Enhanced γ-Aminobutyric Acid–B Receptor Agonist Responses and mRNA Within the Nucleus of the Solitary Tract in Hypertension

Abstract

Abstract-␥-Aminobutyric acid-B (GABA B ) receptor function and regulation in the nucleus of the solitary tract (NTS) was examined in Sprague-Dawley rats made chronically (4 to 5 weeks) hypertensive with the one-kidney, figure-8 renal wrap model of hypertension. NTS microinjection of the GABA B agonist baclofen produced a pressor response that was enhanced in hypertensive rats compared with the response observed in sham-operated normotensive rats (36Ϯ4 mm Hg increase in mean arterial pressure in 8 hypertensive rats compared with 21Ϯ2 mm Hg increase in 7 sham-operated normotensive rats, Pϭ0.03). Responses to microinjection of GABA B antagonists (CGP-55845A and SCH-90511), the GABA A agonist muscimol, the GABA A antagonist bicuculline, and the GABA reuptake inhibitor nipecotic acid were not different comparing normotensive sham-operated and hypertensive rats. Renal sympathetic nerve responses to NTS microinjection of these drugs were not different in hypertensive compared with normotensive rats. Micropunches of the NTS were homogenized and reverse transcriptase-polymerase chain reaction was performed to examine mRNA levels for the GABA B receptor. There was a 3-fold increase in GABA B receptor mRNA levels in the caudal NTS of 7 chronically hypertensive rats compared with levels measured in 8 sham-operated normotensive rats (Pϭ0.01). In conclusion, chronic hypertension is associated with an upregulation of GABA B receptor function; however, the tonic activity of the system does not appear to be different between normotensive and hypertensive rats. The upregulation of GABA B receptor function might be due to an increased number of receptors, as suggested by the elevated levels of GABA B receptor mRNA measured in the NTS of hypertensive rats. All of these alterations suggest that hypertension is associated with dynamic changes in receptor-mediated mechanisms within the NTS, and these alterations could modify baroreflex regulation of cardiovascular function in hypertension. Key Words: kidney Ⅲ tractus solitarius Ⅲ hypertension, renal Ⅲ receptors, aminobutyric acid Ⅲ baclofen Ⅲ reverse transcriptase T he nucleus of the solitary tract (NTS) is the brain stem nucleus where baroreceptor afferent fibers make their initial synapse within the central nervous system. Therefore, information regarding the physiology and pharmacology of NTS neurons is critical to our understanding of baroreflex regulation of cardiovascular function. The region of the NTS where baroreceptor afferents terminate contains a high density of both ␥-aminobutyric acid-A (GABA A ) and GABA B receptors. 1,2 A number of in vivo microinjection studies 3-6 as well as in vivo 7-9 and in vitro 10,11 single unit electrophysiological experiments have demonstrated that both GABA A and GABA B receptors play an important role in the integration of baroreceptor afferent inputs and baroreflex function. Since activation of GABA A receptors evokes postsynaptic inhibition and activation of GABA B receptors evokes both presynaptic and postsynaptic inhibition of NTS neuron...

Responses to GABAA receptor activation are altered in NTS neurons isolated from chronic hypoxic rats

“…1 However, we have previously demonstrated in this model of HT that NTS neurons receiving aortic baroreceptor afferent inputs exhibit normal discharge frequencies and responses to aortic nerve stimulation. 14 We have also demonstrated enhanced responses to activation of GABA B receptors in this model of HT, 15 and this may mitigate the consequences of reduced GABA A -mediated inhibition.…”

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

“…receptor mRNA. 7 A similar study reported that baclofen binding in the NTS was increased in spontaneously hypertensive rats when compared with control rats. 22 The enhanced baclofen effect could be mediated by an increased number of GABA B receptors and/or increased flow through individual channels on second-order neurons after chronic hypertension.…”

“…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. We addressed these questions using an in vitro patch-clamp method to directly investigate the postsynaptic effect of baclofen on second-order baroreceptor neurons in the NTS.…”

Sustained hypertension increases the density of AMPA receptor subunit, GluR1, in baroreceptive regions of the nucleus tractus solitarii of the rat

“…Alternatively, a postulated increase in calcium influx via GluR2-deficient AMPA receptors may lead to activation of a calciumdependent inhibitory conductance (chloride or potassium) that may also reduce the excitability of second-order baroreceptive NTS neurons. A third potential mechanism that may be responsible for the decrease in baroreflex function during hypertension may involve enhanced GABA receptor responses in NTS (Durgam et al, 1999;Tsukamoto and Sved, 1993). Most GABAergic neurons within NTS are directly activated by solitary tract afferents [Bailey, T.W.…”

“…We also do not know if the neurons containing newly formed GluR1 spines are excitatory or inhibitory interneurons (Durgam et al, 1999) or output neurons. Our recent findings of distinct populations of NTS neurons projecting to the caudal ventrolateral medulla and paraventricular nucleus of the hypothalamus support the notion that the functional consequences of these structural changes will greatly depend on the specific population(s) of neurons effected.…”