Altered regulation of the rostral ventrolateral medulla in hypertensive obese Zucker rats

Huber DA, Schreihofer AM.

Dept. of Integrative Physiology, Univ. of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA.

Am J Physiol Heart Circ Physiol. 2011 Jul;301(1):H230-40. Epub 2011 May 2.

http://ajpheart.physiology.org/content/301/1/H230.full.pdf+html

Numerous elegant studies by Professor Alan Sved and other investigators have shown that elevated sympathetic nerve activity (in spontaneously hypertensive rats, Dahl salt-sensitive rats and other hypertenive rat models) is associated with increased tonic activation of RVLM by glutamate and angiotensin II and decreased tonic GABAergic inhibition.  Obese Zucker rats (OZR) have elevated renal and splanchnic sympathetic nerve activity and mean arterial pressure, however the mechanisms are unknown. In order to understand the mechanisms the authors did mutliple experiments and made some significant findings. When RVLM was inhibited it produced a greater decrease in MAP in the OZR compared to their lean counterpart. When AT1 receptors were blocked it produced a modest decrease in splanchnic SNA and MAP in the OZR but not in lean zucker rats (LZR). Ionotropic glutamate receptor antagonists produced comparable differences in the SNA, MAP and HR in OZR and LZR. GABA-A receptor antagonist produced smaller increase in SNA, MAP and HR in OZR compared to LZR. Finally inhibition of CVLM or the NTS produced a smaller increase in SNA and HR in OZR compared to LZR but the pressor responses were normal.  The authors suggest some possible explantion for this unexpected finding. One possibility is that the pressor response is a summation of changes in splanchnic SNA with other other sympathetic responses and another possibility could be related to a threshold effect because of changes in vascular reactivity. Overall the results suggest that elevated MAP and SNA in the OZRs are a measure of increased angiotensinergic activation and reduced GABAergic inhibition of the RVLM.

(In)activity dependent alterations in resting and reflex control of splanchnic sympathetic nerve activity

Mischel, NA and Mueller, PJ.  Am J Physiol Regul Integr Comp Physiol (resubmitted)

I wanted to be the first to post a blog on a hot new paper that is destined to be accepted in AJP: Reg in the next couple of weeks.  It's the first first author paper from a student in an up and coming laboratory examining neuroplasticity in cardiovascular regulation that occurs following sedentary versus physically active conditions.  In the study the author observed increased resting and stimulated sympathetic nerve activity.  Neuroplasticity in the brainstem is a possible mechanism since one of the methods used to increase sympathetic nerve activity was with direct microinjections of the excitatory amino acid, glutamate.  Interestingly, the authors also observed enhanced sympathoexcitation with unloading of arterial baroreceptors with the vasodilator nitroprusside.  Although baroreceptor unloading is typically associated with withdrawel of GABAergic inhibition of the RVLM (i.e. disinhibition), there are a few studies that have implicated glutamate in the the baroreflex (see Maryov and Head, 2003).  Lastly, the authors test vascular sensitivity by injections of the alpha one agonist phenylephrine.  In a classic move, they test the responses in the presence of ganglionic blockade to remove any compensatory actions of the baroreflex from influencing their results.  All an all an interesting paper that is likely to be cited by several since it implicates the splanchnic circulation as a target for physical (in)activty dependent neuroplasticity.  As in their review from 2010, they make use of a "physical (in)activity" nomenclature to promote the idea that these changes could be the result of remaining sedentary, being physically active or both.  They suggest future studies are warrant to distinguish between these possibilities.

-Posted by Pat (upon resubmission of Nick's 1st paper, of course!

Distribution and projection of the medullary cardiovascular control neurons containing glutamate, glutamic acid decarboxylase, tyrosine hydroxylase and phenylethanolamine N-methyltransferase in rats

Takashi Suzuki, Kiyoshige Takayama, Mitsuhiko Miura

The aim of this study is to determine the distribution and projection of the medullary cardiovascular neurons that contain the neurotransmitters or the enzymes involved in cardiovascular regulation. Six male Wistar rats were used, and a mixture of WGA-HRP was injected into the depressor caudal ventrolateral medulla (D-CVLM) and the pressor rostral ventrolateral medulla(P-RVLM). Immunohistochemistry was performed to identify HRP-labelled neurons which were stained with antiserum to glutamate (GLU),glutamic acid decarboxylase(GAD),tyrosine hydroxylase(TH) or phenylethanolamine N-methyltransferase (PNMT). The investigators in this study counted all the single HRP-labeled and the double labeled neurons in the NTS, D-CVLM and P-RVLM either ipsilaterally or contralaterally to HRP injection. They found that: (1)the HRP/GLU-labeled neurons in the NTS project to both the D-CVLM and P-RVLM which indicates divergent excitatory projection, (2)the P-RVLM receives innervation from HRP/GLU- labeled neurons in the D-CVLM, while the D-CVLM receives innervation from HRP-GLU-labeled neurons in the P-RVLM indicating the mutual innervation,(3)the HRP/GAD- labeled neurons in both the CVLM and the NTS project to the P-RVLM indicating the convergent  inhibitory  projection,(4) there are projection of both  HRP/TH- and HRP/PNMT- labeled neurons  to the P-RVLM but they are much less than the HRP/GAD-labeled neurons projections to the P-RVLM .  From these results, they concluded that catecholaminergic  neurons paly a minor role in inhibition of the sympathetic activity of the RVLM neurons, the glutamatergic NTS neurons excite both the P-RVLM and D-CVLM neurons, and the GABA ergic NTS and CVLM neurons inhibit the P-RVLM neurons. 

