Gap Junction Potentiation of Endothelial Function With Rotigaptide in the Human Forearm Arterial Circulation - Effects of Ischaemia Induced Endothelial Dysfunction
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Change in Substance P and ACh vasodilatation caused by potentiation of gap junction communication with Rotigaptide in the context of endothelial dysfunction
研究概览
简要总结
Hypothesis - Rotigaptide will improve endothelial function in the context of endothelial dysfunction.
The lining of blood vessels (endothelium) can react to hormones in the blood stream causing the blood vessel muscle to relax (vasodilatation) and allow more blood to flow. The nitric oxide and prostacyclin pathways are well documented in this process. However, evidence points to the existence of a third powerful relaxant called endothelium derived hyperpolarising factor (EDHF) but its identity and mechanism of action have proved elusive. As well as causing blood vessels to relax and more blood to flow, EDHF may be involved in the endothelium signaling, triggering release of a specialised clot dissolving factor called tissue plasminogen activator (t PA). t PA is important to ensure small clots, which are constantly being formed in the circulation, are rapidly dissolved and do not grow large enough to cause heart attacks and strokes.
Evidence points towards the requirement for 'gap junctions' in the mediation of EDHF responses. Gap junctions are specialised pores which allow small molecules and charge to pass between cells. They are found between endothelial cells and the underlying muscle of the blood vessel. A drug called Rotigaptide has been developed to cause gap junctions to open. It has been safely administered in healthy volunteers and is now in a Phase II drug trial. By opening gap junctions the investigators hypothesise that it could increase EDHF mediated activity and vasodilatation. It represents a useful tool with which to examine the role of gap junctions in EDHF activity in vivo.
Previously the investigators have demonstrated that rotigaptide does not contribute to endothelial function in healthy volunteers. The investigators now wish to examine the effect of rotigaptide in conditions of endothelial dysfunction. By limiting the blood flow to the arm for 20mins the ability of the blood vessel to vasodilate is impaired. By administering an intra-arterial rotigaptide infusion the investigators want to assess any functional preservation.
详细描述
BACKGROUND The endothelium plays a pivotal role in the control of vascular tone and is responsible for the local release of profibrinolytic factors. Nitric oxide (NO), the original endothelium-derived relaxing factor, and prostacyclin (PGI2) have now been well characterised. The elucidation of their roles in vascular physiology and pathophysiology has been fundamental to recent advances in the treatment and prevention of many cardiovascular diseases. Whilst these factors are of major importance, evidence points to the existence of a third powerful vasodilator called endothelium-derived hyperpolarising factor (EDHF).
Endothelium-dependent vasodilatation -
After blockade of both NO and PGI2, a substantial degree of endothelium-dependent vasodilatation is still observed and is attributed to EDHF. Despite almost two decades of research and debate, the exact nature of EDHF and its mechanism of action remain unclear. Consistently, EDHF's role as a vasodilator is most prominent in the smaller resistance arteries that are responsible for the control of systemic blood pressure and local organ perfusion. As well as its involvement in physiological processes, alterations in EDHF activity may contribute to the vascular effects of the myriad of conditions either caused by, or resulting in, endothelial dysfunction. However, the lack of understanding of EDHF has precluded its direct manipulation as a specific therapeutic target.
Endogenous fibrinolysis -
In addition to its function in the control of vascular tone, there is evidence to suggest that EDHF may be responsible for the endothelial release of the pro-fibrinolytic factor, tissue-type plasminogen activator (t-PA).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 64 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy volunteers aged between 18-64 years.
排除标准
- •Lack of informed consent
- •Age <18 or >64 years
- •Current involvement in a clinical trial
- •Clinically significant comorbidity: heart failure, hypertension, known hyperlipidaemia, diabetes mellitus, asthma, coagulopathy or bleeding disorders*
- •Current intake of aspirin, other non steroid anti inflammatory medications or vasodilators*
- •Recent infective/inflammatory condition*
- •Women of child bearing age
- •Recent blood donation (preceding three months) *All cause confounding effects on vascular/endothelial function.
研究组 & 干预措施
Rotigaptide
Prior to 20 mins of ischaemia induced by a blood pressure cuff inflated to 200 mmHg around the upper non-dominant arm, rotigaptide will be infused for 30mins. During the ischaemic period no drug will be infused but the infusion will be restarted once the blood pressure cuff has been deflated and blood flow returns to the limb.
干预措施: Rotigaptide (Drug)
Rotigaptide
Prior to 20 mins of ischaemia induced by a blood pressure cuff inflated to 200 mmHg around the upper non-dominant arm, rotigaptide will be infused for 30mins. During the ischaemic period no drug will be infused but the infusion will be restarted once the blood pressure cuff has been deflated and blood flow returns to the limb.
干预措施: Forearm vascular study (Other)
Saline
Saline will be infused through-out the study.
干预措施: Forearm vascular study (Other)
结局指标
主要结局
Change in Substance P and ACh vasodilatation caused by potentiation of gap junction communication with Rotigaptide in the context of endothelial dysfunction
时间窗: Vasodilatation will be assesed before and after ischaemic periods
次要结局
- Change in Substance P induced t PA release caused by potentiation of gap junction communication with Rotigaptide in the context of endothelial dysfunction(Venous blood samles will be taken at regular time points throught the protocol)