Effects of Urocortins on Forearm Arterial Blood Flow in Healthy Volunteers (Protocol 3)

NCT01096706 | Completed

• 1 other identifier: SV.Protocol 3
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

Impairment of the heart's pumping capacity (heart failure) remains a major clinical problem with a poor prognosis and the search for novel treatments remains an important area of research. Urocortins are proteins that appear to increase blood flow and heart pumping activity. There has been particular interest in the role of Urocortins 2 \& 3 (subtypes of Urocortins) in heart failure. In this study, we will examine the effects and mechanisms of Urocortins 2 \& 3 on forearm blood flow and release of natural blood clot dissolving factors in the forearm circulation of healthy volunteers. In particular, we look at the endothelial mechanisms of vasodilatation of Urocortin 2 and 3. In this study, we will look at the role of the lining of the blood vessel (endothelium) in response to urocortin types 2 and 3. We hypothesise that urocortins 2 \& 3 act via the endothelium to cause dilatation of the blood vessels and release of tissue-plasminogen activating factor (blood clot dissolving factor). We also hypothesise that urocortins have a role in maintaining the normal baseline level of blood flow in forearm arteries. In addition to the above, we will also look at the effect of temporarily blocking the effect of urocortins, using a specially designed blocker drug (Astressin 2B). Utilising the well-established technique of 'forearm venous occlusion plethysmography', we will be able to focus on the local effects of urocortins on arterial blood flow in forearm vessels, without affecting this system in the body as a whole.

Conditions

Vascular Disease; Heart Disease

Keywords

Urocortin 2; Urocortin 3; Nitric Oxide; Plethysmography; Forearm blood flow; Vascular; Heart failure; endothelium; Cyclo-oxygenase pathway; EDHF

Outcome Measures

Primary Outcomes (1)

• Forearm blood flow

  The difference between forearm blood flow in response to incremental doses of Ucn2, Ucn3 and Sub P in the presence vs absence of 'the nitric oxide clamp'

  3 hours

Secondary Outcomes (1)

• Net t-PA release

  3 hours

Study Arms (5)

Nitric Oxide Clamp

EXPERIMENTAL

Forearm blood flow response to Urocortins 2, 3 and Substance P in the presence of Nitric Oxide clamp

Drug: NO clamp

Saline Placebo

PLACEBO COMPARATOR

Forearm blood flow response to Urocortin 2, Urocortin 3 and Substance P in the presence of saline placebo.

Drug: Saline

Fluconazole

EXPERIMENTAL

Forearm blood flow response to Urocortin 2, Urocortin 3 and Substance P in the presence of intra-arterial Fluconazole.

Drug: Fluconazole

Aspirin

EXPERIMENTAL

Forearm blood flow response to Urocortin 2, Urocortin 3 and Substance P in the presence of cyclooxygenase inhibition with Aspirin.

Drug: Aspirin

Combined

EXPERIMENTAL

Forearm blood flow response to Urocortin 2, Urocortin 3 and Substance P in the presence of inhibition of cycloxygenase, EDHF and NO pathways with Aspirin, Fluconazole and NO clamp.

Drug: Combined

Interventions

NO clamp DRUG

After a 20 minute saline washout period, ascending doses of Urocortin 2, Urocortin 3 and substance P (doses as per Protocol 2) will be infused intra-arterially in the presence or the absence of the 'nitric oxide clamp' that will be commenced prior to the infusion of Urocortin 2, Urocortin 3 and substance P, and will be continued throughout the study. Baseline blood samples will be taken from both forearms at the start of the study for full blood count, cholesterol, glucose, renal function and t-PA and PAI-1 activity and antigen concentrations. Bilateral venous blood samples will be taken at baseline, immediately before the start of Ucn2/Ucn3 infusion and at the end of each dose of Ucn2/Ucn3 for subsequent calculation of net release of t-PA and PAI-1.

Also known as: Forearm vascular study - Bilateral forearm blood flow will be measured at baseline and after each dose of Ucn 2, 3 and Substance P

Nitric Oxide Clamp

Saline DRUG

After a 20 minute saline washout, incremental doses of Urocortin 2, Urocortin 3 and Substance P (in doses as per Protocol 2) will be infused in the presence of saline placebo. Baseline blood samples will be taken from both forearms at the start of the study for full blood count, cholesterol, glucose, renal function and t-PA and PAI-1 activity and antigen concentrations. Bilateral venous blood samples will be taken at baseline, immediately before the start of Ucn2/Ucn3 infusion and at the end of each dose of Ucn2/Ucn3 for subsequent calculation of net release of t-PA and PAI-1.

