Rhythmicity, Synchronicity And Spasm In Smooth Muscle
Funder
National Health and Medical Research Council
Funding Amount
$614,520.00
Summary
Many cellular systems undergo rhythmical spontaneous chemical and-or electrical activity . This activity, often referred to as pacemaking, is prevalent in many organs underlying brain waves or causing heart beats or rhythmic contractions of smooth muscle. Our studies on pacemaker rhythmicities in smooth muscle have revealed a novel mechanism, one which is entirely different to that responsible for heart pacemaking, the generally held model for electrical pacemakers. We aim to study the mechanism ....Many cellular systems undergo rhythmical spontaneous chemical and-or electrical activity . This activity, often referred to as pacemaking, is prevalent in many organs underlying brain waves or causing heart beats or rhythmic contractions of smooth muscle. Our studies on pacemaker rhythmicities in smooth muscle have revealed a novel mechanism, one which is entirely different to that responsible for heart pacemaking, the generally held model for electrical pacemakers. We aim to study the mechanism in depth so that we can fully describe its operation. This knowledge will provide insight into phenomena such as spontaneous contractions in blood vessels, lymphatic vessels and in the gastrointestinal tract, activities which are the norm and which are likely to have major influence on blood pressure, the propulsion of lymph and gut peristalsis. The knowledge will in the longer term lead to a better understanding of rhythmicities generally as far ranging as uterine contractions during childbirth to brain waves. An understanding of the pacemaker mechanism may also provide a key to understanding debilitating conditions such as vasospasm which can lead to death or serious disability.Read moreRead less
Spatio-temporal Analysis Of Rat Intestinal Motility In Physiological And Disease Models
Funder
National Health and Medical Research Council
Funding Amount
$358,750.00
Summary
This project addresses the question of how the movements of the gut are controlled in health and disease. The progress of food along the gut is due to movements of the involuntary muscle of the wall of the intestine. Three fundamental mechanisms are involved. One is the spontaneous ability of the intestinal muscle to contract rhythmically and is driven by a delicate net of pacemaker cells. Fast propulsion of food contents depends on nerve circuits in the gut wall that generate a powerful pumping ....This project addresses the question of how the movements of the gut are controlled in health and disease. The progress of food along the gut is due to movements of the involuntary muscle of the wall of the intestine. Three fundamental mechanisms are involved. One is the spontaneous ability of the intestinal muscle to contract rhythmically and is driven by a delicate net of pacemaker cells. Fast propulsion of food contents depends on nerve circuits in the gut wall that generate a powerful pumping behaviour to prevent over-filling or to eject toxic or irritating substances (eg: some laxatives activate this mechanisms). This is often called peristalsis. A third mechanism consists of activity of nerve cells in the gut, that slowly propagates along the intestine and causes the muscle to contract, sweeping along any remnants. The movements generated by these three mechanisms occur in segments of intestine isolated from rats. The major difficulty up until now has been to relate the actual movements in living animals to these fundamental mechanisms. It is now possible to bridge this gap because we have developed methods to record, display and measure graphically the actual movements. Movements are transformed into spatio-temporal maps which show all of the contractions over a period of time. Coordinated activity is visible in these maps as recognisable patterns or visual objects. Measurements can be readily made with conventional statistics. The literature in gastroenterology is full of descriptions of motility based on indirect methods of recordings. In this project we will be able to correlate the previous indirect methods with the new graphic methods and thus establish a clearer, simpler and more accurate classification of normal patterns of intestinal motility. We will then use this to establish what goes wrong in a number of experimental diseases known to affect adversely the movements of the intestine.Read moreRead less
A Novel Mechanism For Intestinal Propulsion: Transit Without Neurons Or Pacemakers
Funder
National Health and Medical Research Council
Funding Amount
$256,973.00
Summary
