Blood pressure is maintained during dehydration by hypothalamic paraventricular nucleus‐driven tonic sympathetic nerve activity

Abstract

Key pointsr At normal resting mean arterial pressure (MAP), sympathetic nerve activity (SNA) mostly consists of respiratory and cardiac rhythmic bursts of action potentials.r In animal models of sympathetic hyperactivity, elevated SNA and MAP become reliant on activity of neurones in the hypothalamic paraventricular nucleus (PVN).r Dehydrated (DH) rats (48 h water deprived) were used as a model of sympathetic hyperactivity.As expected, acute PVN inhibition reduced MAP and integrated splanchnic SNA (sSNA) in DH rats, but had no effect in euhydrated controls. Unexpectedly, the fall of sSNA in DH rats was due to a reduction of irregular, tonic activity as neither respiratory nor cardiac rhythmic bursting was significantly affected.r We conclude that MAP is largely maintained during dehydration by PVN-driven tonic SNA and speculate that a normally quiescent tonic component of SNA might also be recruited in chronic diseases (hypertension, heart failure, obesity) where PVN activation drives sympathetic hyperactivity.Abstract Resting sympathetic nerve activity (SNA) consists primarily of respiratory and cardiac rhythmic bursts of action potentials. During homeostatic challenges such as dehydration, the hypothalamic paraventricular nucleus (PVN) is activated and drives SNA in support of arterial pressure (AP). Given that PVN neurones project to brainstem cardio-respiratory regions that generate bursting patterns of SNA, we sought to determine the contribution of PVN to support of rhythmic bursting of SNA during dehydration and to elucidate which bursts dominantly contribute to maintenance of AP. Euhydrated (EH) and dehydrated (DH) (48 h water deprived) rats were anaesthetized, bilaterally vagotomized and underwent acute PVN inhibition by bilateral injection of the GABA-A receptor agonist muscimol (0.1 nmol in 50 nl). Consistent with previous studies, muscimol had no effect in EH rats (n = 6), but reduced mean AP (MAP; P < 0.001) and integrated splanchnic SNA (sSNA; P < 0.001) in DH rats (n = 6). Arterial pulse pressure was unaffected in both groups. Muscimol reduced burst frequency of phrenic nerve activity (P < 0.05) equally in both groups without affecting the burst amplitude-duration integral (i.e. area under the curve). PVN inhibition did not affect the amplitude of the inspiratory peak, expiratory trough or expiratory peak of sSNA in either group, but reduced cardiac rhythmic sSNA in DH rats only (P < 0.001). The latter was largely reversed by inflating an aortic cuff to restore MAP (n = 5), suggesting that the muscimol-induced reduction of cardiac rhythmic sSNA in DH rats was an indirect effect of reducing MAP and thus arterial baroreceptor input. We conclude that MAP is largely maintained in anaesthetized DH rats by a PVN-driven component of sSNA that is neither respiratory nor cardiac rhythmic.

TRPV4 and KCa ion channels functionally couple as osmosensors in the paraventricular nucleus

“…Our experimental data therefore lead us to the conclusion that central TRPV4 channels play a role in osmosensing within the parvocellular PVN. While recent work confirms that the PVN is important for coupling osmolality to sympathetic nerve activity in vivo (Holbein et al ., 2014 ), further experiments will be required to investigate if these involve TRPV4 and SK channel coupling. Interestingly, it was recently shown that thirst itself does not appear to involve TRPV4 channels as TRPV4−/− mice had no change in ad libitum water consumption (Kinsman et al ., 2014 ).…”

“…Body fluid osmolality is usually regulated within a narrow range (∼290–300 mOsm) and previous studies show that application of hypertonic saline to the hypothalamus increases BP (Chen and Toney, 2001 ; Bourque, 2008 ; Chu et al ., 2010 ), whereas hypotonic challenge decreases sympathetic nerve activity, BP and heart rate (Bourque and Oliet, 1997 ). At least some of this activity appears to be mediated by the paraventricular nucleus (PVN) of the hypothalamus (Holbein et al ., 2014 ). Furthermore, water deprivation increases expression of the early response gene c- fos in pre-autonomic parvocellular neurones of the PVN (Stocker et al ., 2004 ), a nucleus with an established role in both osmotic homeostasis (Bourque, 2008 ) and central cardiovascular control (Nunn et al ., 2011 ).…”

A preliminary study of the effect of a high-salt diet on transcriptome dynamics in rat hypothalamic forebrain and brainstem cardiovascular control centers

“…Similar, to SON, the PVN also accounts for greater secretion of AVP with clear cardinal physiological function i.e., to control renal excretion of water, to regulate hemodynamic parameters dependent of effective blood volume (vasopressor activity) and to regulate secretion of ACTH (from PVN's subdivision of parvocellular neurons) (Sherman et al, 1986). It is also well documented that the hypothalamic levels of AVP mRNA increase following chronic salt-loading and/or dehydration (Greenwood et al, 2015a;Hayashi et al, 2006;Holbein, Bardgett & Toney, 2014;Holbein & Toney, 2015), and this is clearly indicated in the present study which the mRNA expression level of AVP in PVN was increased in the expression insignificantly in SHRs fed with HS diet (Table 3). The SHRs is known for overactivated sympathetic activity even before hypertension development (Simms et al, 2009); thus, several increased in FC in AVP mRNA expression in chronic exposure to salt diet is considered as an estimated outcome.…”

The depressor response to intracerebroventricular hypotonic saline is sensitive to TRPV4 antagonist RN1734

“…This tonic inhibition is not absolute, since paraventricular application of the GABA A agonist muscamol produces powerful inhibition of SNA with associated decreases of HR and BP ( Zhang et al, 2002 ). Toney et al (2003) , however, report that this response is more apparent in chronically dehydrated rats, where tonic inhibition of the PVN is reduced ( Stocker et al, 2004b ; Holbein et al, 2014 ). This reduction in tonic inhibition is due to an additional excitatory input from the MPO, rather than a demonstrable alleviation of the tonic GABAergic inhibition ( Stocker and Toney, 2005 ).…”