Investigating Systemic and Local Vascular Responses to Apelin in the Context of Renin-angiotensin Upregulation

Investigating the Interaction of Apelin and Systemic Angiotensin II Peripheral Resistance Vessels and Systemic Haemodynamics in Vivo in Man

The apelin-APJ system is a relatively new discovery. It has generated interest in part due to it's apparent ability to counteract the renin-angiotensin system, which is frequently overactive in many cardiovascular disease.

Two of the main actions of apelin are to increase the pumping ability of the heart and cause blood vessels to relax. The investigators wish to assess if these actions are altered in the setting of normal renin-angiotensin activation and increased renin-angiotensin activity.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Heart Disease; Vasodilatation
• Intervention / Treatment: Drug: Apelin; Drug: Acetylcholine; Drug: Sodium nitroprusside; Drug: Systemic apelin infusion

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH16 4SA
    • Clincial Research Facility, Royal Infirmary of Edinburgh, 51 Little France Cresc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 85 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• >18yr

Exclusion Criteria:

• Lack of informed consent
• Age < 18 years,
• Current involvement in other research studies,
• Systolic blood pressure >190 mmHg or <100 mmHg
• Malignant arrhythmias
• Renal or hepatic failure
• Haemodynamically significant aortic stenosis
• Severe or significant co morbidity
• Women of childbearing potential.
• Any regular medication
• Previous history of any cardiovascular disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Sodium depletion; Subjects will be randomised to normal diet or sodium depleted diet. The sodium depletion protocol comprises of a single oral dose of 40 mg of furosemide followed by an out-patient diet containing >2000 kcal of energy, >60 g of protein, <12 mmol of sodium and <70 mmol of potassium per day for 3 days prior to study. This diet is know to increase the activity of the renin-angiotensin system.	Drug: Apelin; Using the technique of venous occlusive plethysmography subjects will receive three intrabrachial apelin infusions at 0.3, 1.0 and 3.0 nanomol/ml.; Drug: Acetylcholine; Using the technique of venous occlusive plethysmography subjects will receive three intrabrachial acetylcholine infusions at 5, 10 and 20 microg/min; Drug: Sodium nitroprusside; Using the technique of venous occlusive plethysmography subjects will receive three intrabrachial acetylcholine infusions at 1, 2 and 4 microg/min; Drug: Systemic apelin infusion; Following plethysmography patients will receive systemic infusion of (Pry)Apelin-13 (30, 100 and 300 nmol/min) for 5 mins cardiac output, blood pressure, heart rate and systemic vascular resistance will be measured at 5-min intervals.
PLACEBO_COMPARATOR: Normal diet; Subjects will be randomised to a normal diet, with no restriction on sodium intake during the three days prior to the study.	Drug: Apelin; Using the technique of venous occlusive plethysmography subjects will receive three intrabrachial apelin infusions at 0.3, 1.0 and 3.0 nanomol/ml.; Drug: Acetylcholine; Using the technique of venous occlusive plethysmography subjects will receive three intrabrachial acetylcholine infusions at 5, 10 and 20 microg/min; Drug: Sodium nitroprusside; Using the technique of venous occlusive plethysmography subjects will receive three intrabrachial acetylcholine infusions at 1, 2 and 4 microg/min; Drug: Systemic apelin infusion; Following plethysmography patients will receive systemic infusion of (Pry)Apelin-13 (30, 100 and 300 nmol/min) for 5 mins cardiac output, blood pressure, heart rate and systemic vascular resistance will be measured at 5-min intervals.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in cardiac output	12 months
Change in apelin mediated vasodilatation	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in systemic haemodynamics	12 months
Change in relevant neurohumoral hormones	12 months

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: NHS Lothian; British Heart Foundation

Publications and helpful links

General Publications

• Barnes GD, Alam S, Carter G, Pedersen CM, Lee KM, Hubbard TJ, Veitch S, Jeong H, White A, Cruden NL, Huson L, Japp AG, Newby DE. Sustained cardiovascular actions of APJ agonism during renin-angiotensin system activation and in patients with heart failure. Circ Heart Fail. 2013 May;6(3):482-91. doi: 10.1161/CIRCHEARTFAILURE.111.000077. Epub 2013 Mar 21.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (ACTUAL): May 1, 2010
• Study Completion (ACTUAL): May 1, 2010

Study Registration Dates

• First Submitted: May 13, 2009
• First Submitted That Met QC Criteria: May 13, 2009
• First Posted (ESTIMATE): May 14, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): August 10, 2010
• Last Update Submitted That Met QC Criteria: August 9, 2010
• Last Verified: May 1, 2009

More Information

Terms related to this study

• Keywords: Cardiac output; Apelin; Renin angiotensin system; Vasodilatation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Cholinergic Agents; Cholinergic Agonists; Nitric Oxide Donors; Nitroprusside; Acetylcholine
• Other Study ID Numbers: FS/09/019/26905 - 3