Glycinergic neurotransmission in the rostral ventrolateral medulla controls the time course of baroreflex‐mediated sympathoinhibition

Abstract

Key points To maintain appropriate blood flow to various tissues of the body under a variety of physiological states, autonomic nervous system reflexes regulate regional sympathetic nerve activity and arterial blood pressure. Our data obtained in anaesthetized rats revealed that glycine released in the rostral ventrolateral medulla (RVLM) plays a critical role in maintaining arterial baroreflex sympathoinhibition. Manipulation of brainstem nuclei with known inputs to the RVLM (nucleus tractus solitarius and caudal VLM) unmasked tonic glycinergic inhibition in the RVLM. Whole‐cell, patch clamp recordings demonstrate that both GABA and glycine inhibit RVLM neurons. Potentiation of neurotransmitter release from the active synaptic inputs in the RVLM produced saturation of GABAergic inhibition and emergence of glycinergic inhibition. Our data suggest that GABA controls threshold excitability, wherreas glycine increases the strength of inhibition under conditions of increased synaptic activity within the RVLM. Abstract The arterial baroreflex is a rapid negative‐feedback system that compensates changes in blood pressure by adjusting the output of presympathetic neurons in the rostral ventrolateral medulla (RVLM). GABAergic projections from the caudal VLM (CVLM) provide a primary inhibitory input to presympathetic RVLM neurons. Although glycine‐dependent regulation of RVLM neurons has been proposed, its role in determining RVLM excitability is ill‐defined. The present study aimed to determine the physiological role of glycinergic neurotransmission in baroreflex function, identify the mechanisms for glycine release, and evaluate co‐inhibition of RVLM neurons by GABA and glycine. Microinjection of the glycine receptor antagonist strychnine (4 mm, 100 nL) into the RVLM decreased the duration of baroreflex‐mediated inhibition of renal sympathetic nerve activity (control = 12 ± 1 min; RVLM‐strychnine = 5.1 ± 1 min), suggesting that RVLM glycine plays a critical role in regulating the time course of sympathoinhibition. Blockade of output from the nucleus tractus solitarius and/or disinhibition of the CVLM unmasked tonic glycinergic inhibition of the RVLM. To evaluate cellular mechanisms, RVLM neurons were retrogradely labelled (prior injection of pseudorabies virus PRV‐152) and whole‐cell, patch clamp recordings were obtained in brainstem slices. Under steady‐state conditions GABAergic inhibition of RVLM neurons predominated and glycine contributed less than 25% of the overall inhibition. By contrast, stimulation of synaptic inputs in the RVLM decreased GABAergic inhibition to 53%; and increased glycinergic inhibition to 47%. Thus, under conditions of increased synaptic activity in the RVLM, glycinergic inhibition is recruited to strengthen sympathoinhibition.

Effects of Additional Glycine in Outpatients Being Treated for Urine Storage Disorders

“…The finding in the present study that systolic and diastolic blood pressure decreased after 4 to 8 weeks' administration of glycine may be related to the peripheral vasodilation caused by binding of glycine to N-methyl-D-aspartate receptors in the suprachiasmatic nucleus shell [18]. Glycine also binds to these receptors in the rostral ventral medulla, an area involved in the maintenance of arterial baroreceptor reflex [19]. Furthermore, a study in rats with diabetes showed that oral glycine leads to an increase in blood nitric oxide levels, resulting in vasodilation [20].…”

Nucleus tractus solitarii is required for the development and maintenance of phrenic and sympathetic long-term facilitation after acute intermittent hypoxia

“…Inhibition of nTS neuronal activity produced a large, sustained increase in SSNA, likely due at least in part to blockade of arterial baroreflex function and the prolonged effects of muscimol ( Gao et al, 2019 ). Exposure to AIH had no additional effect on the level of SSNA; elevated SSNA after nTS muscimol was similar in animals subsequently exposed to either TC or AIH.…”

Cortical–brainstem circuitry attenuates physiological stress reactivity

“…Next, we sought to identify the non‐catecholaminergic VLM neurons targeted by the vmPFC. Prior work has demonstrated that a local network of inhibitory neurons acts on VLM catecholaminergic neurons to regulate sympathoexcitation (Gao et al., 2019; Guyenet et al., 1990; Heesch et al., 2006). In fact, GABAergic and glycinergic neurons are recruited by barosensitive‐neurons in the nucleus of the solitary tract to regulate RVLM outflow and control blood pressure (Guyenet, 2006; Schreihofer & Guyenet, 2002).…”