A brain mechanism may explain why approximately 40% of people with hypertension continue to have high blood pressure despite taking medication. The discovery reveals potential targets for new treatments.
Researchers at the University of São Paulo (USP) in Brazil have demonstrated that changes in breathing patterns, especially strong abdominal muscle contractions during exhalation, can trigger hypertension.
Using animal models (mice), the scientists discovered that neurons in the lateral parafacial region (pFL) modulate sympathetic activity during exhalation. This constricts blood vessels, contributing to blood pressure spikes and neurogenic hypertension, which is characterized by dysfunction in the central nervous system.
Conversely, inhibiting these neurons normalizes blood pressure in cases of neurogenic hypertension induced by chronic intermittent hypoxia, a key feature of obstructive sleep apnea involving repetitive alternations between low tissue oxygenation and normal levels.
The pFL, which controls active exhalation, is located in the lowest portion of the brainstem (medulla oblongata), where the brain connects to the spinal cord. The study was published in the scientific journal Circulation Research.
"We were surprised by this finding that neurons involved in active exhalation have the ability to impact cardiovascular function. This has implications for pathological conditions such as hypertension. Therefore, we proposed that the lateral parafacial region be a potential therapeutic target for treating hypertension," explains Professor Davi José de Almeida Moraes , of USP's Biomedical Sciences Institute (ICB) and the corresponding author of the article.
According to Moraes, rather than modulating the central nervous system directly, the therapeutic approach is to pharmacologically manipulate oxygen sensors to reduce the activity of pFL neurons via ATP (adenosine triphosphate) receptors. In addition to being an energy source for cellular activities, ATP functions as a neurotransmitter in the central and peripheral nervous systems (purinergic transmission).
"Ten years ago, we began showing that by inhibiting these receptors in the carotid body, located in the carotid arteries, it was possible to reduce sympathetic activity and blood pressure in neurogenic hypertension [read more at https://www.nature.com/articles/nm.4173 ]. Now we've shown that this depends on pFL neurons," says Moraes, who is supported by FAPESP .
The work also received funding from the Foundation through five other projects and scholarships ( 18/15957-2 , 22/07579-3 , 23/02560-5 , 22/02138-9 , and 19/24060-9 ).
'The silent killer'
Hypertension is the most significant risk factor for cardiovascular disease and is one of the leading causes of heart attacks, strokes, and chronic kidney disease. Several factors influence blood pressure levels, including smoking, alcohol consumption, obesity, stress, high salt intake, high cholesterol, and a lack of physical activity.
Although hypertension is preventable and treatable, it affects an estimated 1.4 billion people worldwide. According to the latest report released in 2025 by the World Health Organization (WHO), only one in five people manage to control the condition, either through medication or by addressing risk factors.
In Brazil, data from the Ministry of Health indicates that hypertension affects approximately 30% of adults. Last year, the Brazilian Societies of Cardiology (SBC), Hypertension (SBH), and Nephrology (SBN) issued a new recommendation that changed the blood pressure threshold considered risky, aligning the guidelines with international standards.
The well-known "12 x 8" (systolic blood pressure of 120 mmHg and diastolic blood pressure of 80 mmHg) is now classified as prehypertension, which warrants attention and reinforcement of preventive measures. Normal blood pressure must remain below this threshold.
Research methodology
The scientists used advanced techniques to manipulate and record neuronal activity in rats.
They manipulated the pFL neurons using viral transfection, a technique that introduces genes into cells via modified viruses. This technique does not cause disease; rather, it reprograms specific cells to help scientists understand how the brain controls certain functions, such as blood pressure and breathing.
Through optogenetic and pharmacogenetic modulation, the scientists excited or inhibited the pFL neurons while recording sympathetic and respiratory activity and blood pressure under different experimental conditions.
Optogenetic activation triggered active exhalation and positively modulated sympathetic activity, raising blood pressure. In contrast, pharmacogenetic inhibition eliminated exhalation-related sympathetic excitation and normalized blood pressure in hypertensive rats.
"It had never been demonstrated that neurons that generate expiratory activity communicated with those that control sympathetic activity and blood vessel diameter to impact blood pressure. This was a groundbreaking finding of the study," adds Moraes, who collaborated with researchers from the Ribeirão Preto School of Medicine (FMRP-USP) and the Cardiac Research Center at the University of Auckland's Faculty of Medical Sciences (New Zealand).
About São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.
