Therapeutic Relevance Of AT2 Receptors In Cardiovascular Disease And Aging
Funder
National Health and Medical Research Council
Funding Amount
$519,279.00
Summary
Pharmacological modulation of the renin angiotensin system is a cornerstone of evidence-based cardiovascular therapeutics. However, their molecular mechanisms are not entirely clear and some therapeutic options have not been utilized to their full potential. The hormone angiotensin II causes both excitatory and inhibitory cardiovascular effects via distinct binding sites. Of particular importance to contemporary society is the shift in the demographic to a more aged population. In Australia in 2 ....Pharmacological modulation of the renin angiotensin system is a cornerstone of evidence-based cardiovascular therapeutics. However, their molecular mechanisms are not entirely clear and some therapeutic options have not been utilized to their full potential. The hormone angiotensin II causes both excitatory and inhibitory cardiovascular effects via distinct binding sites. Of particular importance to contemporary society is the shift in the demographic to a more aged population. In Australia in 2002, 13% of the population (~2.5 million) were aged 65 years or over, and it has been estimated that this number will increase to 18% (~4 million) by the year 2021. While lipid status and smoking are well known risk factors for cardiovascular disease, advanced age by far confers the greatest risk for cardiovascular disease. In this context, we have found a greater role of the inhibitory angiotensin II binding site in aging that may result from breakdown products of angiotensin II having their own unique effects. This project will determine the relative role of various angiotensin products, and novel compounds that may act similarly, to improve vascular tone and reverse cardiovascular disease in the elderly, hypertensive population.Read moreRead less
Nox4-containing NADPH-oxidase As A Protective Enzyme In The Cerebral Circulation
Funder
National Health and Medical Research Council
Funding Amount
$515,812.00
Summary
Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in a stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent research at the basic level to better understand the processes of normal, and then abnormal, regulation of brain artery function. The project will test the importance of a newly discovered mechanism for increasing brain blood flow. This involves activa ....Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in a stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent research at the basic level to better understand the processes of normal, and then abnormal, regulation of brain artery function. The project will test the importance of a newly discovered mechanism for increasing brain blood flow. This involves activation of an enzyme, Nox4-containing NADPH-oxidase, to generate oxygen radicals which then relax the wall of blood vessels causing the arteries to let more blood through. We believe that this process plays an important role in the normal, healthy maintenance of blood supply to the brain. Furthermore, we propose that the activity of this enzyme is elevated and therefore protective in brain arteries during high blood presure - which is the major risk factor for stroke. We will specifically test whether the activity of this enzyme actually helps to limit the amount of brain death following stroke. We will use a variety of techniques to assess the importance of this enzyme in brain arteries in the living body, and also in isolated segments of brain artery from animals that are either healthy or have diseased brain arteries. The results are expected to provide major new insight into processes that help maintain brain blood flow under normal conditions and after a stroke, and the knowledge gained here should lead to safer therapies to prevent or treat stroke.Read moreRead less
Are Novel Nitric Oxide Mimetics Protective In Vascular Disease?
Funder
National Health and Medical Research Council
Funding Amount
$634,044.00
Summary
Nitric oxide (NO) is a biologically active gas which controls blood flow and blood pressure. New drugs which mimic the effects of NO show promise in the treatment of cardiovascular disease. This study investigates the ability of NO mimetics to protect blood vessels in disease, by limiting the production of toxic molecules, improving blood flow and preventing blood clot formation. The information gained may lead to the development of new therapies for blood vessel diseases such as stroke.
Does NADPH Oxidase Link Gender, Hormone Replacement Therapy And Outcome After Stroke?
Funder
National Health and Medical Research Council
Funding Amount
$481,439.00
Summary
This project will assess whether the reduction of a novel mechanism to open brain arteries (i.e. via activation of 'Nox' proteins and generation of oxygen radicals) is a possible explanation of why hormone replacement therapy (HRT) increases the risk of stroke in postmenopausal women. We will compare brain artery function of normal mice with those deficient in certain Nox genes in models of menopause, HRT and stroke. This knowledge should lead to safer stroke therapies in women and men.
Heme-oxidised Soluble Guanylyl Cyclase, A Mechanism-based Target For Vascular Diagnostics And Vasoprotective Therapy
Funder
National Health and Medical Research Council
Funding Amount
$524,456.00
Summary
Nitric oxide is produced in the inner lining of blood vessels and maintains blood flow via binding to a specific protein, sGC. In disease, sGC is defective and can be targeted by a novel group of drugs which are more active in diseased versus normal blood vessels. This project will examine the use of these drugs as markers of cardiovascular disease and in the treatment of high cholesterol and may lead to the development of new diagnostic tools and therapies for vascular complications.
Angiotensin AT2 Receptor: A Novel Target For Cardiovascular Modulation
Funder
National Health and Medical Research Council
Funding Amount
$692,040.00
Summary
The hormone, angiotensin II, circulates in the blood and increases blood pressure and thickens the heart and blood vessels, all of which contributes to high blood pressure (hypertension). Angiotensin II causes these excitatory effects by acting at particular target sites called AT1 receptors. Drugs called AT1 receptor antagonists are known to block these excitatory actions of angiotensin II at AT1 receptors. Consequently, these compounds lower blood pressure in humans because they block the ongo ....The hormone, angiotensin II, circulates in the blood and increases blood pressure and thickens the heart and blood vessels, all of which contributes to high blood pressure (hypertension). Angiotensin II causes these excitatory effects by acting at particular target sites called AT1 receptors. Drugs called AT1 receptor antagonists are known to block these excitatory actions of angiotensin II at AT1 receptors. Consequently, these compounds lower blood pressure in humans because they block the ongoing stimulatory action of angiotensin II. However, it is now thought that angiotensin II may also be able to act at another target site (AT2 receptor) to cause opposite effects, i.e. decrease blood pressure and inhibit growth effects. Therefore, this project will examine if direct stimulation of AT2 sites can alter blood flows measured in different body regions in hypertensive rats as part of their mechanism to lower blood pressure. In addition, the effects of continuous stimulation of the AT2 site will be examined in hypertensive rats which will be implanted with a radiotransmitter to measure blood pressure without interference, and afterwards, structural measurements of the heart and blood vessels will be made. Additionally, this project will investigate whether stimulation of the AT2 site also contributes to the blood pressure-lowering effect of drugs already mentioned (AT1 receptor antagonists). The rationale for this is that the hormone angiotensin II is still 'free' to act at the AT2 site, even with AT1 receptors being blocked, and lower blood pressure. These studies will determine if stimulation of AT2 sites contributes to the beneficial effects (i.e. decreased blood pressure and decreased cardiovascular growth) of AT1 receptor antagonists in the treatment of high blood pressure. More importantly, these findings may also identify a new therapeutic target site (AT2 receptor) for drug development in the treatment of cardiovascular disease.Read moreRead less