Obesity contributes to high blood pressure, but why and how this happens remains unclear. One of the major causes of high blood pressure—or hypertension—is the inappropriate activation of the fight-or-flight sympathetic nervous system response, and most obesity researchers have focused on factors that increase sympathetic activity. Virginia Brooks, Ph.D., however, has been investigating mechanisms that inhibit this activity.
A team led by Brooks, professor of physiology and pharmacology at OHSU, identified a neuromodulator, neuropeptide Y (NPY), that inhibits sympathetic activity in a specific area of the hypothalamus, the paraventricular nucleus. They found that withdrawal of that inhibition is required for an increase in sympathetic activity to occur in certain conditions, like obesity. However, the sources of NPY inhibition to the paraventricular nucleus were unknown.
To investigate the blood pressure effects of NPY neurons, the team used designer receptors exclusively activated by designer drugs (DREADDs) to selectively activate or inhibit these particular neurons in another hypothalamic nucleus, the arcuate, in mice. They demonstrated that the same population of neurons that increases feeding also suppresses blood pressure. Brooks and senior research associate Zhigang Shi, Ph.D., have published their findings that both verify that NPY inhibits sympathetic activity and also identify a new hypothalamic site and neuronal pathway by which NPY suppresses that activity. The paper was published in the Journal of Clinical Investigation.
DREADDs, along with three concurrent technical accomplishments by Shi, made the experiments possible. He may have been the first person to successfully secure an electrode around the sympathetic nerve of a mouse, place a cannulae in blood vessels so the team could measure blood pressure and deliver infusions, and conduct nanoinjections using micropipettes with tips that were about 20 micrometers—the size of a couple of neurons. With these, he was able to inject treatments into the paraventricular nucleus, an area of the brain smaller than a ballpoint pen, while simultaneously measuring sympathetic nerve activity.
Neuropeptide Y antagonists are primary targets in the development of drugs for obesity and anxiety disorders, often without consideration of the effects on blood pressure. In addition to helping develop better drugs to treat high blood pressure in obese patients, research conducted in Brooks’ lab might help to understand the potential cardiovascular side effects of anti-obesity treatments.
Along with Brooks and Shi, Christopher Madden, Ph.D., coauthored the paper. This research was funded in part by NIH grants HL088552 and HL128181 (VLB), AHA15POST23040042 postdoctoral fellowship (ZS), ADA 1-13-BS-120 (CJM), and NINDS P30 NS061800 (PI, S. Aicher).