Proteins regulating water retention in salt-sensitive hypertension identified

ScienceDaily (Oct. 25, 2010) — Research conducted by scientists at LSU Health Sciences Center New Orleans has found that two proteins in the brain act as valves to turn the hormone that regulates water retention in the body on and off. Their findings may lead to advances in treatment for diseases like high blood pressure, congestive heart failure, and cirrhosis of the liver.

The research is published in the Nov. 1, 2010 issue of Endocrinology.

Daniel Kapusta, PhD, Professor of Pharmacology at LSU Health Sciences Center New Orleans, and Richard Wainford, PhD, LSUHSC Instructor of Pharmacology, report the role of these brain proteins, called Gaq and Gaz, in producing elevated secretion of the hormone, vasopressin, and water retention in salt-sensitive hypertension, a condition in which blood pressure becomes elevated when salt is consumed. It is estimated that salt-sensitive hypertension occurs in about 26% of Americans with normal blood pressure and in 58% of those whose blood pressure is already high.

"Throughout the day, vasopressin, a peptide hormone produced by the hypothalamus, is released into the circulation from the pituitary gland and plays a vital role as the flood-gate keeper to prevent excessive loss of water from the kidneys," notes Dr. Kapusta. "Under most conditions, the water-retaining action of vasopressin is vital for survival. However, it has remained essentially a black box as to why, in susceptible individuals, the regulatory mechanisms that control vasopressin secretion cannot turn off when the body already has elevated water content."

For 21-days, the research team fed groups of male salt-resistant and salt-sensitive rats a diet containing either normal or high salt. Then they measured how the treatments influenced the animal's ability to excrete water and how the salt stress altered levels of vasopressin, Gaq and Gaz.

The consumption of high salt triggered a decrease in Gaq proteins in the brain of salt-resistant, but not salt-sensitive, rats. In salt-sensitive rats, the team demonstrated that reducing brain Gaq proteins returned plasma vasopressin to normal levels, decreased salt-induced water retention, and restored the animal's ability to excrete water.

"Our findings are novel and provide evidence that the Gaq sub-unit proteins in the hypothalamus act as a molecular/cellular switch to control the level of vasopressin secretion," says Dr. Wainford.

The researchers concluded that reducing brain Gaq proteins plays a critical counter-regulatory role in preventing the secretion of too much vasopressin in those with salt-resistance and may represent a new therapeutic target in diseases associated with fluid retention.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Louisiana State University Health Sciences Center, via EurekAlert!, a service of AAAS.

Journal Reference:

R. D. Wainford, D. R. Kapusta. Hypothalamic Paraventricular Nucleus Gaq Subunit Protein Pathways Mediate Vasopressin Dysregulation and Fluid Retention in Salt-Sensitive Rats. Endocrinology, 2010; 151 (11): 5403 DOI: 10.1210/en.2010-0345

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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New proteins that regulate blood pressure, flow discovered

ScienceDaily (July 27, 2010) — Researchers at the University of Pittsburgh School of Medicine have identified key players in a little-known biochemical pathway that appears to regulate blood pressure. The findings, reported in the early online version of Cardiovascular Research, have evolved from studies conducted by Jeffrey S. Isenberg, M.D., Eileen M. Bauer, Ph.D., and their colleagues at Pitt's Vascular Medicine Institute.

"Identifying and unraveling this important pathway for blood pressure regulation could lead to a better understanding of who will get high blood pressure and why, as well as allow us to develop better drugs to treat these patients," Dr. Isenberg said. "Poorly controlled hypertension is a major risk factor for heart attacks and heart failure, stroke and kidney failure."

The pathway he and collaborator David D. Roberts, Ph.D., of the National Cancer Institute (NCI), National Institutes of Health (NIH), have been exploring involves nitric oxide (NO) signaling. The cells that line blood vessels, called the endothelium, produce NO in a few biochemical steps. NO promotes blood vessel dilation and increases blood flow. Conversely, endothelial dysfunction, along with loss of NO production, is known to be involved in the development of many forms of cardiovascular disease, including hypertension.

Through cell culture and mouse experiments, the researchers found that a protein called thrombospondin-1 (TSP1) and its receptor, CD47, inhibit activation of the endothelial-based enzyme called endothelial nitric oxide synthase (eNOS), which in turn limits the production of NO and thus prevents blood vessels from relaxing and blood pressure from dropping. Circulating TSP1, at levels consistent with those found in the blood stream, is capable of inhibiting activation of endothelial-based eNOS and thus blocking NO production.

"For some time now, it has not been clear what role TSP1 served in the blood. Experiments in cells told us TSP1 could alter NO signaling. But TSP1 is a protein too large to cross through the endothelial layer and into the blood vessel wall, so it was not obvious how it could alter the muscle tone of the arteries," Dr. Isenberg said. "We also knew that mice genetically engineered to not produce TSP1 or CD47 showed more NO-based blood flow and blood vessel dilation. This suggested to us that perhaps circulating TSP1 was altering the ability of the endothelium to make NO by acting on eNOS."

He and his team are now developing agents that can alter the activity of eNOS by "blocking" the inhibitory signal mediated by TSP1 and CD47, which have the potential to be novel blood pressure-regulating drugs. Some cases of hypertension may arise from gene-based differences in these proteins, Dr. Isenberg noted.

"This work has identified a key pathway that effectively puts the brakes on nitric oxide production, which slows down blood flow," said Mark T. Gladwin, M.D., director of the Vascular Medicine Institute. "Furthermore, drugs that block this pathway have the potential to restore nitric oxide levels and may be useful for the treatment of high blood pressure and other vascular diseases."

The team included other researchers from the Pitt School of Medicine and NCI, as well as the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The work was funded by grants from NCI, NIDDK and NIH.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Pittsburgh Schools of the Health Sciences, via EurekAlert!, a service of AAAS.

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here