Neuronal Networks in Hypertension: Recent Advances

Abstract

Neurogenic hypertension is associated with excessive sympathetic nerve activity to the kidneys and portions of the cardiovascular system. Here we examine the brain regions that cause heightened sympathetic nerve activity in animal models of neurogenic hypertension, and we discuss the triggers responsible for the changes in neuronal activity within these regions. We highlight the limitations of the evidence and, whenever possible, we briefly address the pertinence of the findings to human hypertension. The arterial baroreflex reduces arterial blood pressure variability and contributes to the arterial blood pressure set point. This set point can also be elevated by a newly described cerebral blood flow-dependent and astrocyte-mediated sympathetic reflex. Both reflexes converge on the presympathetic neurons of the rostral medulla oblongata, and both are plausible causes of neurogenic hypertension. Sensory afferent dysfunction (reduced baroreceptor activity, increased renal, or carotid body afferent) contributes to many forms of neurogenic hypertension. Neurogenic hypertension can also result from activation of brain nuclei or sensory afferents by excess circulating hormones (leptin, insulin, Ang II [angiotensin II]) or sodium. Leptin raises blood vessel sympathetic nerve activity by activating the carotid bodies and subsets of arcuate neurons. Ang II works in the lamina terminalis and probably throughout the brain stem and hypothalamus. Sodium is sensed primarily in the lamina terminalis. Regardless of its cause, the excess sympathetic nerve activity is mediated to some extent by activation of presympathetic neurons located in the rostral ventrolateral medulla or the paraventricular nucleus of the hypothalamus. Increased activity of the orexinergic neurons also contributes to hypertension in selected models.

Keywords: baroreflex; carotid body; hypothalamus; leptin; medulla oblongata.

Figure 1:

Differential control of regional SNA with or without neurogenic hypertension, a hypothesis. Organ-specific SNA regulation operates via selective recruitment of RVLM presympathetic neurons and/or preganglionic neurons by inputs from a variety of CNS nodes (PVN, midline medulla, DMH, ARC, etc.; only one is represented). A) differential recruitment of regional SNA produces very little BP change if the baroreflex (NTS + CVLM; box) is unaffected. B) differential recruitment of regional SNA is associated with a rise in BP (potentially causing hypertension) if the baroreflex (NTS + CVLM; box) is simultaneously down-regulated.

Figure 2:

The C1 neurons innervate many nuclei implicated in circulatory control besides the sympathetic preganglionic neurons (see list of abbreviations). The projections of the rostral C1 cells are shown on the left; the projections of the caudal C1 neurons are shown on the right. Note that that both populations target many of the same nuclei.

Figure 3:

leptin and insulin raise BP by activating POMC neurons and inhibiting AgRP neurons in the arcuate nucleus. POMC neurons activate PVN neurons by releasing α-MSH. AgRP neurons inhibit PVN by releasing NPY. Leptin also raises BP by stimulating the carotid bodies. Dashed lines, minor projections of POMC neurons plausibly involved in SNS control.

Figure 4:

Selected nuclei and pathways that contribute to salt or angiotensin-induced hypertension. Inset: mechanism of action of Na in the OVLT (after). Sodium present in the CSF and ECF binds to and opens Na(x) channels, elicits the release of protons from astrocytes and ependymal cells. [H⁺] activates OVLT neurons via acid-sensing ion channel-1a (ASIC). Other types of sodium sensing mechanisms have also been proposed . Other abbrs: see list.

Figure 5:

BP regulation via arterial baroreceptors and brainstem perfusion: a hypothesis. A reduction in cerebral blood flow within the RVLM (box) is detected by astrocytes via hypoxia, acidification or end-feet mechanosensitivity elicited by changes in vascular diameter, the latter symbolized by double arrows. The flow-mediated reflex (slow pathway) and the conventional baroreflex (fast pathway, at right of diagram) converge on RVLM PSNs.