The influence of the central nervous system on long-term blood pressure levels and the relationship between blood pressure and stress pathways in the brain is a major focus of the studies in the Neuropharmacology Laboratory.
The research centres on cardiovascular neuroscience and fills a niche between the clinic and basic research. Work is carried out to understand the mechanisms that trigger cardiovascular diseases through environmental factors. Stress and hypertension is a main area of investigation, and research is also being conducted on the effects on the central nervous system and control of the cardiovascular system of obesity and other metabolic disorders.
Major recent discoveries from a mouse bred for high blood pressure are that a small region of the brain, called the amygdala that is known to regulate emotion, is also the cause of the hypertension through activation of the nervous system. These mice also have exaggerated day night differences in blood pressure. Professor Head and his team hope that better understanding circadian patterns, the day/night oscillations of blood pressure, will shed light on why people are two to three times more likely to have a stroke or other cardiovascular event in the early part of the day. By analysing ambulatory blood pressure in patients against Professor Head’s mathematical model, the underlying mechanisms that trigger heart attack and stroke can be better understood.
Another research focus of this laboratory is investigating a better treatment for congestive heart failure. People with heart failure — a serious, progressive disease — have as little as a 50 per cent, five year survival rate. ElaCor Pty Ltd is a company established in 2005 to further develop research conducted in collaboration with IMBCom at the University of Queensland. The ElaCor technology is based on the discovery of a group of natriuretic peptides — part of the body's natural response to heart failure — isolated from the venom of the Taipan snake. The lead compound is showing great promise as a treatment for congestive heart failure and has outperformed human natriuretic peptides in early studies.
- Determining the cause and consequence of the morning surge in blood pressure in humans.
- Contribution of the sympathetic nervous system to hypertension in Schlager mice.
- Role of the brain renin-angiotensin system in cardiovascular regulation.
- Central pathways mediating obesity related hypertension in rabbits.
- Whether a high fat maternal diet ‘programs’ hypertension.
- Snake derived natriuretic peptides for the treatment of heart failure.
Mechanisms responsible for neurogenic hypertension in Schlager mice
Project leader: Pam Davern
We discovered that the Schlager hypertensive BPH/2J mouse has a neurogenic form of hypertension characterised by an exaggerated blood pressure response to stress and also a much greater cardiovascular circadian rhythm. Both of these are accompanied by a much greater activity of neurons in the amygdala and hypothalamus. The hypertension can be blocked by inhibiting the sympathetic nervous system (SNS) and also by specific lesions of the medial amygdala. We recently identified that a specific region of the amygdala is the cause of a tonic activation of the SNS explaining most of the hypertension and that the mechanism involves inhibitory GABAA receptors. We also discovered that BPH mice have a greater dependence on the renin angiotensin system (RAS) that is associated with higher levels of renin mRNA due to less microRNA (miR-181a) in the kidney. We are currently investigating these central mechanisms, pathways and neuromodulators as well as the connection between the SNS and renal mechanisms contributing to hypertension in BPH mice.
Contribution of sympathetic activity to maternally programmed obesity hypertension
Project leaders: Joon Lim
Over 1 billion people suffer from obesity related hypertension. Although adult behavioural and environmental factors promote obesity and hypertension, the environment encountered in development can also "program" the development of these diseases. We have shown that obesity related hypertension is associated with very high levels of renal sympathetic nerve activity and hypothesise that this is central to the development of programmed hypertension. We have also shown that in programmed hypertension, neurons in the hypothalamus may respond differently to number of appetite signalling molecules. This may underlie increased sympathetic activity. We are now identifying which neurons are involved, where they are located and whether the appetite signalling molecules leptin or insulin are responsible for sympathetic overdrive. We are also examining whether renal denervation can ameliorate programmed obesity related hypertension.