Hot off the press!! Splanchnic sympathetic nerves in the development of mild DOCA-salt hypertension.

Hi everyone, sorry for the gap since my last post, but I hope I can make up for it with this exciting new paper from our friends down the road at Michigan State.

Recent work from Greg Fink's lab (last author) and others has highlighted the importance of examining splanchnic sympathetic activity in the development and/or maintanance of hypertension. For example, experimental hypertension induced in rats using exogenous angiotensin II and a high salt diet is characterized by differential sympathetic responses depending on which "sympathetic regions", including splanchnic, are examined. In that model, renal nerve activity is decreased and lumbar nerve activity remains unchanged as measured by chronic nerve recordings in conscious rats. If the splanchnic sympathetic bed is denervated by removing the celiac ganglia (CGx) in the same model, blood pressure falls dramatically, suggesting that sympatehtic activity to the splanchnic bed is increased.
In this new study, they examine the role of the splanchnic bed in another clinically relevant model of hypertension, the DOCA-salt model. Similar to the ANGII-salt model, it appears that the combination of high salt with overexposure to a blood pressure regulating hormone, in this case the aldosterone-like molecule deoxycorticosterone acetate (DOCA), produces significant hypertension.
The lead author implanted a long-term release DOCA pellet in rats at the same time as implanting a radiotelemeter to measure arterial pressure chronically. Some rats were subjected to  CGx and some underwent the same surgery except not denervated. Over a period of two weeks to a month, blood pressure significantly increased in both groups, but the increase was significantly attenuated in CGx rats. At the end of the experiment, tissue supplied via the spalnchnic circulation was harvested and analyzed for norepinephrine (NE) content. NE was markedly diminished in the sampled tissues, indicating that CGx was effective. Additionally, the lead author infused radiolabeled NE into the rats until it reached steady state concentrations, then simultaneously sampled arterial and venous splanchnic blood for radiolabeled and endogenous NE levels. A calculation of the differences between arterial and venous values of radiolabeled and endogenous NE indicates how much endogenous NE is has been used by sympathetic nerve terminals as a neurotransmitter and then "spilled over" into venous blood. This procedure is a way to measure NE handling in specific tissues, with increased NE spillover indicating increased sympathetic outflow to the tissue. They found that whole-body NE spillover and NE plasma levels were decreased in CGx during the control period, but not during DOCA-salt. Similar findings were observed with splanchnic NE spillover.
The data indicate that the splanchnic bed certainly contributes to hypertension in this model but is not wholly responsible for it. In addition, splanchnic SNA does not appear to be increased in this model when assessed by the NE spillover method. Thus, it is possible that, in this model, increased reactivity of the splanchnic vasculature decreased arterial and venous compliance and leads to increased central arterial pressure.

-Nick

Angiotensin-II-induced reactive oxygen species along the SFO-PVN-RVLM pathway: implications in neurogenic hypertension

V.A. Braga, I.A. Medeiros, T.P. Ribeiro, M.S. França-Silva, M.S. Botelho-Ono and D.D. Guimarães
Laboratório de Tecnologia Farmacêutica, Universidade Federal da Paraíba, João Pessoa, PB, Brasil.

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2011007500088&lng=en&nrm=iso&tlng=en

This is an interesting review about how angiotensin-II (Ang-II)-induced reactive oxygen species (ROS) produces some forms of neurogenic hypertension. The most interesting aspect is that it discusses about the three important areas, subfornical organ (SFO), paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) and their contributions individually and in combination with one another for the pathogensis of neurogenic hypertension. Direct microinjection studies in the brain using Ang-II have shown that oxidative stress is an important mechanism by which Ang-II increases blood pressure. However the question of how circulating Ang-II acts on these brain centers without crossing blood brain barrier, resulting in increased sympathetic nerve activity and causing hypertension remains to be answered. Numerous hypothesis have been postulated, one widely accepted hypothesis is that Ang-II acts on the neurons in the circumventricualr organ (CVO) which lacks blood brain barrier, which inturn alter the other brian regions by increasing the production of local Ang-II. This review mainly address the mechanisms by which Ang-II acts on the neurons in the SFO (one of the CVOs), and how SFO communicates with PVN and RVLM in ROS production, regulating sympathetic activation and altering blood pressure. This review points out at numerous studies that directly and indirectly have shown how ROS production in all the three regions SFO, PVN and RVLM could contribute to neurogenic hypertension. The figure in the last page summarizes how Ang-II could induce the production of ROS and inturn neuronal firing.  The possible pathway interconnecting all these regions to the pathogenesis of neurogenic hypertension could have been more elaborate.

- Madhan