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

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ClinicalTrials.gov Identifier: NCT02086253
Recruitment Status : Completed
First Posted : March 13, 2014
Last Update Posted : March 24, 2015
Sponsor:
Information provided by (Responsible Party):
University Hospital, Rouen

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Healthy Conditions Drug: BQ-788 and/or BQ-123 Not Applicable

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Official Title: Role of Endothelin-1 in Mediating Flow-mediated Dilatation of Conduit Arteries During Sustained Hyperemic Stimulation
Study Start Date : February 2014
Actual Primary Completion Date : May 2014
Actual Study Completion Date : May 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Aneurysms

Arms and Interventions
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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


Outcome Measures
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Primary Outcome Measures :
  1. Effect of ETB receptor blockade on flow-mediated dilatation [ Time Frame: One hour after BQ-788 brachial infusion ]
    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.


Secondary Outcome Measures :
  1. Effect of ETA and ETA/ETB receptor blockade on flow-mediated dilatation [ Time Frame: One hour after BQ-123 alone or with BQ-788 brachial infusion ]
    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.

  2. Effect of ETA and/or ETB receptor blockade on ET-1, NO and EET bioavailability [ Time Frame: One hour after BQ-788 and/or BQ-123 brachial infusion ]
    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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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 .
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02086253


Locations
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France
CHU - Hôpitaux de Rouen
Rouen, Normandy, France, 76031
Sponsors and Collaborators
University Hospital, Rouen
Investigators
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Principal Investigator: Robinson JOANNIDES, Doctor Chu - Hôpitaux de Rouen
More Information
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Responsible Party: University Hospital, Rouen
ClinicalTrials.gov Identifier: NCT02086253     History of Changes
Other Study ID Numbers: 2013/161/HP
2013-004425-87 ( EudraCT Number )
First Posted: March 13, 2014    Key Record Dates
Last Update Posted: March 24, 2015
Last Verified: March 2015
Keywords provided by University Hospital, Rouen:
Endothelin, endothelium, flow-mediated dilatation
Additional relevant MeSH terms:
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Aneurysm
Dilatation, Pathologic
Vascular Diseases
Cardiovascular Diseases
Pathological Conditions, Anatomical
cyclo(Trp-Asp-Pro-Val-Leu)
 BQ 788
Antihypertensive Agents
Endothelin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Endothelin B Receptor Antagonists