Mechanisms and consequences of renal denervation in chronic kidney disease
Project leader: Geoff Head (collaborative project with Markus Schlaich and Kate Denton)
Chronic kidney disease (CKD) contributes substantially to the global burden of cardiovascular (CV) morbidity and mortality. Even a moderate reduction in glomerular filtration rate (GFR) is predictive of an increased risk for coronary heart disease. Accordingly, hypertensive patients with reduced GFR are at greater risk of developing cardiovascular disease than end-stage renal disease. Unfortunately, the incidence of CKD is expected to rise further, particularly due to the increasing incidence of diabetes and hypertension. Sympathetic overactivity is implicated in the development and progression of CKD, and independently predicts cardiovascular events and mortality in end stage renal disease. Afferent signaling derived from the failing kidneys plays a causal role in renal efferent sympatho-excitation and potentiate the adverse impact of chronically increased sympathetic drive. Consequently, interruption of efferent and afferent renal fibres may provide a unique possibility to interfere with this vicious cycle not only to reduce sympathetic nervous system activation and arterial blood pressure, and to improve outcomes in this high risk patient population. While there is evidence to suggest that this technology may be particularly useful in CKD, it is essential to understand the mechanisms and potential adverse consequences of renal denervation in the setting of CKD before it can be implemented in clinical practice. We are currently determining, using a chronic rabbit model of renal failure, whether the hypotensive effects of renal denervation are due to loss of afferent or efferent nerves.
Role of the brain renin angiotensin system in cardiovascular system
Project leader: Geoff Head (collaborative project with Andrew Allen)
The regulation of blood pressure is achieved by the complex interaction of neural, hormonal and local control mechanisms. The brain renin-angiotensin system forms part of this very important mechanism for the integration of autonomic response patterns particularly to normal and also to aversive situations. However, the way angiotensin contributes can change and slowly adapt over a time frame of weeks to months. This process is thought to be the key to understanding how the brain can progress to a state of high sympathetic activity associated with hypertension. The difficulty has been to determine the individual contribution of angiotensin peptides in different regions which are often opposing. In collaboration with Andrew Allen at the University of Melbourne, we are using new lentiviral delivery technology combined with the cre-loxP conditional gene deletion to determine the cardiovascular effects of eliminating AT1-receptors in specific nuclei within the brain. We are also determining the cardiovascular effects of expressing normal and constitutively active angiotensin receptors in catecholamine neurons in mice devoid of angiotensin receptors. The transfections last for several months allowing long term using radio telemetry measurement of blood pressure in conscious mice. This project will show us the mechanism by which there is a long term adaptive change in the contribution of angiotensin to autonomic reflex control of blood pressure and where in the brain that process occurs.
Development of systemic applied natruiretic peptides for congestive heart
Congestive heart failure is a fatal disease and a major disease burden for the community affecting nearly half a million Australians. In collaboration with Paul Alewood from the University of Queensland and David Kaye from the Baker Institute, we have identified a novel natriuretic peptide isolated from the venom of the inland Taipan, and optimised it as a treatment for congestive heart failure. Natriuretic peptides are part of the body's natural response to heart failure and have multiple effects, including vasodilation, increasing sodium excretion, diuresis and decreasing the synthesis of injurious neurohormones. The benefit of this work is that the peptide has been optimised for potency and stability allowing it to be administered by subcutaneous injection, rather than by continuous intravenous infusion. This would improve the quality of life for patients, reduce hospital costs, and hopefully improve the efficacy of the treatment.
Cardiovascular risk associated with the morning surge in blood pressure
Project leader: Geoff Head (collaborative project with Chris Reid)
There is an urgent need for a better understanding of the use of measures of ambulatory blood pressure recording in absolute risk assessment, initiating treatment, and altering therapy in established hypertensive patients. Subjects with a large morning blood pressure surge have been shown to have a higher risk of stroke, independent of other risk factors. However, methods for determining these parameters are limited. We have developed a novel method for determining the rate and the "power" of rise of morning blood pressure using standard ambulatory blood pressure (ABP) recordings. The morning power is calculated as the rate of rise times the amplitude of the rise. Such measures have the potential both to improve cardiovascular risk assessment and to be used as treatment targets. While this appears to encapsulate what is thought likely to be of the most relevance to cardiovascular risk, the value of the rate and power of the morning surge has not been evaluated scientifically. These techniques are now being applied in a wide range of collaborative projects at the Baker Institute, within Australia and also internationally. Together with colleagues from Japan and Monash University, we are developing mathematical and epidemiological models to predict cardiovascular risk based on ABP indices, incorporating our new method of analysis of ABP recordings from Japan and Australia. Importantly, we have now completed a population assessment of ABP within Australia as part of the AusDiab3 study.