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

Study Overview
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Brief Summary
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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.

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

Conditions
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Heart Disease, Heart Failure, Vasodilatation

Intervention / Treatment
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* Drug: Apelin
* Drug: Acetylcholine
* Drug: Sodium nitroprusside
* Drug: Systemic apelin infusion


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sodium depletion<br>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<br>* Using the technique of venous occlusive plethysmography subjects will receive three intrabrachial apelin infusions at 0.3, 1.0 and 3.0 nanomol/ml.<br>Drug: Acetylcholine<br>* Using the technique of venous occlusive plethysmography subjects will receive three intrabrachial acetylcholine infusions at 5, 10 and 20 microg/min<br>Drug: Sodium nitroprusside<br>* Using the technique of venous occlusive plethysmography subjects will receive three intrabrachial acetylcholine infusions at 1, 2 and 4 microg/min<br>Drug: Systemic apelin infusion<br>* 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.<br>|
| Placebo Comparator: Normal diet<br>Subjects will be randomised to a normal diet, with no restriction on sodium intake during the three days prior to the study. | Drug: Apelin<br>* Using the technique of venous occlusive plethysmography subjects will receive three intrabrachial apelin infusions at 0.3, 1.0 and 3.0 nanomol/ml.<br>Drug: Acetylcholine<br>* Using the technique of venous occlusive plethysmography subjects will receive three intrabrachial acetylcholine infusions at 5, 10 and 20 microg/min<br>Drug: Sodium nitroprusside<br>* Using the technique of venous occlusive plethysmography subjects will receive three intrabrachial acetylcholine infusions at 1, 2 and 4 microg/min<br>Drug: Systemic apelin infusion<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renin angiotensin system, Apelin, Cardiac output, Vasodilatation