Raising hopes for high blood pressure

High blood pressure is one of the most prevalent health problems in the developed world. Existing treatments focus on lifestyle changes and relaxing or widening the blood vessels themselves. Now, a team led by Prof Robert M Carey, of the University of Virginia Health System, is exploring a new approach to treating high blood pressure, making use of molecular systems in the kidney which control the body’s balance of water and salt.

High blood pressure (hypertension) affects an astonishing one in four adults in the western world, and contributes to some of the leading causes of death and disability, including heart attacks, strokes, kidney disease and dementia.

Ninety percent of high blood pressure cases are classed as ‘primary’ hypertension (also known as ‘essential’ hypertension) which means there is no known underlying biological or medical cause. In these cases, the high blood pressure is usually put down to a mixture of genetic and environmental factors, and treated with a combination of lifestyle changes (reducing salt intake, alcohol consumption, and caffeine use; losing weight; increasing exercise; and improving sleep) and, if these measures fail, antihypertensive medication. Existing medications for high blood pressure tend to act on the blood vessels, either relaxing their walls or widening the vessels themselves, to reduce the pressure within.

Sodium takes the blame
However, the immediate cause of high blood pressure is retention of sodium (one of the elements contained in salt, sodium chloride), by the kidneys. Sodium retention causes the body to retain fluids. The increased circulating volume increases pressure on blood vessels, causing hypertension. In fact, Prof Carey points out, all forms of hypertension, both in humans and laboratory animals, involve disruption of the body’s natural systems for eliminating excess sodium.

All forms of hypertension involve disruption of the body’s natural systems for eliminating excess sodium.

Thus, any treatment that encourages the body to excrete sodium should help to lower fluid volume and, thereby, blood pressure. With this in mind, Prof Carey’s lab is focusing on understanding the body’s natural molecular pathway for sodium excretion by the kidneys, in the hope of finding targets for new drug treatments.

Harnessing a natural system
Prof Carey is an international authority on hormonal control of blood pressure. Many of our body’s physiological processes are controlled by hormones — and the maintenance of a healthy salt and water balance by the kidneys is no exception. Prof Carey’s current research focuses on how this is controlled through a molecular network known as the ‘renin-angiotensin system’ (RAS).

Schematic representation of the agents and conditions for and resulting actions of AT2 receptor (AT2R) activation in the kidney

The key player in the RAS system is a molecule known as angiotensin II. This molecule can interact with two different receptor molecules, each controlling a different pathway of the RAS. If an angiotensin II molecule “meets” a ‘type 1’ receptor (known as AT1R), a detrimental set of reactions is triggered which causes inflammation, blood vessel constriction, sodium accumulation, and increased blood pressure.

If, however, angiotensin II meets a ‘type 2’ receptor (AT2R), an alternative, protective pathway is activated, stimulating the kidneys to excrete sodium, lowering blood pressure and reducing inflammation. Prof Carey’s lab is currently working on a project, funded by the US National Institutes of Health, to understand and ultimately harness the AT2R pathway, to develop new treatments for primary hypertension.

Activating AT2R
Although the role of angiotensin II and AT1R in increasing blood pressure has been relatively well studied, the second role of angiotensin II, via AT2R, has — until now — slipped under the radar. Prof Carey’s lab has recently begun to characterise this pathway and have already made multiple discoveries.

Basic research to understand the underlying mechanisms of sodium retention by the kidneys is crucial for developing treatment for diseases such as hypertension.

Firstly, they found that AT2R activation is most effective when angiotensin II is converted, by an enzyme called aminopeptidase, to a related molecule, angiotensin III. Animal models using rats have shown that the protective RAS pathway is impaired — i.e., sodium is not excreted and blood pressure is raised — in individuals in which angiotensin III is destroyed before it is able to interact with AT2R.

Secondly, recent studies have suggested that medicines known as angiotensin receptor blockers, used to treat high blood pressure by blocking the interaction between angiotensin II and AT1R, may in fact have a dual-action effect, also activating AT2R and its protective pathway, causing the kidneys to excrete sodium and thereby lower blood pressure.

Finally, Prof Carey’s lab has also shown that AT2R activation stimulates the production of molecules including nitric oxide. Nitric oxide can then stimulate the body to produce more molecules of AT2R, forming a positive feedback loop that could reinforce the body’s ability to excrete sodium and reduce hypertension. Thus, Carey’s team is furthering our understanding of multiple steps in the protective pathway against high blood pressure, both before and after the AT2R itself.

In their current study, the lab now aims to further test the hypothesis that high blood pressure can be caused by a failure to excrete sodium when the AT2R-mediated pathway is impaired, and that this is due to a lack of angiotensin III. They then aim to test whether artificially activating AT2R can improve sodium excretion and reduce hypertension, and whether AT2R could ultimately be a useful target for therapies to prevent and reduce high blood pressure.

Co-opting Compound 21
Research into the role of angiotensin and the AT2R receptor in treating hypertension has recently been given a huge boost by the development of the mysterious ‘Compound 21’ — an artificial activator of AT2R. Prof Carey’s lab can make use of Compound 21 in two ways: firstly, they can use it experimentally to manipulate and characterise the function of AT2R in the kidneys and its role in sodium excretion and reducing blood pressure. Secondly, Compound 21 may prove to be the first in a new class of therapeutic agents that could provide new treatments for hypertension and related conditions, either alone or in combination with existing therapies such as angiotensin receptor blockers. In fact, in rats, the lab has shown that Compound 21 is as effective at preventing high blood pressure as it is at treating it.

The work of Prof Carey’s lab shows that basic research to understand the molecular pathways underlying the workings of the human body can be crucial to developing potential treatments for, and even averting, disease.

Click here to see the full article.