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Hypoxia elevates splanchnic sympathetic nerve activity (SNA) with differential effects during inspiration and expiration by unresolved central mechanisms. We examined the hypothesis that cardiovascular-related neurones in the caudal ventrolateral medulla (CVLM) contribute to the complex sympathetic response to hypoxia. In chloralose-anaesthetized, ventilated, vagotomized rats, acute hypoxia (10% O2, 60 s) evoked an increase in SNA (103 +/- 12%) that was characterized by a decrease in activity during early inspiration followed by a prominent rise during expiration. Some recorded baro-activated CVLM neurones (n = 13) were activated by hypoxia, and most of these neurones displayed peak activity during inspiration that was enhanced during hypoxia. In contrast, other baro-activated CVLM neurones were inhibited during hypoxia (n = 6), and most of these neurones showed peak activity during expiration prior to the onset of hypoxia. Microinjection of the glutamate antagonist kynurenate into the CVLM eliminated the respiratory-related fluctuations in SNA during hypoxia and exaggerated the magnitude of the sympathetic response. In contrast, microinjection of a GABA(A) antagonist (bicuculline or gabazine) into the CVLM dramatically attenuated the sympathetic response to hypoxia. These data suggest the response to hypoxia in baro-activated CVLM neurones is related to their basal pattern of respiratory-related activity, and changes in the activity of these neurones is consistent with a contribution to the respiratory-related sympathetic responses to hypoxia. Furthermore, both glutamate and GABA in the CVLM contribute to the complex sympathetic response to acute hypoxia.

GABAergic neurons in the caudal ventrolateral medulla (CVLM) are driven by baroreceptor inputs relayed via the nucleus tractus solitarius (NTS), and they inhibit neurons in rostral ventrolateral medulla to reduce sympathetic nerve activity (SNA) and arterial pressure (AP). After arterial baroreceptor denervation or lesions of the NTS, inhibition of the CVLM continues to increase AP, suggesting additional inputs also tonically activate the CVLM. This study examined whether the NTS contributes to baroreceptor-independent drive to the CVLM and whether glutamate promotes baroreceptor- and NTS-independent activation of the CVLM to tonically reduce SNA. In addition, we evaluated whether altering central respiratory drive, a baroreceptor-independent regulator of CVLM neurons, influences glutamatergic inputs to the CVLM. Splanchnic SNA and AP were measured in chloralose-anesthetized, ventilated, paralyzed rats. The infusion of nitroprusside decreased AP below threshold for baroreceptor afferent firing (<50 mmHg) and increased SNA to 209+/-22% (P<0.05), but the subsequent inhibition of the NTS by microinjection of the GABA(A) agonist muscimol did not further increase SNA. In contrast, after inhibition of the NTS, blockade of glutamatergic inputs to CVLM by microinjection of kynurenate increased SNA (274+/-54%; P<0.05; n=7). In vagotomized rats with baroreceptors unloaded, inhibition of glutamatergic inputs to CVLM evoked a larger rise in SNA when central respiratory drive was increased (219+/-16% vs. 271+/-17%; n=5; P<0.05). These data suggest that baroreceptor inputs provide the major drive for the NTS-mediated excitation of the CVLM. Furthermore, glutamate tonically activates the CVLM to reduce SNA independent of the NTS, and this excitatory input appears to be affected by the strength of central respiratory drive.

