Heart failure and hypertension are both prevalent and serious health concerns, and progress toward understanding their underlying mechanisms could significantly impact development of therapeutic approaches. The hypothalamus is critical in bodily homeostasis and visceral reflex control, and understanding its role in these diseases is an area of critical importance.
Within the hypothalamus, neuroendocrine neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) respond to stressors via release of vasopressin and oxytocin into the systemic circulation (Brown et al. 2013; Carmichael & Wainford, 2015). These hormones contribute to the cardiovascular response to a variety of reflexes or diseases. In animal models of heart failure and hypertension, increased excitability of the hypothalamus contributes to elevated circulating vasopressin and sympathetic nervous system activity (Carmichael & Wainford, 2015). Heart failure and hypertensive patients also show elevated circulating vasopressin, which is predictive of disease severity and mortality (Lanfear et al. 2013), and vasopressin receptor antagonists have shown some success in improving the health of heart failure patients (Wasilewski et al. 2016).
In this issue of The Journal of Physiology, Zhang et al. (2017) examined the contribution of the glutamatergic NMDA receptor (NMDAR) and transient A‐type potassium channel, and its current (I A), in controlling excitability of SON neurons in renovascular hypertension (RVH). Transient A‐type channels activate near the spiking threshold of many excitable cells. This is relevant as I A delays the onset and modulates the shape of the action potential, limits repetitive discharge and back propagation of action potentials, and modulates synaptic transmission and its plasticity. The authors previously demonstrated NMDAR activation inhibits I A, which limits excitability in neurosecretory SON neurons from normal rats (Naskar & Stern, 2014) as well as in pre‐autonomic PVN neurons that project to the rostroventral lateral medulla following RVH (Sonner et al. 2008). The present study is unique in that it demonstrates a profound role of I A in neuroendocrine SON neuronal excitability in RVH. The authors show that tonic I A is less in RVH, elevating SON excitability and possibly contributing to enhanced vasopressin secretion. These results illustrate a potential mechanism in the SON for the observed hypertension in this model, and possibly other models as well.
This study raises interesting questions for further investigation: what is the I A channel and its alteration in RVH? Kv1.4a, Kv3.4, Kv4.2 and Kv4.3 all contribute to generate I A (Carrasquillo & Nerbonne, 2014). The authors have previously shown Kv1.4 and Kv4.3 are expressed in the PVN (Sonner & Stern, 2007), but the expression profile for A‐type channels in the SON and in RVH requires further study. Kv4.2 is expressed in the SON (Alonso & Widmer, 1997), but whether it contributes to these currents is unclear.
The present study further demonstrates activation of the calcium‐permeable, extrasynaptic NMDAR induces the decrease in I A, but in RVH, NMDA was largely ineffective in decreasing I A, and one may predict this was due to reduced expression and/or function of NMDARs. Because two NR1 subunits are required, along with two copies of NR2 and/or NR3 subunits, for functional NMDAR receptor assembly (Traynelis et al. 2010), the authors examined the expression of NMDAR subunits. mRNA analysis for NR1 and NR2A‐D demonstrates comparable expression between groups. While the authors did not determine the subunits which compose the functional NMDAR in RVH, receptor function was similar between groups. These results suggest mechanisms other than altered NMDARs account for the attenuated I A in RVH – an important step toward understanding the processes for elevated excitation.
Similar to other forms of hypertension (Li & Pan, 2007; Carmichael & Wainford, 2015), SON neurons after RVH express enhanced glutamate tone which contributes to elevated excitability. Inhibition of NMDARs hyperpolarized neurons and reduced excitability more in RVH than Sham cells. NMDAR block also relieved A‐type channel inhibition to elevate I A in RVH. Thus, after RVH elevated tonic glutamatergic and NMDAR excitation enhances neuronal discharge, due to persistent inhibition of I A. These results further suggest that in RVH the blunted response to exogenous NMDA on I A is due to existing I A inhibition by elevated ambient glutamate or intracellular pathways. The origin of this elevated excitatory tone requires further examination, but may be due to reduced ratio of glutamate to GABA tone or augmented excitatory inputs from other nuclei, among other possibilities.
What intracellular pathway may link NMDA currents to reduced I A? Given that RVH augmented glutamatergic tone and NMDAR activation, which elevates intracellular calcium, it is tempting to speculate increased contribution of one or more Ca2+‐dependent second messengers. In other central neurons, A‐type channels are phosphorylated by protein kinase A, protein kinase C, extracellular‐regulated kinase and Ca2+/calmodulin‐dependent kinase II (Carrasquillo & Nerbonne, 2014). Notably, the activity of many of these kinases is affected by neuronal activity via elevated calcium, and phosphorylation of A‐type channels often leads to their removal from the membrane. The authors have previously found protein kinase C contributes to the reduction in I A in normal rats (Naskar & Stern, 2014). Thus, RVH may reduce A‐type channel expression or function by altering its phosphorylation state via one or more kinases. Future studies are required to confirm this notion.
Excitatory amino acid transporters (EAATs, GLAST and GLT‐1), located on astrocytes which ensheath the presynaptic terminal and postsynaptic cell, remove glutamate from the extracellular space to control neuronal and synaptic activity (Danbolt, 2001). The authors previously demonstrated a role of EAATs in modulating hypothalamic neuronal activity (Fleming et al. 2011). Thus, they predicted that in RVH a reduced glutamate uptake by EAATs contributes to elevated ambient glutamate and subsequent NMDAR activation. Contrarily, EAATs were enhanced in RVH. The authors suggest this elevated transporter activity may be a compensatory mechanism to the elevated glutamate. Similar to exogenous NMDA, EAAT block decreased I A yet this reduction was less in RVH. These results suggest even modest physiological elevations of extracellular glutamate modify I A. Moreover, the relatively rapid time frame by which this occurs suggests modulation of I A via its channel modification rather than its removal from the membrane, although this remains to be determined.
The work by Zhang et al. (2017) adds to the emerging understanding of the importance of hypothalamic plasticity in cardiovascular function. This plasticity occurs not only in pre‐autonomic and neuroendocrine neurons but also in astrocytes surrounding them, and their interplay is likely to be critical to homeostatic and viscerosensory reflex function. Given that elevated glutamatergic activity in the hypothalamus contributes to exaggerated sympathoexcitation and hypertension (Carmichael & Wainford, 2015), this study provides potential mechanism(s) by which hypertension may occur. This work may also lend insight to other central nuclei that are altered in and contribute to hypertension (Guyenet, 2006). Translation of this work to the whole animal is a logical next step, as well as determining how NMDAR–I A coupling alters viscerosensory reflexes and their underlying neural circuits during which robust elevations of glutamate may occur. Lastly, the pathways delineated by the authors provide several modes by which excitability may be fine‐tuned to change the gain of critical pathways. Together, these results provide strong rationale to study deeper the role of the hypothalamus.
Additional information
Competing interests
None declared.
Funding
The author received support from NIH grants RO1 HL098602 and RO1 HL128454 while working on this manuscript.
Linked articles This Perspective highlights an article by Zhang et al. To read this article, visit https://doi.org/10.1113/JP274327.
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