Role of Endothelin-1 in Flow-mediated Dilatation

Study Overview
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Brief Summary
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Endothelial dysfunction of conduit arteries contributes to the increased morbidity and cardiovascular mortality in patients with essential hypertension and appears increasingly as an independent therapeutic target. We have shown previously that besides a decrease in the availability of NO and other endothelium-derived vasodilators factors, the epoxyeicosatrienoic acids, an increase in the vasoconstrictor endothelin-1 (ET-1) may play a role in the pathophysiology of this endothelial dysfunction. Indeed, the local concentrations of endothelin-1 during the endothelium-dependent dilation of the radial artery in response to a sustained increase in blood flow decreased significantly in healthy volunteers controls but not in hypertensive patients. This lack of adaptation of the endothelinergic system could be due to a decreased clearance of endothelin-1 by endothelial ETB receptors, potentiating the vasoconstrictor action of endothelin-1 mediated by ETA receptor activation at the muscular level. However, to validate this hypothesis , it is needed to demonstrate the physiological role of ETA receptor and ETB in sustained flow-mediated dilatation of conduit arteries.

Official Title
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Role of Endothelin-1 in Mediating Flow-mediated Dilatation of Conduit Arteries During Sustained Hyperemic Stimulation

Conditions
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Healthy Conditions

Intervention / Treatment
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* Drug: BQ-788 and/or BQ-123


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male, Caucasian, aged 18 to 35 years Non-Smoking Resting heart rate> 50 and <90 bpm SBP <140 mmHg and DBP <90 mm Hg at rest in the supine position for 10 minutes Normal ECG Exclusion Criteria: Known allergy Intolerance to glyceryl trinitrate Intolerance to lidocaine Family history of hypertension Excessive alcohol consumption ( more than 50 g / day) Addiction or presumption of illicit drug use Subject refusing blood samples for serology of hepatitis B , C and HIV History of illness or psychological or sensory abnormality that may prevent the subject to understand the requirements for participation in the protocol or prevents giving informed consent Metabolic or endocrine disease Immunological diseases Renal or hepatic impairment Ischemic or obstructive heart disease Neoplastic disease Gastrointestinal disease Neurological disease , intracranial hypertension , seizure disorders Compulsive overeating , bulimia, anorexia Severe psychiatric illness Presence of a clinically significant abnormality in laboratory tests carried out at the inclusion visit . HBs Ag , HCV Ab , Ac HIV 1 or HIV 2 positive . The use of any drug in the range of less than 5 half-life time, in particular betablockers, sildenafil, cimetidine, amiodarone .

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

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

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BQ-788<br>Effect of BQ-788 on the magnitude of sustained flow-mediated dilatation | Drug: BQ-788 and/or BQ-123<br> <br> |
| Experimental: BQ-123<br>Effect of BQ-123 on the magnitude of sustained flow-mediated dilatation | Drug: BQ-788 and/or BQ-123<br> <br> |
| Experimental: BQ-788 + BQ-123<br>Effect of BQ-788+BQ-123 on the magnitude of sustained flow-mediated dilatation | Drug: BQ-788 and/or BQ-123<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of ETB receptor blockade on flow-mediated dilatation | This study will evaluate the effect of the ETB receptor blockade on the magnitude of the flow-mediated dilatation of the radial artery in response to distal skin heating in 8 healthy subjects. Radial artery diameter and blood flow will be measured by high-resolution echotracking coupled to Doppler. | One hour after BQ-788 brachial infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of ETA and ETA/ETB receptor blockade on flow-mediated dilatation | This study will evaluate the effect of ETA receptor and combined ETA/ETB receptor blockade on the magnitude of the flow-mediated dilatation of the radial artery in response to distal skin heating in 8 healthy subjects. Radial artery diameter and blood flow will be measured by high-resolution echotracking coupled to Doppler. | One hour after BQ-123 alone or with BQ-788 brachial infusion | 
| Effect of ETA and/or ETB receptor blockade on ET-1, NO and EET bioavailability | This study will evaluate the effect of ETA and/or ETB blockade on the variations in the local concentrations of ET-1, NO and EETs during sustained flow-mediated dilation in 8 healthy subjects. For this purpose, local blood samples will be drawn before (34°C) and at the end of hand skin heating (44°C). Plasma nitrite, indicator of NO availability will be quantified by chemiluminescence.Plasma EETs will be quantified by LC-MS. Plasma ET-1 will be quantified with an immunoassay. | One hour after BQ-788 and/or BQ-123 brachial infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endothelin, endothelium, flow-mediated dilatation