Sympathetic Nervous System Contribution To Hypertension : CNS Pathways, Neurotransmitters And Neuroeffector Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$450,750.00
Summary
High blood pressure (hypertension) is a major public health problem in Western society with approximately 20% of adults affected. If left untreated, serious damage to organs can occur and the risk of sudden cardiac death or stroke is greatly increased. While many factors contribute to the development of hypertension such as lifestyle, genes, diet, weight and exercise levels, a common feature in the early stages is an overactive nervous system in the kidney and in the heart which is most likely d ....High blood pressure (hypertension) is a major public health problem in Western society with approximately 20% of adults affected. If left untreated, serious damage to organs can occur and the risk of sudden cardiac death or stroke is greatly increased. While many factors contribute to the development of hypertension such as lifestyle, genes, diet, weight and exercise levels, a common feature in the early stages is an overactive nervous system in the kidney and in the heart which is most likely due to altered signals from the brain. We need to understand why this occurs. One possibility is that renin (a chemical released from the kidney) that is known to control body fluid, also acts in the brain to increase nerve activity to the kidney and heart and in this way contributes to high blood pressure. It does this indirectly by producing another hormone called angiotensin. Our research has shown that in conditions where the kidney releases excess of the hormone renin, which may occur if the blood supply to the kidney is reduced, a change occurs in the way in which the nervous system affects blood pressure. The nervous system is activated to increase the release of renin from the kidney. The effect of this is to make blood pressure increase further in what can become a vicious circle. At present it is not understood why and how this change occurrs. The major thrust of this project is to determine the mechanims by which the renal hormones signal the central nervous system to change the nature of the nervous activity back to the kidney. We want to know what parts of the brain are involved, how the nature of the activity in the nerves changes and also how the nervous control of the kidney changes (i.e. how the kidney changes its responsivness to the nerve activity). Because similar processes probably occur in nearly all forms of high blood pressure, our results will greatly improve our understanding of how this dangerous condition develops.Read moreRead less
I am a physiologist working to understand how disturbances during pregnancy can alter fetal development and increase the risk of developing adult onset diseases such as cardiovascular disease, renal disease and diabetes. In particular I am interested in how alterations in kidney development may play a crucial role in disease development.
Mechanisms Responsible For Hypertension Caused By Perinatal Omega-3 Fatty Acid Deficiency
Funder
National Health and Medical Research Council
Funding Amount
$280,650.00
Summary
Does the nourishment we receive as babies, or even before birth, affect our adult health? The recent findings from Barker, Meaney, Langley-Evans and their co-workers, has established that intra-uterine and early post-natal factors, particularly nutrition, influence adult neural development and cardiovascular function. It appears that the dietary intake of omega-3 fatty acids in early life may be a critical factor in the development of hypertension. We reported (Nature Medicine 2001, 7: 258-259) ....Does the nourishment we receive as babies, or even before birth, affect our adult health? The recent findings from Barker, Meaney, Langley-Evans and their co-workers, has established that intra-uterine and early post-natal factors, particularly nutrition, influence adult neural development and cardiovascular function. It appears that the dietary intake of omega-3 fatty acids in early life may be a critical factor in the development of hypertension. We reported (Nature Medicine 2001, 7: 258-259) for the first time that the essential omega-3 fatty acid, alpha-linolenic acid (ALA), supplied in the early developmental period, affects blood pressure later in life. The work showed that moderate omega-3 fatty acid deficiency in the perinatal period resulted in hypertension, despite reversal of the deficiency at a time months before the assessment of blood pressure. These findings are suggestive of a critical period, during which time the development of normal blood pressure control mechanisms appears, at least partially, dependent upon the supply of omega-3 fatty acids. These findings suggest that omega-3 deficiency early in life may affect fatty acid metabolism, transport or uptake systems, such that re-feeding of the nutrients is functionally ineffective. Alternatively, deficiency of omega-3 fatty acids early in life may arrest development of one or more of the key signalling pathways in the control of blood pressure, such as the Brain Angiotensin System. The influence of dietary omega-3 fatty acid supply, relative to the critical period, on expression of genes involved in the control of blood pressure as well as in fatty acid metabolism, will be defined. Also, the role of the brain angiotensin system in omega-3 fatty acid deficiency-induced hypertension will be determined. We expect that the results of this study will profoundly affect hypertension research, as well as nutrition, particularly that for infants.Read moreRead less
Study Of The Functional Consequences Of Angiotensin II Induced Increases In Renal Innervation
Funder
National Health and Medical Research Council
Funding Amount
$393,750.00
Summary
