New drug hope to target silent killer

In the Media
An exciting new treatment for very high blood pressure is on the horizon after a world-first discovery by a team of Australian heart researchers.

Heart Research Institute scientists have uncovered a brain chemical instrumental in triggering hypertension, the so-called silent killer responsible for the deaths of thousands of people each year.

The researchers are optimistic the results, published this week in the American Journal of Physiology-Heart and Circulatory Physiology, will ultimately lead to a powerful new treatment that blocks a neurotransmitter and frees patients from the dangers of hypertension.

“We know people with hypertension also have elevated brain activity causing their blood vessels to constrict, and their heart rate to rise, but although many effective treatments are available, more are still needed,” explains lead researcher Zohra Kakall.

“Now, thanks to our research, we have a novel new target to test, a neurotransmitter called PACAP, or pituitary adenylate cyclase activating polypeptide. We hope that with further development, a new drug that can block PACAP will be able to lower blood pressure.”

Hundreds of thousands of people suffer from severe high blood pressure, or hypertension, a dangerous disorder either passed down through genes or triggered by chronic conditions like diabetes, kidney disease, obesity, and obstructive sleep apnoea (OSA). It develops slowly and insidiously, gradually destroying blood vessels, the heart, brain and kidneys as well as other organs. Because of the time that hypertension takes to reveal itself, it’s dubbed the ‘silent killer’, causing thousands of heart disease deaths and strokes each year.

Scientists know the best early indicator of hypertension is excessive brain activity in the part of the brain that controls blood vessel constriction and relaxation. In OSA patients, repeated apneas – a blockage in the throat during sleep that stops breathing and limits oxygen flow – sensitise brain neurons over time, causing them to be over-active. Eventually this causes a hyper-excitation of the nerve pathways that constrict blood vessels and cause the heart to beat faster.

Microscope image of activation of cells in the adrenal gland following repeated hypoxia (low oxygen levels). These activated cells are responsible for causing excessive constriction of blood vessels in the periphery, resulting in high blood pressure. The ‘on’ signal for these cells arises in the brain – specifically, the brainstem. Image provided by Zohra Kakall.

“Critically, these changes occur in the absence of any blood pressure elevations, hinting that neurons become over-active before any permanent changes in blood vessel constriction, and therefore increases in blood pressure, can occur,” Ms Kakall says. “Given this, it’s vital that we find early detection techniques and interventions to prevent the over-active neurons from leading to the development of hypertension in at-risk individuals.”

In this lab study, HRI’s High Blood Pressure Research Group, led by Professor Paul Pilowsky, investigated the role of two neurotransmitters, glutamate and PACAP, in causing this increased activity in brains affected by OSA.

“Excitingly, we found that by blocking the neurotransmitter PACAP we were able to dampen over-active neurons, suggesting PACAP receptors are a novel target for preventing the progression of over-active brain activity to hypertension,” Ms Kakall says.

The team is now looking to see if the neurotransmitter is also able to predict hypertension in lab models of diabetes and obesity, before further investigating the use of a PACAP drug in human patients.

The study, Glutamate and PACAP co-transmission in the rat rostral ventrolateral medulla is necessary for sympathetic long term facilitation, is available to view here: www.ncbi.nlm.nih.gov/pubmed/29212793.

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