapezoid/parafacial respiratory group (RTN/pFRG) is activated and plays a critical role in the generation of active expiration (Abdala et al 2009;Molkov et al 2010Molkov et al , 2011. Intermingled with the BötC and pre-BötC neurons are the presympathetic neurons of the RVLM, which anteroposterior distribution is as long as 700 m from the caudal end of the facial nucleus to the caudal ventrolateral medulla (CVLM) (Dobbins and Feldman 1994;Wang et al 2002Wang et al , 2009).…”