Biomedicine Raising hopes for high blood pressure

High blood pressure is one of the most prevalent health problems in is controlled through a molecular network the developed world. Existing treatments focus on lifestyle changes and known as the ‘renin-angiotensin system’ relaxing or widening the blood vessels themselves. Now, a team led by (RAS).

Prof Robert M Carey, of the University of Virginia Health System, is The key player in the RAS system is a exploring a new approach to treating high blood pressure, making use molecule known as angiotensin II. This of molecular systems in the kidney which control the body’s balance of molecule can interact with two different water and salt. 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 igh blood pressure pressure is retention of sodium (one of the inflammation, blood vessel constriction, (hypertension) affects an elements contained in salt, sodium chloride), sodium accumulation, and increased blood astonishing one in four adults by the kidneys. Sodium retention causes pressure. in the western world, and the body to retain fluids. The increased contributes to some of the circulating volume increases pressure on If, however, angiotensin II meets a ‘type 2’

leading causes of death and disability, blood vessels, causing hypertension. In receptor (AT2R), an alternative, protective Hincluding heart attacks, strokes, kidney fact, Prof Carey points out, all forms of pathway is activated, stimulating the kidneys disease and dementia. hypertension, both in humans and laboratory to excrete sodium, lowering blood pressure animals, involve disruption of the body’s and reducing inflammation. Prof Carey’s lab Ninety percent of high blood pressure natural systems for eliminating excess is currently working on a project, funded cases are classed as ‘primary’ hypertension sodium. by the US National Institutes of Health, to

(also known as ‘essential’ hypertension) understand and ultimately harness the AT2R which means there is no known underlying Thus, any treatment that encourages the pathway, to develop new treatments for biological or medical cause. In these cases, body to excrete sodium should help to lower primary hypertension. the high blood pressure is usually put down fluid volume and, thereby, blood pressure. to a mixture of genetic and environmental With this in mind, Prof Carey’s lab is focusing ACTIVATING AT2R factors, and treated with a combination of on understanding the body’s natural Although the role of angiotensin II and

lifestyle changes (reducing salt intake, alcohol molecular pathway for sodium excretion by AT1R in increasing blood pressure has been consumption, and caffeine use; losing weight; the kidneys, in the hope of finding targets for relatively well studied, the second role of

increasing exercise; and improving sleep) new drug treatments. angiotensin II, via AT2R, has – until now – and, if these measures fail antihypertensive slipped under the radar. Prof Carey’s lab has medication. Existing medications for high HARNESSING A NATURAL SYSTEM recently begun to characterise this pathway blood pressure tend to act on the blood Prof Carey is an international authority on and have already made multiple discoveries.

vessels, either relaxing their walls or widening hormonal control of blood pressure. Many Firstly, they found that AT2R activation is most the vessels themselves, to reduce the of our body’s physiological processes effective when angiotensin II is converted, pressure within. are controlled by hormones – and the by an enzyme called aminopeptidase, to maintenance of a healthy salt and water a related molecule, angiotensin III. Animal SODIUM TAKES THE BLAME balance by the kidneys is no exception. Prof models using rats have shown that the However, the immediate cause of high blood Carey’s current research focuses on how this 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 AT R. All forms of hypertension involve 2 Secondly, recent studies have suggested disruption of the body’s natural that medicines known as angiotensin systems for eliminating excess sodium receptor blockers, used to treat high blood

www.researchfeatures.com 15 Biomedicine

pressure by blocking the interaction between angiotensin II and AT R, may in fact have a Basic research to understand the 1 Detail dual-action effect, also activating AT2R and its protective pathway, causing the kidneys underlying mechanisms of sodium RESEARCH OBJECTIVES to excrete sodium and thereby lower blood retention by the kidneys is crucial for Dr Carey’s research focuses on pressure. What are the problems and/or blood pressure induced by AT1 receptor determining new molecular targets developing treatment for diseases limitations of existing treatments for activation. for the treatment and prevention of Finally, Prof Carey’s lab has also shown that high blood pressure? hypertension. His lab’s work has largely

AT2R activation stimulates the production such as hypertension Three pharmacologic classes of There seem to be many potential looked at the mechanisms of the renin- of molecules including nitric oxide. Nitric antihypertensive agents are currently angiotensin system, particularly focusing ways to use AT2R to promote sodium oxide can then stimulate the body to recommended as first-line for the excretion (through angiotensin on angiotensin II peptides. produce more molecules of AT2R, forming a has recently been given a huge boost combination with existing therapies such as treatment of hypertension: thiazide receptor blockers, through nitric positive feedback loop that could reinforce by the development of the mysterious angiotensin receptor blockers. In fact, in rats, diuretics, calcium channel blockers oxide, through new treatments such FUNDING the body’s ability to excrete sodium and ‘Compound 21’ – an artificial activator of the lab has shown that Compound 21 is as and inhibitors of the renin-angiotensin as compound 21, and I’m sure others). •National Heart, Lung, and Blood reduce hypertension. Thus, Carey’s team AT2R. Prof Carey’s lab can make use of effective at preventing high blood pressure system (RAS) (ACE inhibitors and ARBs). Which do you think is currently the Institute (NHLBI) is furthering our understanding of multiple Compound 21 in two ways: firstly, they can as it is at treating it. Approximately 13% of hypertensive most promising? steps in the protective pathway against high use it experimentally to manipulate and patients do not achieve their blood While inhibition of AT1 receptors can COLLABORATORS blood pressure, both before and after the characterise the function of AT2R in the The work of Prof Carey’s lab shows that pressure targets with all three classes increase AT2 receptor activation, the best Helmy M Siragy, MD, Professor of

