Regulation of sympathetic vasomotor activity by the hypothalamic paraventricular nucleus in normotensive and hypertensive states

Abstract

The hypothalamic paraventricular nucleus (PVN) is a unique and important brain region involved in the control of cardiovascular, neuroendocrine, and other physiological functions pertinent to homeostasis. The PVN is a major source of excitatory drive to the spinal sympathetic outflow via both direct and indirect projections. In this review, we discuss the role of the PVN in the regulation of sympathetic output in normal physiological conditions and in hypertension. In normal healthy animals, the PVN presympathetic neurons do not appear to have a major role in sustaining resting sympathetic vasomotor activity or in regulating sympathetic responses to short-term homeostatic challenges such as acute hypotension or hypoxia. Their role is, however, much more significant during longer-term challenges, such as sustained water deprivation, chronic intermittent hypoxia, and pregnancy. The PVN also appears to have a major role in generating the increased sympathetic vasomotor activity that is characteristic of multiple forms of hypertension. Recent studies in the spontaneously hypertensive rat model have shown that impaired inhibitory and enhanced excitatory synaptic inputs to PVN presympathetic neurons are the basis for the heightened sympathetic outflow in hypertension. We discuss the molecular mechanisms underlying the presynaptic and postsynaptic alterations in GABAergic and glutamatergic inputs to PVN presympathetic neurons in hypertension. In addition, we discuss the ability of exercise training to correct sympathetic hyperactivity by restoring blood-brain barrier integrity, reducing angiotensin II availability, and decreasing oxidative stress and inflammation in the PVN.

Keywords: autonomic nervous system; hypothalamus; paraventricular nucleus; sympathetic nervous system; synaptic plasticity; synaptic transmission.

Fig. 1.

Top: sagittal section of the rat brain showing the location of the brain nuclei that have a major role in the regulation of the sympathetic vasomotor outflow by the hypothalamic paraventricular nucleus (PVN) under normal conditions. Bottom: flow diagram showing the inputs to, and outputs from, PVN presympathetic neurons that regulate the sympathetic vasomotor outflow under normal conditions. Note that under pathological conditions (e.g., hypertension, heart failure, or chronic intermittent hypoxia) or after sustained behavioral changes (e.g., exercise training) the activity of PVN presympathetic neurons may also be altered by other inputs. Arc, arcuate nucleus; MnPO, median preoptic nucleus; NTS, nucleus of the solitary tract; RVLM, rostral ventrolateral medulla; SFO, subfornical organ; OVLT, organum vasculosum lamina terminalis.

Fig. 2.

Imbalance of excitatory and inhibitory synaptic inputs to paraventricular nucleus (PVN) presympathetic neurons in the spontaneously hypertensive rat model. Impaired inhibitory GABAergic synaptic inputs include a depolarizing shift of GABA reversal potential due to Na⁺-K⁺-Cl⁻ cotransporter-1 (NKCC1) upregulation and reduced GABA_B receptor activity. Enhanced excitatory glutamatergic synaptic inputs include increased N-methyl-d-aspartate receptors (NMDAR)-mediated presynaptic glutamate release, increased activity of postsynaptic NMDARs and metabotropic glutamate receptor 5 (mGluR5), and a switch to Ca²⁺-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The impaired GABAergic and enhanced glutamatergic inputs lead to hyperactivity of PVN presympathetic neurons and heightened sympathetic vasomotor tone in hypertension. CK, casein kinase; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II.

Fig. 3.

Effects of exercise training on the paraventricular nucleus (PVN) in spontaneously hypertensive rats (SHRs). Exercise training (T) decreases angiotensinogen immunoreactivity (Aogen ir; A) content and causes a prompt and maintained (from second up to eighth week of training) reduction on FITC-10 kDa (green) extravasation from capillaries (rhodamine-70 kDa, red) into the brain parenchyma (B). Simultaneous intracerebroventricular infusion of angiotensin II in trained SHRs blocks the beneficial effects of training observed in saline-infused SHRs (C) and augments microglia activation in the PVN (IBA1 immunoreactivity; D). [Modified from Chaar et al. (23) and Buttler et al. (17) with permission.]

Fig. 4.

Effects of a 2-wk exercise training (T) period on baroreceptor reflex control of heart rate (HR) in the spontaneously hypertensive rat (SHR) model. Right: sequential events induced by exercise training on local blood-brain barrier (BBB), the brain renin-angiotensin system, paraventricular nucleus intracellular signaling pathways, and neuronal activity-driven changes on baroreflex sensitivity (BrS). The baroreceptor function curve of sedentary normotensive rats (WKY-S) is shown for comparison. HR, heart rate [in beats/min (bpm)]; MAP, mean arterial pressure; Aogen ir, angiotensinogen immunoreactivity; PICs, proinflammatory cytokines; SNA, sympathetic nerve activity; PSNA, parasympathetic nerve activity; SAP, systolic arterial pressure; PI, pulse interval. *P < 0.05, vs. WKY-S; †P < 0.05, vs. SHR-S. [Modified from Masson et al. (116) with permission.]