Gap Junction Potentiation of Endothelial Function With Rotigaptide

NCT00901563 | Completed

• 1 other identifier: CZB/4/520/b
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Vascular Disease; Heart Disease

Keywords

Gap Junctions; Rotigaptide; Ischaemia reperfusion; t-PA; Fibrinolysis; Endothelial function; Venous occlusion plethysmography

Outcome Measures

Primary Outcomes (1)

• Change in Substance P and ACh vasodilatation caused by potentiation of gap junction communication with Rotigaptide in the context of endothelial dysfunction

  Vasodilatation will be assesed before and after ischaemic periods

Secondary Outcomes (1)

• 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

Study Arms (2)

Rotigaptide

ACTIVE COMPARATOR

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.

Drug: Rotigaptide; Other: Forearm vascular study

Saline

PLACEBO COMPARATOR

Saline will be infused through-out the study.

Other: Forearm vascular study

Interventions

Rotigaptide DRUG

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.

Rotigaptide

Forearm vascular study OTHER

Forearm blood flow measured by venous occlusion plethysmography during interarterial infusion of substance P (2,4,8 pmol/min) or Acetylcholine (5, 10 , 20 micromol/min) . Venous blood sampling via cannula in antecubital fossa.

Rotigaptide; Saline

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy volunteers aged between 18-64 years.

You may not qualify if:

• 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\*
• Smoker\*
• 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.

Sponsors & Collaborators

• University of Edinburgh: lead
• Chief Scientist Office of the Scottish Government: collaborator
• NHS Lothian: collaborator

Study Sites (1)

Clincial Research Facility, Royal Infirmary of Edinburgh, 51 Little France Cresc

Edinburgh, EH16 4SA, United Kingdom

Location

Related Publications (1)

• Pedersen CM, Venkatasubramanian S, Vase H, Hyldebrandt JA, Contractor H, Schmidt MR, Botker HE, Cruden NL, Newby DE, Kharbanda RK, Lang NN. Rotigaptide protects the myocardium and arterial vasculature from ischaemia reperfusion injury. Br J Clin Pharmacol. 2016 Jun;81(6):1037-45. doi: 10.1111/bcp.12882. Epub 2016 Mar 10.

  PMID: 26750458 RESULT

MeSH Terms

Conditions

Vascular Diseases; Heart Diseases

Interventions

rotigaptide

Condition Hierarchy (Ancestors)

Cardiovascular Diseases

Study Officials

• David E Newby, MD

  University of Edinburgh

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 13, 2009
• First Posted: May 14, 2009
• Study Start: March 1, 2009
• Primary Completion: August 3, 2015
• Study Completion: August 3, 2015
• Last Updated: June 21, 2021

Record last verified: 2021-06

Locations

GB (1)