Also known as: Forearm vascular study - Bilateral forearm blood flow will be measured at baseline and after each dose of Ucn 2, 3 and Substance P.

Saline Placebo

Fluconazole DRUG

After a 20 minute saline washout period, ascending doses of Urocortin 2, Urocortin 3 and substance P (doses as per Protocol 2) will be infused intra-arterially in the presence of Fluconazole (which serves to inhibit the EDHF pathway) that will be commenced prior to the infusion of Urocortin 2, Urocortin 3 and substance P, and will be continued throughout the study. Baseline blood samples will be taken from both forearms at the start of the study for full blood count, cholesterol, glucose, renal function, plasma Ucn 2 and 3 and t-PA and PAI-1 activity and antigen concentrations. Bilateral venous blood samples will be taken at after the top dose of Ucn2/Ucn3 infusion and before and after each dose of Substance P for subsequent calculation of plasma Ucn 2/ Ucn 3 and net release of t-PA and PAI-1.

Fluconazole

Aspirin DRUG

Oral Aspirin (600mg stat) will be administered 30 minutes before start of the study. After a 20 minute saline washout period, ascending doses of Urocortin 2, Urocortin 3 and substance P (doses as per Protocol 2) will be infused intra-arterially in the presence of saline. Baseline blood samples will be taken from both forearms at the start of the study for full blood count, cholesterol, glucose, renal function, plasma Ucn 2 and 3 and t-PA and PAI-1 activity and antigen concentrations. Bilateral venous blood samples will be taken at after the top dose of Ucn2/Ucn3 infusion and before and after each dose of Substance P for subsequent calculation of plasma Ucn 2/ Ucn 3 and net release of t-PA and PAI-1.

Aspirin

Combined DRUG

Oral Aspirin (600mg stat) is administered 30 minutes before start of the study. After a 20 minute saline washout period, ascending doses of Urocortin 2, Urocortin 3 and substance P (doses as per Protocol 2) will be infused intra-arterially in the presence of the 'nitric oxide clamp' that will be commenced prior to the infusion of Urocortin 2, Urocortin 3 and substance P, and will be continued throughout the study. Intra-arterial Fluconazole is also commenced at the time of the Nitric oxide clamp. This serves to inhibit the cyclooxygenase, EDHF and NO pathways of endothelial vasodilatation. Blood samples are taken as per previous arms.

Combined

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy male volunteers between 18 - 65 years (inclusive)

You may not qualify if:

• Lack of informed consent- Age \<18 years \> 65 years
• Current involvement in a clinical trial
• Severe or significant co-morbidity including bleeding diathesis, renal or hepatic failure
• Smoker
• History of anaemia
• Recent infective/inflammatory condition
• Recent blood donation (prior 3 months)
• Positive baseline urine test for drugs of abuse (including cannabinoids, benzodiazepines, opiates, cocaine and amphetamines)
• History of allergy to Aspirin

Sponsors & Collaborators

• University of Edinburgh: lead
• NHS Lothian: collaborator

Study Sites (1)

Wellcome Trust Clinical Research Facility, Royal Infirmary of Edinburgh

Edinburgh, Mid Lothian, EH16 4SA, United Kingdom

Location

Related Publications (1)

• Venkatasubramanian S, Griffiths ME, McLean SG, Miller MR, Luo R, Lang NN, Newby DE. Vascular effects of urocortins 2 and 3 in healthy volunteers. J Am Heart Assoc. 2013 Jan 31;2(1):e004267. doi: 10.1161/JAHA.112.004267.

  PMID: 23525432 DERIVED

MeSH Terms

Conditions

Vascular Diseases; Heart Diseases; Heart Failure

Interventions

Substance P; Sodium Chloride; Fluconazole; Aspirin

Condition Hierarchy (Ancestors)

Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Tachykinins; Kinins; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Neuropeptides; Oligopeptides; Proteins; Nerve Tissue Proteins; Autacoids; Inflammation Mediators; Biological Factors; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• David E Newby, PhD FRCP

  University of Edinburgh

  PRINCIPAL INVESTIGATOR

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: March 30, 2010
• First Posted: March 31, 2010
• Study Start: July 1, 2011
• Primary Completion: January 1, 2012
• Study Completion: January 1, 2012
• Last Updated: May 15, 2012

Record last verified: 2012-05

Locations

GB (1)