AT2R itself. kidneys and its role in sodium excretion basic research to understand the molecular taken together and are classified as way of activating AT2 receptors is direct Medicine; Shetal H Padia, MD, Assistant

and reducing blood pressure. Secondly, pathways underlying the workings of the having treatment resistant hypertension. activation with AT2 receptor agonists. Professor of Medicine; Susanna R Keller,

In their current study, the lab now aims to Compound 21 may prove to be the first in a human body can be crucial to developing The number of second line agents that Indeed, direct AT2 receptor activation MD, Associate Professor of Medicine; further test the hypothesis that high blood new class of therapeutic agents that could potential treatments for, and even averting, are available to be added to bring blood improves sodium excretion and lowers John J Gildea, PhD, Professor of pressure can be caused by a failure to excrete provide new treatments for hypertension disease. pressure under control is limited, and we blood pressure especially in animals that Pathology; Donald F Hunt, PhD, Professor sodium when the AT2R-mediated pathway and related conditions, either alone or in clearly need additional pharmacological have already had their AT1 receptors of Chemistry; Robin A Felder, PhD, is impaired, and that this is due to a lack of classes to lower blood pressure in blocked. Professor of Pathology; Brandon A Kemp, angiotensin III. They then aim to test whether patients with refractory hypertension. Senior Laboratory Specialist; Nancy L artificially activating AT2R can improve Many of the current secondary agents Compound 21 is a potent, selective AT2 Howell, Senior Laboratory Specialist sodium excretion and reduce hypertension, are less effective and have more receptor agonist that can be given orally and whether AT2R could ultimately be a useful adverse side effects than the first line and is ready for testing in humans BIO target for therapies to prevent and reduce AT 2R Agonists agents. Clearly, then, there is a need for based on experimental animal Dr Carey received his medical high blood pressure. additional pharmacological classes that studies. In limited preliminary phase degree from Vanderbilt provide complimentary actions to the I trials, Compound 21 is safe to University in 1965. He CO-OPTING COMPOUND 21 first line agents. AT2 receptor agonists administer to humans. AT2 receptors completed his medical Research into the role of angiotensin and ng endogenous likely provide complimentary actions stimulate nitric oxide production, residency at the New York the AT R receptor in treating hypertension for the inhibitors of the RAS and also an but since nitric oxide is a gas it cannot Hospital-Cornell Medical Center 2 βrong additional site of diuretic action within the be administered to animals or humans; and fellowships in endocrinology at kidney tubule. even if it could, targeting the correct and Vanderbilt University and in hypertension ugmentation appropriate cellular and tissue distribution at St. Mary’s Hospital, London, England, RAS Activity What is the significance of angiotensin would be difficult to impossible in humans. before beginning his career in academic Schematic representation of medicine at the University of Virginia in the agents and conditions for II’s dual role within the RAS? A1R Blockade The dual role of angiotensin II is an and resulting actions of AT2 What do you find most exciting? 1973. Between 1986 and 2002, he served receptor (AT R) activation in 2 important natural safety check on the RAS. Finding out how our bodies work? Or as Dean of the University of Virginia the kidney A2R Recruitment Angiotensin II acting via AT receptors School of Medicine. AT 2R 1 finding ways to treat them when they NO-induced AT2R increases sodium and fluid reabsorption in go wrong? Activation transcription the kidney resulting in volume expansion Both learning underlying mechanisms of CONTACT and hypertension. Angiotensin II and disease and developing new treatments Robert M. Carey, MD, MACP, FAHA, especially its heptapeptide derivative are important and exciting. However, FRCPI – Professor of Medicine

angiotensin III acting via AT2 receptors one must know the underlying normal Dean, Emeritus, School of Medicine increases sodium and fluid excretion, pathways and how they are deranged in Division of Endocrinology and c lowering blood pressure. The beneficial disease in order to design new therapeutic Metabolism action of angiotensin II at AT2 receptors approaches. Therefore, knowledge of the Department of Medicine P.O. Box 801414 thus serves a protective function to limit underlying mechanisms is prerequisite to University of Virginia Health System abnormal increases in sodium, volume and introduction of new treatment. Charlottesville, VA 22908-1414 USA

Both learning underlying mechanisms of T: +1 434-924-5510 BP Renal • Natriuresis E: [email protected] • Ang II-dependent HTN issue • Pressure-natriuresis disease and developing new treatments W: http://www.healthsystem.virginia.edu/ internet/carey/ • Salt-sensitive HTN Protection are important and exciting

16 www.researchfeatures.com www.researchfeatures.com 17