The Silent Killer
Research Models
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Stephen Wilson

The Silent Killer

Hypertension, or high blood pressure, is a stealth-like condition that can wield a large and very dangerous stick.

As its name suggests, blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps blood. If this pressure rises and stays high over time, it can damage the body in many ways.

High blood pressure can trigger a whole host of complications, including damage to blood vessels or other organs. It is also a major risk factor for stroke, heart attack, heart failure, aneurysms, and kidney disease. About 1 in 3 adults in the United States—and about 1 billion worldwide--have high blood pressure, but because the condition usually has no obvious signs or symptoms most people can have it for years without realizing it.

Hypertension also puts enormous pressure on people’s wallets. In 2010, high blood pressure cost the United States $76.6 billion in health care services, medications and missed days of work, a report by the American Heart Association in the journal Circulation suggests.[i] 

While there are effective ways of controlling hypertension, such as diuretics, the hypertension puzzle is far from complete. Scientists do not know how to cure it, nor in most instances do they really know what causes it. But they are filling in some of the pieces by studying how this elusive condition plays out in our four-legged friends. Animal models help scientists mimic the human condition and offer an opportunity to study the safety and efficacy of potential therapies that might prevent a cascade of unfortunate events.

Genetic vs. induced
The animal models used in hypertension research generally fall into two categories—genetic models in which specific genes have been altered to mimic certain conditions associated with this condition and induced models, where a disease or condition is artificially introduced. Both are useful in different ways.

Genetic models include selective breeding of animals—typically rats—that exhibit a trait associated with hypertension, such as obesity. Two such models include the spontaneously hypertensive rat (SHR), a popular choice among researchers because of its wide availability, and the Dahl salt-sensitive rat, whose blood pressure spikes more rapidly than a genetically-modified salt-resistant rat when salt is added to the daily diet. .Both models are useful in the assessment of drugs designed to reduce blood pressure.

There are also several substrains of the SHR, including the obese (SHROB), stroke-prone (SHRSP) and heart failure (SHHF) models. These substrains have been bred to exhibit other disease characteristics important in our understanding of the mechanisms driving hypertension or resulting complications.

Another kind of genetic model is the transgenic animal—typically a mouse—which is generated by over-expressing a specific gene. Transgenic mice can be particularly useful in targeting the role of a specific gene associated with hypertension. An example of a transgenic model is the TGR (mREN2)27 transgenic rat, which suppresses endogenous renal renin,[ii] a hormonal system that regulates blood pressure and fluid balance.

In contrast to genetic models, induced models are surgical, dietary or pharmacological challenges that result in hypertension. A classic model was characterized nearly 80 years ago by Cleveland pathologist Harry Goldblatt. Goldblatt also attempted to prove that renin—an enzyme secreted and stored in kidneys—was the essential origin of hypertension.

Other kinds of induced animal models mimic the effects of long-term exposure to diets high in salt, fat or sugar—which many of us love but which unfortunately don’t love us back.

Pressure points
No matter the model, monitoring blood pressure is key. For a pint-sized rodent, those pulsating sleeves ubiquitous at drug stores and doctors’ offices may not necessarily be the way to go. Researchers generally rely on a few methods to measure BP in laboratory animals. The most robust involves telemetry—the implanting of devices designed to collect continuous measurements in conscious, unrestrained animals. Not only are the data highly accurate, the sensitivity of the data can often lead to a reduction in the number of animals required per group. Telemetry also allows for the collection of data for days, weeks or even months, which can be especially valuable when investigating acute effects over a specified time period, or the impact of long-term drug therapies.
 
Another popular method used to monitor BP is a tail cuff.  The data can be collected at specific time points, typically once a day, though more often is feasible. To account for variability, between 5 and 10 readings are completed at each time point. Care must be taken to minimize the potential for inter-reader variability. Because of the intermittent collection intervals, this type of monitoring is most useful for studies conducted over days or months and with a large number of animals per group.
 
The list of animal models used to study hypertension is quite lengthy, and it is not uncommon for investigators to question which models and techniques are appropriate for their research. It is also important to note that no one model fully mimics the human condition. Selection of the appropriate model will depend on what the drug compound is designed to target—is it attacking flagging renal circulation, for instance—and the methods used to monitor blood pressure changes will depend upon the lab’s expertise and the data needed to meet the objectives of the study.
 
And the beat goes on.


[i] Lloyd-Jones D, Adams RJ, Brown TM et al. (February 2010). "Heart disease and stroke statistics--2010 update: a report from the American Heart Association". Circulation 121 (7): e46–e215. doi:10.1161/CIRCULATIONAHA.109.192667. PMID 20019324

[ii] Bader M, Zhao Y, Sander M, Lee MA, Bachmann J, Böhm M, Djavidani B, Peters J, Mullins JJ, and Ganten D (1992).  Role of tissue rennin in the pathophysiology of hypertension in TGR(mREN2)27 rats.  Hypertension 19 681-686.