How the body regulates blood pressure in response to daily stress is the focus of a study geared toward helping people whose pressure is out of control.
"Research shows that two-thirds of patients' high blood pressure is not controlled despite the best efforts of their doctors. That is terrible," says Dr. Gregory Harshfield, director of the Georgia Prevention Institute at the Medical College of Georgia.
"We are trying to identify the mechanisms through which blood pressure is regulated under normal everyday conditions - which is what stress is - and take that information back to the clinic to better determine what sort of therapy is going to be most effective at treating your blood pressure or your grandfather's."
More than a dozen researchers have teamed up to do parallel studies in animal models and young adults to learn more about what factors like genes, stress and obesity contribute, their synergy and novel ways to control them.
"This research will give us information that allows us to identify what treatment is going to be effective in what individual by genotype, by obesity and other factors. What kind of treatment is going to be effective at keeping an individual's blood pressure down or maybe preventing it from ever getting high," says Dr. Harshfield, principal investigator on the $10.6 million Program Project grant renewal from the National Institutes of Health's National Heart, Lung and Blood Institute. 72 million Americans - 1 in 3 - are hypertensive, according to the NHLBI.
Studies will explore fundamentals such as why about 30 percent of young healthy blacks and 15 percent of whites can't effectively excrete sodium, a problem that raises blood pressure by increasing the body's fluid volume. "We think there is a defect in their kidneys, in the normal mechanisms that allow them to excrete salt," said Dr. David Pollock, renal physiologist at MCG's Vascular Biology Center and a program project leader. "When blood pressure goes up due to stress, their kidneys ought to get rid of more salt so their blood pressure will come down, and they don't."
Dr. Harshfield's studies identified this impaired stress-induced sodium natriuresis. He believes it's also a primary reason blood pressure remains elevated at night in some blacks, rather than dipping as it should, which keeps stressing the cardiovascular system.
Using a rat bred to be salt-sensitive, the researchers are working to identify more about the genetics of impaired sodium-handling. "We have animal model data that says the endothelin system normally functions to help your kidneys get rid of salt," says Dr. Pollock. His studies have shown the kidney's endothelin B receptor plays a critical role in promoting excretion of acute and chronic salt loads by activating the precursor to nitric oxide, a powerful dilator of blood vessels. In the new studies, he'll control the rats' diet and see whether stress slows down sodium excretion. Preliminary evidence suggests it does. He'll also give the rats an endothelin antagonist, which blocks this hormone, and see if sodium excretion improves. He'll also see how a high-fat diet and obesity alter the equation.
Meanwhile, for about a week, young study participants with impaired sodium excretion will take a drug to block the powerful blood vessel constrictor, angiotensin. "From our point of view, angiotensin promotes sodium retention directly and it also increases aldosterone, another hormone which promotes sodium retention," Dr. Harshfield says. The researchers chose to study endothelin and angiotensin because they believe they work together. To explore the genetics, they'll also look at young adults with a different version of the angiotensin receptor gene that they believe exacerbates sodium-handling problems. MCG researchers identified this genetic variation in people who retain sodium; blocking the receptor gene will provide more evidence about the importance of angiotensin, says Dr. Harshfield.
They'll mimic the way many people work - an hour of stress, a few minutes of relief, then back to stress - by getting the young people to play competitive video games, then measuring how gene blockers affect sodium excretion. "Ultimately, you want to know how to treat people with this variation," Dr. Harshfield says. "There is still a need to figure out why some people respond to some therapies and other don't," adds Dr. Pollock. "That is not our specific question but these studies will help address that. We have to identify what is it about different individuals that make them react more to stress, makes them retain more salt."
Obesity, which is associated with increased blood pressure reactivity, is probably a differentiator, Dr. Pollock says. Fat cells actually secrete angiotensin, which gets into the bloodstream. "We are arguing in our study that you might want to treat patients differently depending on whether or not they are obese. The angiotensin receptor blocker may be more effective in obese individuals who have angiotensin falling out into their bloodstream," says Dr. Harshfield. Consequently they'll also compare the effectiveness of the blocker in obese and normal-weight individuals with impaired sodium excretion.
Another project is exploring the role of oxidative stress, or reactive oxygen species, in raising blood pressure. In an animal model genetically predisposed to salt-sensitive hypertension, Dr. Jennifer Pollock, biochemist in MCG's Vascular Biology Center and a program project leader, has shown a prolonged recovery to normal blood pressure following stress. She's also found oxidative stress levels go up with stress. Oxidative stress, or reactive oxygen species, helps make normal chemical reactions in the body but, in excess, can cause havoc. In fact, when she gives the rats an antioxidant before a stressor, blood pressure doesn't rise as high and recovery is more normal. "We also found out that endothelin actually is the stimulus for increasing reactive oxygen species," Dr. Jennifer Pollock says. "When we gave the rats a specific type of endothelin blocker, that also blocked the increase in oxidative stress, blocked the blood pressure increase and improved recovery."
Now they want to know the specific sources of the reactive oxygen species. Earlier work by Dr. Frank Treiber, MCG vice president for research and principal investigator on the original Program Project grant in 2002, has shown increased blood pressure reactivity in children who are obese and/or have low socioeconomic status.
Looking at how obesity weighs in, Dr. Jennifer Pollock also is putting the rats on high-fat diets. It's known these rats become hypertensive on a high-salt or high-fat diet and they've found that, as with people, fat also increases blood pressure reactivity. Now she is going to find out how.