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Topic Name: Cornell University's researchers discover hormone that may lead to safe treatment for hypertension

Category: Biomedical

Research persons: Frank Schroeder

Location: Boyce Thompson Institute for Plant Research, Cornell University, United States

Details

For more than 40 years, researchers have suspected there must be a natural hormone that could safely flush sodium out of the body and could be harnessed to develop more effective and safer treatments for high blood pressure, or hypertension. Currently, drugs that lower sodium levels all have serious side effects because they also reduce potassium levels.

Researchers at Cornell and the Boyce Thompson Institute for Plant Research (BTI) have used a new technique and identified a hormone from human urine -- a xanthurenic-acid derivative -- that seems able to do the job. The discovery opens the door to developing novel medications to control sodium levels and treat hypertension.

Frank Schroeder, an assistant scientist at BTI and co-author of the paper, which appeared in a recent issue of Proceedings of the National Academy of Sciences, developed a new technique for analyzing complex mixtures of small molecules, making it possible to finally identify the hormone.

Prior to the discovery, researchers knew that a human steroid called aldosterone activates the kidney to reabsorb sodium and excrete potassium, which led them to suspect that there must be another hormone that would trigger the kidney to do the opposite: excrete sodium and reabsorb potassium. Many had tried to find such a hormone in human urine, but urine contains a mix of hundreds of molecules, and the correct one could not be isolated, probably because the suspected hormone breaks down easily during traditional chemical analysis.

Most researchers had given up searching for this "holy grail" of kidney hormones, until, in 2003, a private company, Naturon Corp., contacted Schroeder, then a research associate at Cornell and Harvard Medical School.

To do the job, Schroeder developed an approach based on nuclear magnetic resonance (NMR) spectroscopy of partially purified urine. Traditionally, NMR spectroscopy, arguably the most powerful tool chemists use to determine the structures of unknown compounds, has only been used for the analysis of purified compounds. Schroeder's approach allows NMR to identify compounds without isolating them, for example in a complex mixture such as partially fractionated urine. The technique revealed three completely new compounds, each of which was subsequently synthesized and injected into rats. The rats' urine was then monitored.

Two of the identified compounds, derivatives of a common metabolite xanthurenic-acid, raised sodium levels in the rat's urine but kept potassium levels constant. Schroeder said that while aldosterone (which does the opposite) is a steroid hormone, this newly discovered molecule is structurally more similar to such amino acid-derived neurotransmitters as dopamine and serotonin and, therefore, may also play other roles in the body.

"Now, we want to know what other functions these compounds have and whether they directly influence blood pressure," said Schroeder.

The study was funded by Naturon Pharmaceutical Corp.

Note for Hypertension

Hypertension, commonly referred to as "high blood pressure" or HTN, is a medical condition in which the blood pressure is chronically elevated. While it is formally called arterial hypertension, the word "hypertension" without a qualifier usually refers to arterial hypertension. Hypertension can be classified as either essential (primary) or secondary. Essential hypertension indicates that no specific medical cause can be found to explain a patient's condition. Secondary hypertension indicates that the high blood pressure is a result of (i.e. secondary to) another condition, such as kidney disease or certain tumors (especially of the adrenal gland). Persistent hypertension is one of the risk factors for strokes, heart attacks, heart failure and arterial aneurysm, and is a leading cause of chronic renal failure. Even moderate elevation of arterial blood pressure leads to shortened life expectancy. At severely high pressures, mean arterial pressures 50% or more above average, a person can expect to live no more than a few years unless appropriately treated.

Note for Nuclear magnetic resonance

Nuclear magnetic resonance (NMR) is a physical phenomenon based upon the quantum mechanical magnetic properties of an atom's nucleus. NMR also commonly refers to a family of scientific methods that exploit nuclear magnetic resonance to study molecules.

All nuclei that contain odd numbers of protons or neutrons have an intrinsic magnetic moment and angular momentum. The most commonly measured nuclei are hydrogen-1 (the most receptive isotope at natural abundance) and carbon-13, although nuclei from isotopes of many other elements (e.g. 15N, 14N 19F, 31P, 17O, 29Si, 10B, 11B, 23Na, 35Cl, 195Pt) can also be observed.

NMR resonant frequencies for a particular substance are directly proportional to the strength of the applied magnetic field, in accordance with the equation for the Larmor precession frequency.

NMR studies magnetic nuclei by aligning them with an applied constant magnetic field and perturbing this alignment using an alternating electric field, those fields being orthogonal. The resulting response to the perturbing magnetic field is the phenomenon that is exploited in NMR spectroscopy and magnetic resonance imaging, which use very powerful applied magnetic fields in order to achieve high resolution spectra, details of which are described by the chemical shift and the Zeeman effect.

About Researcher

As a child in Hamburg, Germany, Cornell research associate Frank Schroeder had a chemistry laboratory in his grandmother's basement. There, he built rockets that he fired from her backyard and made such corrosive, volatile and toxic chemicals as elemental bromine.

"I was obsessed with making new chemicals and devices. I basically spent all my afternoons and evenings in that basement, which I probably poisoned irrevocably," says the 6-foot, 10-inch Schroeder, who has since channeled that curiosity into work that is making him an emerging leader in the nascent field of chemical ecology, the study of chemicals involved in the interactions of organisms.

The son of a German television cameraman and a hearing-aid sales rep, Schroeder split his youth between his parents' modest home and his grandmother's house. His grandmother, now 93, is "the one who encouraged me to pursue an academic career," he said.

Since earning his undergraduate (1992) and Ph.D. degrees (1998) from the University of Hamburg, Schroeder has been working with Jerrold Meinwald, Cornell's Goldwin Smith Professor of Chemistry, and Jon Clardy, professor at Harvard Medical School, formerly of Cornell.