Effects of Urocortins on Forearm Arterial Blood Flow in Healthy Volunteers (Protocol 3) - Full Text View

Purpose

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	Intervention
Vascular Disease Heart Disease	Drug: NO clamp Drug: Saline Drug: Fluconazole Drug: Aspirin Drug: Combined


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacodynamics Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Basic Science
Official Title:	Effects of Urocortins on Forearm Arterial Blood Flow in Healthy Volunteers

Resource links provided by NLM:

Drug Information available for: Aspirin Nitric oxide Fluconazole

U.S. FDA Resources

Further study details as provided by University of Edinburgh:

Primary Outcome Measures:

Forearm blood flow [ Time Frame: 3 hours ] [ Designated as safety issue: No ]
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:

Net t-PA release [ Time Frame: 3 hours ] [ Designated as safety issue: No ]
Net release of t-PA evoked by Ucn 2, Ucn 3 and Substance P, in the presence vs absence of a 'nitric oxide clamp'.


Enrollment:	10
Study Start Date:	July 2011
Study Completion Date:	January 2012
Primary Completion Date:	January 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.

Eligibility


Ages Eligible for Study:	18 Years to 65 Years (Adult)
Genders 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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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

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

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.


Responsible Party:	University of Edinburgh
ClinicalTrials.gov Identifier:	NCT01096706 History of Changes
Other Study ID Numbers:	SV.Protocol 3
Study First Received:	March 30, 2010
Last Updated:	May 14, 2012
Health Authority:	United Kingdom: Research Ethics Committee

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 Substance P Neurokinin A Nitric Oxide 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 Antifungal Agents Anti-Infective Agents 14-alpha Demethylase Inhibitors Cytochrome P-450 Enzyme Inhibitors Steroid Synthesis Inhibitors Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists

Heart Diseases
Vascular Diseases
Cardiovascular Diseases
Aspirin
Fluconazole
Substance P
Neurokinin A
Nitric Oxide
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
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on September 30, 2016