A Novel Ionic Current Contributing To Spasm Of Small Blood Vessels
Funder
National Health and Medical Research Council
Funding Amount
$287,500.00
Summary
Vascular smooth muscle can produce strong constrictions or spasms that can severely limit blood flow. Disorders arising from such spasms include sudden death, neurological deficits, visual and hearing loss or impairment, Raynaud's phenomenon (painful episodic contraction of the fingers and toes) and intestinal necrosis. Common mechanisms are likely to underlie the spasms associated with these disparate disorders. In a recent electrophysiological study of vascular smooth muscle, we discovered a n ....Vascular smooth muscle can produce strong constrictions or spasms that can severely limit blood flow. Disorders arising from such spasms include sudden death, neurological deficits, visual and hearing loss or impairment, Raynaud's phenomenon (painful episodic contraction of the fingers and toes) and intestinal necrosis. Common mechanisms are likely to underlie the spasms associated with these disparate disorders. In a recent electrophysiological study of vascular smooth muscle, we discovered a novel membrane current which we refer to as the plateau current. This current has a strong depolarizing influence that is likely to make a major contribution to the spasms, particularly in arterioles and small arteries which are more dependent on depolarization for contraction. Block of this current is expected to minimize the depolarization and therefore prevent or ameliorate spasm of the vessels. Thus the plateau current represents a new field of therapeutic potential for addressing vascular problems that have significant health implications. However, therapeutic manipulation of the current requires knowledge of its properties. In this project we will determine the biophysical and pharmacological properties of this current using voltage-clamp techniques. We will then use this information to assess its functional significance by recording membrane potential with intracellular microelectrodes simultaneously with contractile activity. We will also compare small vessels obtained from volunteers with or without the vasospastic disorder of Raynaud's phenomenon. Our previous work using these techniques was described in J Physiol as a microelectrode, patch clamp and myograph study of the highest quality and of supreme technical difficulty and scored a Top-Ten hit rate. Since we are the only ones to record the plateau current, we are in a unique position to make significant progress to our understanding of contraction, including spasm, in small blood vessels.Read moreRead less
Voltage Dependent Calcium Channels And Vascular Function: Do Microdomains Determine Function?
Funder
National Health and Medical Research Council
Funding Amount
$597,682.00
Summary
Blood flow depends on arterial diameter which can change with contraction of muscle in the vessel wall. Calcium influx through one type of channel in the muscle cells has been considered critical, but drugs targeting these channels have not succeeded in treating the arterial spasm which occurs after stroke and head injury. Our study will investigate the existence and role of other calcium channels in brain arteries. Knowledge gained will likely lead to development of new drug targets for stroke.
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