The ventrolateral medulla and sympathetic regulation of arterial pressure.

ANN M. SCHREIHOFER AND ALAN F. SVED.  The ventrolateral medulla and sympathetic regulation of arterial pressure. In: Central regulation of autonomic functions.  2^nd Edition. Eds: I.J. Llewellyn-Smith and A.J. Verberne Oxford University Press, Inc. New York, 2011.

So in honor of our guest from Australia I thought it was timely to provide a posting on one of the chapters from Ida's recent book that will likely be considered the bible on neural control for at least the next 5-10 years.  The particular chapter I chose is of course most relevant to our studies on the RVLM, although other chapters in this book are also important in terms of our understanding of brainstem control of arterial pressure.  In this chapter Ann Schreihofer and Alan Sved provide a nice overview of the history and development of what the current knowledge is on brainstem control of sympathetic outflow.  They do a great job in discussing the number of techniques used to examine the ventrolateral medulla in term of it's anatomy and physiology.  Several nice figures combine immunohistochemistry, histology, BP and SNA responses etc. to illustrate the relationship between the CVLM and the RVLM.  There is also some clarification on the confusion caused by the original nomenclature of the C1 cells and that while serving as a useful marker for barosensitive, bulbospinal neurons controlling SNA, use glutamate not epinephrine serves as the primary neurotransmitters of RVLM neurons.  A thorough discussion of the roles of the RVLM and CVLM is provided.   There is a section of the caudal pressor area which while interesting, seems to pale in comparison to the importance of the CVLM and RVLM.  Finally, the last two sections are devoted to differential control and the role of the VLM in hypertension.  Both nice summaries but also highlight the number of unaswered questions that remain to be answered, some of which are being addressed in our laboratory.  Overall this is a chapter that every student, postdoc and faculty working in the field needs to be well-versed in so if you haven't done so recently or already, I would suggest giving it a look soon.

Posted by Pat

Addressing an ongoing controversy: Do C1 neurons contribute to resting blood pressure?

Control of sympathetic vasomotor tone by catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata.

Marina N, Abdala AP, Korsak A, Simms AE, Allen AM, Paton JF, Gourine AV.

This study was designed to investigate the role of rostral ventral medullary catecholaminergic neurons in the control of resting blood pressure. We all know that most of supraspinal resting vasomotor tone comes from some neurons that "live" in the rostral portion of the ventrolateral medulla (RVLM). We also know that many neurons in RVLM are "C1" neurons, that is, they can synthesize catecholamines. Finally, we know that both C1 and non-C1 neurons send axons to sympathetic preganglionic neurons in the spinal cord, with most being C1. At the time of these discoveries it was assumed that C1 neurons were a major source of resting and relfex RVLM-mediated sympathetic activity. However, studies done in the past ten years have been able to investigate the function of C1 neurons by specifically targeting them with antibodies and viruses. Schreihofer and Guyenet showed that when about 75% of C1 neurons were ablated, sympathoexcitatory responses to direct or reflex-mediated stimulation were markedly reduced, but resting tone of SNA and MAP were unaffected. Further work from this lab showed that specific direct activation of C1 neurons produced increases in SNA and MAP. Also, work from another lab showed that specific "re-expression" of angiotensin II receptors in C1 neurons of an angiotensin receptor knockout mouse model restored SNA responses to angiotensin II in the RVLM. Together, these data suggest a prominent role for C1 neurons in SNS responses but doesn't fully address the role of C1 neurons in the maintanance of resting tone.

The very innovative and unique aspect of this study was the system the authors designed to test direct acute inhibition of C1 neurons in vivo. This was accomplished using lentiviruses specific for C1 neurons, but instead of the virus encoding for something that kills the cell, it encodes an inhibitory G protein-coupled receptor that has a specific ligand (allatostatin) which is not present in mammals. After RVLM injection of the virus and a 5 to 6 week recovery period, rats were anesthetized and instrumented to record MAP and renal SNA. They showed convincingly that acute specific inhibition of C1 neurons in vivo causes a reversible fall in MAP and RSNA in animals that recieved the virus but not in sham rats. They then tested the role of C1 neurons in the SNS response to hypercapnia, or high levels of arterial CO2. Interestingly, if C1 neurons were inhibited before experimentally varying CO2 levels, the response was the same as control. If C1 neurons were inhibited during high CO2, the peak response was attenuated. Also, they suggest that blockade of ionotropic glutamate receptors did not affect this phenomenon. I engourage anyone reading this post to look at the results of this second-to-last experiment and decide for yourself what the results suggest. Finally, they used an isolated heart-brainstem preparation to show that C1 neurons generate much of the respiratory-related SNA bursts.

These data contrast with previous work described. However, the authors note an important distinction in the discussion. By using a toxin that killed C1 neurons over the course of days, other vasomotor centers had the opportunity to increase their activity in compensation. Importantly, they showed in this study that the inhibition was immediate and reversible. Additionally, it appears (to me) that glutamatergic inputs on C1 neurons do have some role in the sympathetic response to hypercapnia, although I admit that the results from this study don't clearly suggest whether they do or do not. Finally, C1 neurons clearly are responsible for respiratory-related bursts of SNA in the authors' in situ  heart-brainstem prep. They could confirm these results in vivo by performing experiments similar to those from Ann Schreihofer's lab of the past 5 years or so.