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

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ClinicalTrials.gov Identifier: NCT01096706
Recruitment Status : Completed
First Posted : March 31, 2010
Last Update Posted : May 15, 2012
Sponsor:
Collaborator:
NHS Lothian
Information provided by (Responsible Party):
University of Edinburgh

Study Description
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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.


Condition or disease Intervention/treatment Phase
Vascular Disease Heart Disease Drug: NO clamp Drug: Saline Drug: Fluconazole Drug: Aspirin Drug: Combined Not Applicable

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: Effects of Urocortins on Forearm Arterial Blood Flow in Healthy Volunteers
Study Start Date : July 2011
Actual Primary Completion Date : January 2012
Actual Study Completion Date : January 2012
Arms and Interventions
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Arm Intervention/treatment
Experimental: Nitric Oxide Clamp
Forearm blood flow response to Urocortins 2, 3 and Substance P in the presence of Nitric Oxide clamp
 Drug: NO clamp

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.

Other Name: Forearm vascular study - Bilateral forearm blood flow will be measured at baseline and after each dose of Ucn 2, 3 and Substance P
Placebo Comparator: Saline Placebo
Forearm blood flow response to Urocortin 2, Urocortin 3 and Substance P in the presence of saline placebo.
 Drug: Saline

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.

Other Name: Forearm vascular study - Bilateral forearm blood flow will be measured at baseline and after each dose of Ucn 2, 3 and Substance P.
Experimental: Fluconazole
Forearm blood flow response to Urocortin 2, Urocortin 3 and Substance P in the presence of intra-arterial Fluconazole.
 Drug: Fluconazole

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

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.
Experimental: Combined
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

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.


Outcome Measures
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Primary Outcome Measures :
  1. Forearm blood flow [ Time Frame: 3 hours ]
    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'


Secondary Outcome Measures :
  1. Net t-PA release [ Time Frame: 3 hours ]
    Net release of t-PA evoked by Ucn 2, Ucn 3 and Substance P, in the presence vs absence of a 'nitric oxide clamp'.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

  • 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
Contacts and Locations
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01096706


Locations
United Kingdom
Wellcome Trust Clinical Research Facility, Royal Infirmary of Edinburgh
Edinburgh, Mid Lothian, United Kingdom, EH16 4SA
Sponsors and Collaborators
University of Edinburgh
NHS Lothian
Investigators
Principal Investigator: David E Newby, PhD FRCP University of Edinburgh
More Information
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: University of Edinburgh
ClinicalTrials.gov Identifier: NCT01096706     History of Changes
Other Study ID Numbers: SV.Protocol 3
First Posted: March 31, 2010    Key Record Dates
Last Update Posted: May 15, 2012
Last Verified: May 2012

Keywords provided by University of Edinburgh:
Urocortin 2
Urocortin 3
Nitric Oxide
Plethysmography
Forearm blood flow
 Vascular
Heart failure
endothelium
Cyclo-oxygenase pathway
EDHF

Additional relevant MeSH terms:
Heart Diseases
Vascular Diseases
Cardiovascular Diseases
Aspirin
Fluconazole
Nitric Oxide
Substance P
Neurokinin A
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
 Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Bronchodilator Agents
Autonomic Agents
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Neurotransmitter Agents