Sympathoexcitation by PVN-Injected Bicuculline Requires Activation of Excitatory Amino Acid Receptors

Abstract

Abstract-Acute blockade of ␥-aminobutyric acid (GABA)-A receptors in the hypothalamic paraventricular nucleus (PVN) increases mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity (SNA). However, the underlying neural mechanisms have not been fully determined. We tested the hypothesis that responses to GABA-A receptor blockade in the PVN require activation of local ionotropic excitatory amino acid ( Key Words: heart failure Ⅲ hypertension, arterial Ⅲ sympathetic nervous system Ⅲ arterial pressure T he inhibitory neurotransmitter ␥-aminobutyric acid (GABA) plays a pivotal role in the central regulation of cardiovascular function. One site where GABA has a tonic influence on arterial blood pressure (ABP), heart rate (HR), and sympathetic nerve activity (SNA) is the hypothalamic paraventricular nucleus (PVN). Indeed, studies conducted over the past 12 years have documented that acute blockade of GABA-A receptors in the PVN leads to large-amplitude increases in ABP, HR, and SNA. 1-4 However, the neural mechanisms that underlie these responses have yet to be fully elucidated.The ability of GABA-A receptor blockade to produce such dramatic cardiovascular effects indicates that the PVN has not only a functionally high level of inhibitory GABAergic tone but a local source of membrane excitation as well. This is the case because inhibition by GABA-A receptors is due to hyperpolarization of membrane potential. Consequently, blockade of GABA-A receptors only removes hyperpolarization; alone, it does not cause membrane potential to depolarize to the threshold for action potential formation. The latter requires either an intrinsic or extrinsic source of excitation. Intrinsic mechanisms of excitation such as pacemaker potentials have not been described among sympathetic and cardiovascular regulatory neurons of the PVN and thus the likely source would seem to arise from extrinsic synaptic input.The PVN is innervated by a number of excitatory transmitters, 5-9 but among the most prominent is L-glutamate. Not only does the PVN contain an abundance of glutamatergic nerve terminals, recent evidence also indicates that neurons in autonomic regions of the nucleus express ionotropic excitatory amino acid (EAA) receptors in high density. 10 Given the wealth of inhibitory GABAergic and EAA inputs to the PVN, it is reasonable to postulate that interactions between these two opposing influences may provide an important mechanism to regulate neuronal excitability. In this study, we tested the hypothesis that full manifestation of cardiovascular and sympathetic responses to blockade of GABA-A receptors in the PVN requires actions of EAAs mediated through ionotropic receptors. These results were presented previously in abstract form. 11

Suprachiasmatic GABAergic Inputs to the Paraventricular Nucleus Control Plasma Glucose Concentrations in the Rat via Sympathetic Innervation of the Liver

“…Future studies will have to show how the SCN (via the sympathetic and parasympathetic branches of the ANS) controls the balance between glycogenolysis and glycogenesis. In this regard, glutamatergic SCN outputs might also be important (Csaki et al, 2000;Chen et al, 2003;Perreau-Lenz et al, 2004). Indeed, apart from GABA, glutamatergic (SCN) inputs to the PVN may also show a daily variation.…”

Glutamatergic Inputs in the Hypothalamic Paraventricular Nucleus Maintain Sympathetic Vasomotor Tone in Hypertension

“…14,16,26 Previous studies have shown that microinjection of the glutamate receptor antagonist alone into the PVN has little effect on the sympathetic output and arterial blood pressure in normotensive rats. 15,27 These data suggest that the glutamatergic input in the PVN is not critically involved in tonic control of sympathetic vasomotor tone in normotensive conditions. However, little is known about whether glutamatergic input in the PVN plays a role in the regulation of resting sympathetic outflow and blood pressure in hypertension.…”

In Vivo Discharge Properties of Hypothalamic Paraventricular Nucleus Neurons With Axonal Projections to the Rostral Ventrolateral Medulla

“…Electrode resistance was measured in vivo and averaged 25-35 M⍀. Electrodes were lowered vertically into the PVN at the following stereotaxic coordinates (in mm): Ϫ1.6 to Ϫ2.3 mm from bregma, 0.2-0.8 mm lateral to midline, and 7.2-mm ventral to the brain surface Toney 2001, 2003a,b;Chen et al 2003). The PVN was probed for single-unit activity by advancing the recording electrode in 2-m vertical steps with a piezoelectric micropositioner (EXFO-Burleigh, Quebec, Quebec, Canada).…”

“…In spite of receiving strong tonic inhibitory input (Chen and Toney 2003b;Chen et al 2003;Kenney et al 2003;Li et al 2006;Martin et al 1991), PVN neurons nevertheless do contribute to ongoing SNA. In anesthetized rats, for example, studies have shown that acute inhibition of PVN neuronal activity or blockade of excitatory inputs reduces ongoing renal SNA (RSNA) (Akine et al 2003;Allen 2002;Stocker et al 2004b, lumbar SNA , and ABP (Akine et al 2003;Allen 2002;Freeman and Brooks 2007;Stocker et al 2004b.…”