Tag Archives: research

A Brief Introduction

This post dates to last October, but I thought it would be worth re-posting over here since I’ve migrated in that time.  It’s an extended abstract of my research project that I submitted to the Charlotte Life Sciences conference last Fall.  I was among ten finalists selected from a pool of 20 regional universities to present our work to a panel of scientific advisors, business strategists, and private equity investors.  I doubted I had much of a shot of winning the $1,000 first place prize, but it did allow me to write about what exactly I study in a language that people outside the ivory tower (mine is actually brick) can somewhat understand.  Which is sort of exactly what I’d like to do with my career, only to a much greater extent than how it is “simplified” below.

I’m posting my introduction here mostly for posterity.  It’s fleshed out way more than it would be for my usual audience of cardiovascular scientists.  However, I am exceedingly proud that my former theatre major friend kind of understood what I wrote with the help of a few definitions.  If you’re particularly curious and/or bored, feel free to read on and learn how some of your tax dollars have been used the past few years:


Endocannabinoid Modulation of Baroreflex Sensitivity in a Model of Renin-Angiotensin System-Dependent Hypertension

As of 2012, one in 3 U.S. adults is hypertensive, defined as having a resting blood pressure greater than 140/90 millimeters of mercury.  While hypertension itself is asymptomatic, the statistics of cardiovascular diseases are startling: 69% of patients with a first heart attack, 77% with a first stroke, and 74% with congestive heart failure are hypertensive.  In 2008 the estimated direct and indirect cost of managing high blood pressure, including medications, doctor visits and hospital admissions, was $50.6 billion, up from $43.5 billion the previous year.  Hypertension thus represents a massive health and economic burden.

Despite significant advances in the ability to manage high blood pressure, its root causes remain elusive.  The two components of the autonomic nervous system, the sympathetic and parasympathetic nervous systems, have emerged as prime research targets for their role in blood pressure regulation.  Hypertension is usually accompanied by an autonomic imbalance in which the sympathetic nervous system predominates over the parasympathetic branch.  Some direct consequences of this imbalance include elevation of circulating sympathetic hormones, increased blood vessel constriction, increased heart rate, and reduced baroreflex sensitivity.

The impairment of baroreflex sensitivity (BRS) for control of heart rate, measured as the reduction of heart rate in response to increases in blood pressure, often precedes the onset of hypertension.  The arterial baroreflex is the primary feedback control system for the short-term regulation of blood pressure and is an important indicator of vagus nerve function.  The effectors of the baroreflex are the baroreceptors: stretch-sensitive mechanoreceptors concentrated in the walls of the aortic arch and carotid sinus that can detect changes in blood pressure.

Baroreceptors are innervated by fibers of the vagus and glossopharyngeal nerves, which make their first synapse at the solitary tract nucleus (NTS) of the brainstem, a major autonomic integration center.  When arterial pressure increases, baroreflex afferent neurons transmit excitatory signals to the NTS.  The NTS will then increase downstream activity of the vagus nerve, yielding a decrease in heart rate to help return blood pressure to resting baseline.  Therefore, identification of biological factors that may influence BRS is critically important for understanding the development of hypertension and other negative cardiovascular outcomes.

Tonic upregulation of the endocannabinoid system, endogenous compounds that act at the same receptors as marijuana, is strongly associated with hypertension and its risk factors.  The endocannabinoid system is a ubiquitous cellular signaling system that modulates cellular activity in peripheral organs and the central nervous system.   CBcannabinoid receptors, the principal neuronal target of the endocannabinoids, are densely expressed on nerve terminals in the NTS.  Previous studies show cannabinoid ligands, such as delta-9-THC and the endogenous cannabinoid anandamide, can modulate neuronal activity within the NTS via CB1 receptors.  Therefore, we hypothesized that activation of NTS CBreceptors would alter BRS for control of heart rate in live, normotensive Sprague-Dawley rats.  We further hypothesized that we would find evidence of upregulated CBreceptor tone in the NTS of a monogenetic model of hypertension, the (mRen2)27 rat, contributing to impaired baseline BRS in this strain.


Essentially, I study how marijuana-like molecules in your brain affect your body’s control of blood pressure and heart rate.  And if you’re wondering, yes, smoking up chronically does interfere with your body’s ability to do this.  If you’re also wondering, no, I do not have access to weed in the lab. (That’s the most common question I get asked at conferences)


Insignificant data: n = 2!

Just thought I’d write an update about my project now that I’m through with the first batch of animals.  I hope this may alleviate some of the frustration it brought me over the weekend, and help me better organize and prepare for the next batch.  To summarize the background, briefly: hypertensive rats are receiving daily oral injections of the CB1 cannabinoid receptor antagonist SR141716 (SR) or its vehicle for 4 weeks, starting at 16 weeks of age, and once a week for the first three I’m recording their blood pressures, heart rates, food and water consumption, and blood glucose.  During the last week of dosing they are outfitted with femoral artery catheters so that on Day 28 I can take direct conscious recordings of blood pressure and heart rate, from which I can determine their baroreflex sensitivity and heart rate variability.  These values are both indices of autonomic function, specifically of  parasympathetic vagus nerve activity, that the brain uses to control blood pressure and heart rate.

I’m happy to report that the last 28 days have yielded me some decent preliminary data!  I dosed only four rats total in this first batch, so each group has two subjects so far.  Of course, that means these data are not yet statistically analyzable, but the trends in each set show promise.  And they remind me of this gem:

Let’s start with body weights of each group.  I weighed animals every day to determine the injection volume each would receive, so body weights were my most frequent measurement and thus my only window into the drug’s effects for most of the study.  Note that because just two animals are in each group, the bars on each point represent the raw values and NOT the standard error.  The points are the average of the two values for that day.



The top graph represents the animals’ body weights each day just prior to dosing (which was always in the afternoon, between 2:30 and 3:30 pm).  The bottom graph represents changes in body weights from each animal’s baseline (i.e. body weight on Day X – Day 0).  So, anything jump out?

To address the most salient feature of each graph, Day 24 was the catheter surgery day.  Surgery is obviously a stressful event and I expected it to arrest weight gain.  However, I did not expect them to lose weight for three consecutive days, and fearing that significant weight loss would affect the conscious recordings, I terminated the experiment early and recorded on Days 26 and 27.  Going forward I will probably allow just one or two full days for recovery before proceeding with the conscious recordings (the primary issue is allowing the anesthesia to clear the body because it dampens autonomic nervous system activity).  Although the weight loss looks precipitous, it is less than 10% of peak body weight, which my advisor believes would not significantly interfere with autonomic function.  I’m skeptical, since that would be like a 200 lb person dropping 20 lbs in 3 days.  But these are rats, not people, so… try to do better next time?  Now that I think about it, they may not have been drinking much water, in addition to eating less (if at all), during those post-surgery days.  That could definitely lead to rapid weight loss irrespective of fat or muscle tissue loss (which would definitely affect blood pressure).

Surgical ramifications aside, there’s definitely an exciting trend.  Rats given the drug gained less weight than their cagemates receiving vehicle.  I think I’ll need to report this as something like “maximum weight gained” or “weight gained by Day 26” to circumvent the effect of the catheter surgery.  Also, rats seemed to slightly lose weight at the start of treatment and did not begin gaining weight until after Day 8.  I believe the initial stress from injections through an oral gavage may account for much of this effect.  Going forward I intend to train rats to receive vehicle injections starting a week prior to their experimental baseline (Day 0).

I’ll stop here for tonight and pick it up tomorrow.  This exercise has been therapeutic.  I’m looking forward to organizing more of this mess as the weekend shockwave fades.