Hypertension alters GABA receptor-mediated inhibition of neurons in the nucleus of the solitary tract

Abstract

. Hypertension alters GABA receptor-mediated inhibition of neurons in the nucleus of the solitary tract. Am J Physiol Regul Integr Comp Physiol 285: R1276-R1286, 2003 10.1152/ajpregu. 00255.2003.-Previous studies have demonstrated that microinjection of baclofen, a GABA B receptor agonist, into the nucleus of the solitary tract (NTS) results in an enhanced pressor response in hypertensive (HT) rats compared with normotensive (NT) rats, suggesting a possible alteration in the responses of neurons in this area to activation of GABA B receptors. The following studies were designed to determine whether HT alters the sensitivity of neurons in the NTS to GABA receptor agonists. Sham-operated NT and unilateral nephrectomized, renal-wrap HT Sprague-Dawley rats were anesthetized, and the responses of NTS neurons receiving aortic nerve (AN) afferent inputs to iontophoretic application of GABA, the GABA A receptor agonist muscimol, and the GABA B agonist baclofen were examined. The AN input was classified as monosynaptic (MSN) if the cell responded to each of two stimuli separated by 5 ms with an action potential. If the cell did not respond, the input was considered polysynaptic (PSN). In MSNs, inhibition of AN-evoked discharge by GABA was not altered in 1 wk of HT but was reduced in 4 wk of HT, whereas in PSNs, sensitivity to GABA was reduced at 1 and 4 wk of HT. In HT rats, inhibition of AN-evoked discharge by baclofen was enhanced in MSNs, but not in PSNs, after 1 and 4 wk of HT, whereas inhibition by muscimol was reduced in MSNs and PSNs at 1 and 4 wk of HT. Changes in sensitivity to muscimol and baclofen within MSNs were the same whether the MSN received a slowly or a rapidly conducted AN afferent input. The results demonstrate that early in HT the sensitivity of NTS neurons to inhibitory amino acids is altered and that these changes are maintained for Ն4 wk. The alterations are dependent on the subtype of GABA receptor being activated and whether the neuron receives a mono-or polysynaptic baroreceptor afferent input. (12), and GABA B receptors are metabotropic, G protein-coupled receptors that mediate presynaptic and postsynaptic inhibition by reductions in calcium conductance or increases in potassium conductance, respectively (8). Activation of GABA A receptors on NTS neurons results in chloride-dependent membrane hyperpolarization and inhibition of baroreceptor-evoked discharge (10,19). Activation of GABA B receptors can evoke presynaptic and/or postsynaptic inhibition of NTS neurons (1, 19) and inhibit baroreceptor-evoked discharge in NTS neurons (19).The sensitivity of NTS neurons to the selective GABA A agonist muscimol was the same whether the neuron received a monosynaptic or a polysynaptic aortic nerve (AN) input (19). In contrast, NTS neurons receiving a monosynaptic AN input were much less sensitive to the inhibitory effects of the GABA B agonist baclofen than were NTS neurons receiving a polysynaptic AN input (19). An in vitro study reported that presynaptic inhibition of monosynaptic tractus inputs t...

Chronic Hypertension Enhances the Postsynaptic Effect of Baclofen in the Nucleus Tractus Solitarius

“…Baclofen decreases the action potential discharge of NTS neurons receiving baroreceptor afferent inputs 6,8 and induces a pressor response. 3 Activation of GABA B receptors can presynaptically inhibit excitatory neurotransmitter release and decrease postsynaptic neuronal excitability via activation of a potassium conductance, 13 thus reducing the transmission of baroreceptor afferent inputs to other sites in baroreflex pathways.…”

“…Previous studies from this laboratory have demonstrated that renal-wrap hypertension is associated with increased GABA B receptor-mediated inhibition of baroreceptor-evoked discharge in NTS neurons 8 and increased expression of GABA B receptor mRNA in the NTS. 7 To clarify GABA B receptor-mediated cellular mechanisms in the neuronal adaptations to chronic hypertension, the present study investigated the postsynaptic effect of baclofen on NTS neurons receiving monosynaptic afferent inputs from baroreceptors and the influence of chronic hypertension on the postsynaptic response to baclofen.…”

Organization and Properties of GABAergic Neurons in Solitary Tract Nucleus (NTS)

“…Disruptions in local NTS GABAergic transmission profoundly upsets homeostatic systems, including respiratory (Wasserman et al 2002), gastrointestinal (Travagli et al 2006), and cardiovascular systems (Mei et al 2003). In the case of anesthetics, targets within NTS include greatly enhanced GABAergic transmission at second-order NTS neurons (McDougall et al 2008a), as well as descending GABAergic inputs (Jia et al 1997;Jordan et al 1988).…”

“…Block of GABAergic signaling in the NTS broadly impacts cardiovascular, respiratory, and gastrointestinal regulation (Andresen and Mendelowitz 1996;Kubin et al 2006;Travagli et al 2006). GABA mechanisms may be altered during disease states such as hypertension (Mei et al 2003). Despite this rich physiological background, less is known about the precise patterns of organization of the relationship between ST afferents and the various potential pathways within NTS (i.e., intra-NTS) that control of GABAergic neurons, especially in the absence of anesthetics that broadly facilitate GABA transmission (McDougall et al 2008b).…”

Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS)

“…Arterial baroreceptors and respiratory afferents terminate within medial portions of the caudal NTS and are a source of excitatory glutamatergic input onto second-order NTS neurons (Mendelowitz et al, 1992;Doyle & Andresen, 2001; Kubin et al, 2006). GABAergic transmission in NTS is also critical to normal cardiorespiratory reflex performance Kubin et al, 2006) as well as pathophysiological conditions (Urbanski & Sapru, 1988;Callera et al, 2000;Mei et al, 2003;Tolstykh et al, 2004).…”