Short Bio: Made in Britain. Favorites: tea, sushi, good Italian and Indian food, motorcycles, wine, music, guitars, Caribbean, friendly folks, etc. Collaborates freely.

Real Bio: I received my Ph.D. in Biochemistry in 1979, from what is now called the Glasgow Caledonia University. From 1979-1981, I was a postdoctoral fellow in Alan Senior's laboratory in the Department of Biochemistry at the University of Rochester, NY. There, I worked on the biochemistry of pancreatic bicarbonate secretion. I decided to switch from biochemistry to physiology because I realized I was interested in high blood pressure and so I came to the Department of Physiology at the University of Maryland to work on that problem. My work led to the discovery of endogenous ouabain. In the years that followed, I was fortunate to be involved with work going from molecules all the way through to clinical studies.

Currently, I am a Professor, a full member of the Graduate School, and a faculty member of the NIH training program in Integrative Membrane Biology.

In contemporary thinking, our research might be termed; "OUABAINOMICS". The latter term is derived from Ouabain - the name given to an unusual steroid that is found in certain rare plants of African origin. Ouabain was first used as an arrow poison and is a high affinity reversible inhibitor of the sodium pump. It has been used therapeutically for the acute treatment of shock, cancer, atrial arrhythmias and heart failure. Its clinical utility was limited by poor oral bioavailability, hence the need to administer the compound parenterally - a route that confined its therapeutic and other effects to the acute rather than chronic setting. Therefore, it was most unexpected when a very similar steroid was found during the screening of 2 tons of human blood for endogenous inhibitors of the sodium pump. Because the donors could not have received ouabain therapeutically - the drug had been withdrawn from clinical use many years before - the presence of such a compound in the human circulation was most mysterious. The circulating steroid was initially identified as either ouabain or a closely related isomer. Some recent work suggests it might be an 11B-hydroxy isomer of ouabain. Like ouabain, the isolated human analog (we call it endogenous "ouabain") can affect the balance of ions across the plasma membrane, and in so doing changes the function of neurons, cardiac and vascular smooth muscle cells. In addition, there are indications that the endogenous ouabain may have some unique properties and physiological actions not found in other cardiac glycosides. Our overall goal is to determine the fine molecular configuration of the compound, and the key genes that govern its synthesis and effects on blood pressure (see below for details).

Identification of Endogenous "Ouabain"

In the human endogenous "ouabain", the position and/or orientation of one or more of the oxygen atoms may differ from those in plant ouabain. We think this difference could be extremely important for several reasons (see Hamlyn et al, 2003). Is it crucial that a definitive solution to the structure of the human compound be obtained ? We think so. Among several methods, NMR spectrometry and mass spectral methods are two powerful tools that can resolve this question ... So why are we waiting for the definitive data? The answer is that one must have enough pure human material for the structural studies - and no reasonable person would attempt the task of processing the 2 tons of human plasma that might be needed without the appropriate resources. Natural product chemists understand the issue, while most modern cell and molecular biologists, as well as the members of many study sections have rarely wrestled with any liquid volume larger than a few liters.

Signaling Mechanisms and Adrenocortical Secretion of Endogenous Ouabain

Endogenous ouabain is secreted by the adrenal gland. We are interested in the way in which the synthesis and secretion of endogenous ouabain is controlled. Accordingly, we use cell culture systems and combine that approach with clinical studies (Collaborator Dr. Bruce Hamilton: hamilton.bruce_p@baltimore.va.gov) in humans that look at how the secretion of endogenous ouabain is really regulated. While the impression from the cell studies and the clinical data are often in harmony, there are several phenomena specific to the cultured cells that do not appear to be physiologically significant in humans - hence the reliance on a combined approach with cell biology and clinical investigation.

Proteomics and the Biosynthesis of Endogenous Ouabain

We are working on the biosynthetic pathway for endogenous ouabain. We have begun to locate novel biosynthetic intermediates for structural analyses. A long range goal will be to isolate the enzymes for the various transformations so that we can study their structures and catalytic mechanisms and the way in which they are regulated.

Genetics of Hypertension

We have proposed that a primary event in the development of common high blood pressure in at least one third of patients involves the elevation of endogenous "ouabain" in the circulation. To follow up on some of the genetic implications of that observation, we developed two new strains of rats. One of the strains is hypersensitive to endogenous ouabain and spontaneously develops high blood pressure. The counterpart strain is resistant to both endogenous and exogenous ouabain and maintains blood pressures that are lower than normal and that do not rise with age. We have studied the phenotypes of every animal arising from sib mating for ten generations. Now we wish to collaborate with partners who have access to high throughput genomic technologies that can be used to locate the key genes that determine the phenotypes. Once those genes have been located and identified, one can begin to ask questions regarding their function and utility as disease markers. The proteins arising from those genes might be useful targets for new kinds of therapeutics.

Mechanisms of Ouabain Induced Hypertension

How do endogenous ouabain and plant ouabain actually raise blood pressure ? Hemodynamic studies show that total peripheral vascular resistance is raised in the hypertensive rats. But by what mechanism is the vascular resistance elevated ? There are two prevailing hypotheses which are not mutually exclusive. The first hypothesis proposed by Blaustein in Baltimore is that endogenous ouabain raises blood pressure because it can directly affect calcium handling mechanisms in the vascular wall (including the Na/Ca exchanger, the Na/K pump and store operated channels). There is very substantial evidence supporting that hypothesis and more is being accumulated. The second hypothesis advocated by the Leenen group in Ottawa is that endogenous ouabain raises blood pressure by tonically affecting the function of the hypothalamus which, in turn, causes an increase in the sympathetic nerve activity reaching the peripheral vasculature. One problem with that hypothesis is that the hypothalamus orchestrates a number of basic functions including, temperature, appetite, salt and water balance, blood pressure, and reproduction, etc. So it is mysterious that endogenous ouabain might selectively affect pathways that impact on long term blood pressure when all quarters of the hypothalamus are decorated with sodium pumps that are thought to bind the steroid with high affinity. One obvious possibility is that there may be new kinds of receptors for ouabain that have never been seen before. Along those lines, we recently described novel binding sites for ouabain in the adrenal cortex (Ward et al 2002) and we have found similar sites in the brain. In addition to the CNS, changes in the function of the peripheral nervous system may be important and we have provided the first evidence along those lines.