Role of Endothelin-1 in Flow-mediated Dilatation (Endothelin)

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Conditions
• Intervention / Treatment: Drug: BQ-788 and/or BQ-123

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Normandy
    • Rouen, Normandy, France, 76031
      • CHU - Hôpitaux de Rouen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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 .

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Rouen
• Investigators: Principal Investigator: Robinson JOANNIDES, Doctor, CHU - Hôpitaux de Rouen

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: February 18, 2014
• First Submitted That Met QC Criteria: March 11, 2014
• First Posted (Estimate): March 13, 2014

Study Record Updates

• Last Update Posted (Estimate): March 24, 2015
• Last Update Submitted That Met QC Criteria: March 23, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Endothelin, endothelium, flow-mediated dilatation
• Additional Relevant MeSH Terms: Pathological Conditions, Anatomical; Dilatation, Pathologic; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Endothelin B Receptor Antagonists; BQ 788
• Other Study ID Numbers: 2013/161/HP; 2013-004425-87 (EudraCT Number)