A significant complication of premature births is that the mechanisms that regulate normal intestinal movements have not yet fully developed. We have recently identified a novel pattern of contraction that is seen predominantly in the colon of mice that have not yet developed either the normal nerve circuits that control gut movement and also lack the pacemaker cells that are intrinsic to the muscle coat. This motor pattern appears to be responsible for the movement of gut content during the dev ....A significant complication of premature births is that the mechanisms that regulate normal intestinal movements have not yet fully developed. We have recently identified a novel pattern of contraction that is seen predominantly in the colon of mice that have not yet developed either the normal nerve circuits that control gut movement and also lack the pacemaker cells that are intrinsic to the muscle coat. This motor pattern appears to be responsible for the movement of gut content during the development and maturation of the nerve circuits that regulate this process in more adult animals. However, the mechanisms responsible for this process have not been identified. This project is directed at identifying these mechanismsRead moreRead less
Molecular Mechanisms Of Nitric Oxide Modulation Of Calcium-activated Potassium Channels In Smooth Muscle
Funder
National Health and Medical Research Council
Funding Amount
$411,622.00
Summary
The inappropriate production of nitric oxide (NO) is increasingly being linked to the pathogenesis of numerous disease states such as septic shock, hypoxic-ischaemic brain damage, anti-microbial defense and inflammation. In mammalian visceral smooth muscle organs, the release of NO plays an essential role in the processes that underlie the endothelial-dependent relaxation of vascular smooth muscle, as well as the relaxation of many smooth muscles evoked upon stimulation of intrinsic non-adrenerg ....The inappropriate production of nitric oxide (NO) is increasingly being linked to the pathogenesis of numerous disease states such as septic shock, hypoxic-ischaemic brain damage, anti-microbial defense and inflammation. In mammalian visceral smooth muscle organs, the release of NO plays an essential role in the processes that underlie the endothelial-dependent relaxation of vascular smooth muscle, as well as the relaxation of many smooth muscles evoked upon stimulation of intrinsic non-adrenergic non-cholinergic (NANC) inhibitory motor nerves. It is becoming clear that the inappropriate release of NO may also contribute to a number of disorders of visceral organs. In fact, NO donors and NO synthesis blockers are presently being tested in >15 NIH sponsored clinical trials of treatments of such disparate diseases as acute myocardial infarction, endothelial dysfunction during atherosclerosis or coronary heart disease, aspiration syndrome or persistent pulmonary hypertension in infants, and hormone therapy in postmenopausal women. This project represents a unique international collaboration of Drs Lang (Monash Uni.) and Neylon (Baker Inst.) with Dr Reinhart (Duke Uni.)(Neylon et al 1999). We intend to establish the precise site and mechanisms of action of NO on both naturally occurring and artificially reconstructed K channels obtained from intestinal and vascular smooth muscle. These experiments will for the first time establish the molecular site of NO action on the K channels that set the membrane potential and excitability of smooth muscle. This specific knowledge may well lead to a rational development of drugs that specifically restore smooth muscle function in a number of disorders such as slow gastric emptying and slow transit constipation.Read moreRead less
The Plasmalemmal Calcium Pump And Vascular Smooth Muscle Cell Proliferation.
Funder
National Health and Medical Research Council
Funding Amount
$179,593.00
Summary
Excessive growth of smooth muscle cells can lead to adverse effects in our arteries. The level of calcium inside the muscle cells that line our arteries appears to regulate their growth. In these studies we will assess the changes in the synthesis (expression) of a pump which removes calcium from cells. We will also characterise the effects of modifiers of cell growth on the expression of the calcium pump. The effect of directly inhibiting the production of the calcium pump, on the growth of smo ....Excessive growth of smooth muscle cells can lead to adverse effects in our arteries. The level of calcium inside the muscle cells that line our arteries appears to regulate their growth. In these studies we will assess the changes in the synthesis (expression) of a pump which removes calcium from cells. We will also characterise the effects of modifiers of cell growth on the expression of the calcium pump. The effect of directly inhibiting the production of the calcium pump, on the growth of smooth muscle cells and the regulation of calcium will be determined for the first time.Read moreRead less