Hypertension (high blood pressure) is a major public health problem in Australia, being a key risk factor for cardiovascular diseases such as heart attack and stroke. More ominously, recent WHO reports show that cardiovascular disease is the major health burden facing developing countries, particularly in our region. Although some of the burden of cardiovascular diseases may be reduced by effective public health measures (e.g., to reduce saturated fat intake), hypertension remains largely imperv ....Hypertension (high blood pressure) is a major public health problem in Australia, being a key risk factor for cardiovascular diseases such as heart attack and stroke. More ominously, recent WHO reports show that cardiovascular disease is the major health burden facing developing countries, particularly in our region. Although some of the burden of cardiovascular diseases may be reduced by effective public health measures (e.g., to reduce saturated fat intake), hypertension remains largely impervious to preventative public health measures. While treatment of established high blood pressure can reduce the incidence of cardiovascular disease, preventing the development of hypertension in the first place is not possible at this time. A major impediment to the development of effective public health measure is our lack of knowledge of the pathological mechanisms involved, despite over 100 years of active research effort. The experiments planned in this study will probe below the surface of two important facts known about hypertension but not previously brought together - that the kidney's blood vessels and nerves are remodeled in hypertension, and that the kidney's control of the level of blood pressure must be changed in order for high blood pressure to develop in the first place. We hope that pursuit of this experimental line of enquiry will provide new clues on where to look for initiating factors in human hypertension.Read moreRead less
Mechanisms Involved In Reduced Cardiac Contractility As A Consequence Of Growth Restriction During Fetal Development
Funder
National Health and Medical Research Council
Funding Amount
$317,810.00
Summary
Functional development of the heart muscle has been a focus of intense research over the last 40 years. Despite our current understanding of the changes in how excitation of the cardiomyocyte leads to contraction, a process broadly termed excitation-contrcation (E-C) coupling, a major model used to study paralells of human fetal development, the sheep, has not been examined in this context. As such, it remains unclear how E-C coupling evolves from the fetus to the adult. Understanding normal phy ....Functional development of the heart muscle has been a focus of intense research over the last 40 years. Despite our current understanding of the changes in how excitation of the cardiomyocyte leads to contraction, a process broadly termed excitation-contrcation (E-C) coupling, a major model used to study paralells of human fetal development, the sheep, has not been examined in this context. As such, it remains unclear how E-C coupling evolves from the fetus to the adult. Understanding normal physiology is imperative to subsequetly understand pathological states, such as interuterine growth restriction (IUGR). In Australia, the incidence of IUGR leading to low birth weight babies is 7%. IUGR is caused by maternal undernutrition, maternal smoking-drug use and placental insufficiency. It is associated with an increase in perinatal mortality, respiratory problems, SIDS and morbidity. Epidemiological studies show that low birth weight babies are also at an increased risk of cardiovascular disease, including heart failure, in adult life. To date, there is little information on the impact of fetal growth restriction on the normal development and function of the heart muscle. Understanding the impact of IUGR on heart muscle development will allow the elucidation of the underlying physiological mechanisms linking these two temporally distinct events. This mechanistic understanding will allow improved clinical management of those individuals at risk of cardiovascular disease in adult life arising from IUGR. It may also allow for early intervention strategies that can improve cardiovascular function. Therefore, we propose to examine both the normal developmental changes to E-C coupling so that we can understand how placental insufficiency leading to IUGR impairs normal heart muscle development. This will result in impaired function at a cellular level, which will ultimately manifest as an increased susceptibility of the heart to injury in later life.Read moreRead less
Identification Of Heterogeneity In Vasodilator Function In Human And Rat Resistance Vessels: Potential Drug Targets?
Funder
National Health and Medical Research Council
Funding Amount
$595,330.00
Summary
The balance between the ways that blood vessels decrease in size (constrict) and increase in size (dilate) determine how blood vessels normally function. There are many differences in the ways that blood vessels control this balance in different parts of the body. Such differences are altered in vascular diseases, such as hypertension and diabetes, which are prevalent in obesity, such that constriction generally outweighs dilation. However, what these differences are and how they occur are not w ....The balance between the ways that blood vessels decrease in size (constrict) and increase in size (dilate) determine how blood vessels normally function. There are many differences in the ways that blood vessels control this balance in different parts of the body. Such differences are altered in vascular diseases, such as hypertension and diabetes, which are prevalent in obesity, such that constriction generally outweighs dilation. However, what these differences are and how they occur are not well understood. While current drugs for treating vascular disease either reduce vessel constriction or increase dilation, they are not specific for individual arteries; a situation that would allow us to control vascular diseases in a very specific manner. Recently, we have described differences between the ways that individual vessels are controlled. These changes relate to differences in the way that different vessels dilate. AIMS - To further understand normal blood vessel function and the changes that occur in blood vessels in cardiovascular disease, with a focus on the ways that blood vessels dilate in normal states and in obesity-related diseases, such as in hypertension and diabetes. - The eventual aim is to identify the specific ways that arteries function, so that artery-specific drug targets can be identified to treat disease-related changes in cardiovascular disease in a very specific manner. EXPECTED OUTCOMES This project will contribute to understanding blood vessel function in health and disease. The expected eventual outcome is the identification of the mechanisms that underlie the function of different arteries in different parts of the body, so that specific individual vessel function can be targeted to treat vascular disease. Additionally, this work will also verify the relevance of the diet-induced obesity animal model, in terms of the characteristics and causes of human obesity and related cardiovascular disease.Read moreRead less