Cholecystokinin (CCK) is released after a meal to promote digestion and satiety. Circulating CCK inhibits splanchnic sympathetic nerve activity (sSNA), which may contribute to postprandial increases in mesenteric blood flow. The CCK-induced sympathoinhibition occurs by activation of vagal afferent nerves and inhibition of a subset of presympathetic rostral ventrolateral medullary (RVLM) neurons. The present study sought to determine whether the caudal ventrolateral medulla (CVLM) may also play a role in the CCK-induced changes in sSNA. Rats were anesthetized with chloralose, artificially ventilated, paralyzed, and prepared for recording arterial pressure (AP), heart rate (HR), sSNA, and activity of individual CVLM neurons. Injection of CCK-8 (8-10 microg/kg, iv) decreased sSNA, AP, and HR. Most baro-activated CVLM neurons were excited by CCK (n = 25, 3.4-fold increase), whereas other baro-activated CVLM neurons were not affected (n = 7) or were inhibited (n = 3). A subset of baro-activated CVLM neurons that were activated (n = 8) or unaffected (n = 2) was confirmed to be GABAergic by the presence of GAD67 mRNA. Bilateral inhibition of the CVLM by microinjections of muscimol reversed the decreases in sSNA and AP to a prominent sympathoactivation and increase in AP (n = 18). These data suggest that systemic injection of CCK leads to the activation of most baro-activated GABAergic CVLM neurons and that the CVLM is essential for the production of CCK-induced inhibition of sSNA. The differential responses of baro-activated GABAergic CVLM neurons to CCK may contribute to the diverse responses of presympathetic RVLM neurons and sympathetic outflows observed with systemic CCK.

The sympathetic nerves that maintain blood pressure are modulated by the central respiratory generator. Neurones in the rostral ventrolateral medulla (RVLM) that drive this sympathetic nerve activity (SNA) also display central respiratory drive (CRD)-related activity, suggesting integration of respiratory and cardiovascular regulatory systems within the brainstem. Whether CRD-related activity in the RVLM is due to direct inputs from central respiratory neurones or modulation of cardiovascular-related neurones that influence the RVLM is not known. The caudal ventrolateral medulla (CVLM) contains GABAergic neurones that tonically inhibit presympathetic RVLM neurones and are essential for the production of numerous cardiovascular reflexes. The present study sought to determine whether cardiovascular-related GABAergic neurones in the CVLM display CRD-related activity. The firing patterns of individual barosensitive CVLM neurones were examined in relation to phrenic nerve activity in chloralose-anaesthetized, ventilated, neuromuscularly blocked, vagotomized rats. Histograms of phrenic-triggered CVLM neuronal activity showed that all baro-activated CVLM neurones displayed one of four patterns of CRD-related activity: (i) inspiratory peak (n = 15), (ii) inspiratory depression (n = 15), (iii) inspiratory peak with postinspiratory depression (n = 10), and (iv) postinspiratory peak (n = 9). A subset of each type of CVLM neurone was identified as GABAergic by individually filling the recorded neurone with biotinamide and observing expression of GAD67 mRNA by in situ hybridization (n = 10). These data suggest that the activity of GABAergic neurones in the CVLM is regulated by cardiovascular and respiratory inputs, and baro-activated GABAergic CVLM neurones may contribute to CRD-related modulation of presympathetic RVLM neurones and SNA.

Hypoxia elevates splanchnic sympathetic nerve activity (SNA) with differential effects during inspiration and expiration by unresolved central mechanisms. Pre-sympathetic neurons in the rostral ventrolateral medulla (RVLM), which are necessary for the sympatho-excitatory response to hypoxia, are activated by hypoxia with oscillations entrained to the respiratory cycle. GABAergic baro-activated neurons in the caudal ventrolateral medulla (CVLM) provide the major tonic inhibition to RVLM neurons and have patterns of activity related to central respiratory drive. We examined the hypothesis that CVLM neurons are influenced by hypoxia and that the nature of their response may coincide with their pattern of respiratory modulation. We recorded from 18 baroactivated CVLM neurons with respiratory-related activity in choralose-anesthetised, vagotomized, paralyzed rats. Most CVLM neurons (13/18) were activated by hypoxia induced by inhalation of 10% O2, but others (5/18) were inhibited or silenced. The response to hypoxia was related to the pattern of central respiratory-related activity (P <0.05, Chi-square). Most (11/13) hypoxia-activated CVLM neurons had inspiratory-related activity. In contrast, most (4/5) hypoxia-inhibited neurons had expiratory-related activity. These data provide the first evidence that the CVLM may contribute to the complex sympathetic responses to hypoxia. [ABSTRACT FROM AUTHOR]