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Hypertension or high blood pressure affects many Australians and is a leading cause of myocardial infarction (heart attack), stroke, kidney failure, blindness and pregnancy-related complications. The basic and clinical research projects of the HBPRU have the common aim of understanding the pathophysiology of hypertension.
Professor Judith Whitworth |
Studies by this laboratory have identified that glucocorticoids alter the normal production and function of nitric oxide (NO). NO is a potent biochemical that has many actions throughout the body. It is its ability to dilate blood vessels and thus lower blood pressure that is of prime interest to us. We are investigating this glucocorticoid-nitric oxide interaction in animal and human studies in collaboration with several investigators.
HOBAT (1-hydroxy-2-oxo-3,3-bis(2-aminethyl)-1-triazene) is a polyamine zwitterion developed by Dr Bill Cowden (Division of Immunology and Genetics, JCSMR) that spontaneously releases NO in solution.
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When mice that were normotensive or hypertensive (due to administration of adrenocorticotrophic hormone - the stimulatory peptide hormone released from the anterior pituitary to induce glucocorticoid release from the adrenal glands) were administered HOBAT, there was a short-term but profound fall in blood pressure. Oxygen is essential to life, but under certain conditions it changes its form to a superoxide and becomes toxic to cells. One of our hypotheses is that glucocorticoids increase the production of superoxide and indirectly other free radicals. Dr Chris Schyvens |
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We have become interested in superoxide and its ability to interact with NO and remove it from the circulation. To counter this effect, the body has set up certain defenses to scavenge the superoxide, which is further complemented by our diet which provides anti-oxidants. This year we have investigated the superoxide-scavenging ability of various anti-oxidants: Vitamins C and E, allopurinol and tempol. Tempol can prevent and reverse established glucocorticoid-induced high blood pressure indicating an important role for superoxide. Further work continues with the vitamins and in quantifying the production of superoxide species in the body with Dr Kevin Croft (University of WA).
Genetic influences on the development of high blood pressure are of great interest to health and disease, and we are using three approaches to help us understand how glucocorticoids affect blood pressure. Firstly, in collaboration with Dr Tim Cole (University of Melbourne), we are investigating how mice deficient in the receptor for glucocorticoids maintain and control their blood pressure, using implantable blood pressure devices that allow us to measure their blood pressure continuously over 24 hours. Secondly, in collaboration with Prof Brian Morris (Basic & Clinical Genomics Laboratory, University of Sydney) we have been investigating the functional and genetic effects of tumor necrosis factor, a stimulator of nitric oxide production, on high blood pressure. Thirdly, in collaboration with Dr Frances Shannon (Division of Molecular Bioscience, JCSMR) we are investigating changes in gene expression in the rat kidney as a result of long-term glucocorticoid treatment. The latter uses innovative gene-chip technology (micro-array) to simultaneously account for the expression of several thousand genes.
Our laboratory has close links with the clinic. In collaboration with Dr George Mangos and A/Prof John Kelly (St George Hospital, Sydney) clinical studies were conducted: (1) to determine whether cortisol inhibits cholinergic vasodilatation in the forearm circulation when given locally as opposed to systemically (a randomized, placebo-controlled crossover study in healthy volunteers); and (2) to determine the effect of cortisol on the interaction between NO and vasodilator prostaglandins in the forearm vascular bed (a randomized, double blind cross over study also in healthy volunteers). We have also an active collaboration with Dr David Torpy (Royal Adelaide Hospital) examining the role of cortisol and its binding protein in the genesis of the common and debilitating chronic fatigue syndrome.
In summary, our laboratory and clinical studies have continued to examine the mechanism(s) by which glucocorticoids modify blood pressure, which in turn allows us to explore potential strategies to overcome the development or induce the reversal of hypertension.