Role of Endothelin-1 in Mediating Flow-mediated Dilatation of Conduit Arteries During Sustained Hyperemic Stimulation
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Sponsor
- Enrollment
- 8
- Locations
- 2
- Primary Endpoint
- Effect of ETB receptor blockade on flow-mediated dilatation
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Other
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 35 Years (Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- Yes
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 .
Arms & Interventions
BQ-788
Effect of BQ-788 on the magnitude of sustained flow-mediated dilatation
Intervention: BQ-788 and/or BQ-123 (Drug)
BQ-123
Effect of BQ-123 on the magnitude of sustained flow-mediated dilatation
Intervention: BQ-788 and/or BQ-123 (Drug)
BQ-788 + BQ-123
Effect of BQ-788+BQ-123 on the magnitude of sustained flow-mediated dilatation
Intervention: BQ-788 and/or BQ-123 (Drug)
Outcomes
Primary Outcomes
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 Outcomes
- Effect of ETA and/or ETB receptor blockade on ET-1, NO and EET bioavailability(One hour after BQ-788 and/or BQ-123 brachial infusion)
- Effect of ETA and ETA/ETB receptor blockade on flow-mediated dilatation(One hour after BQ-123 alone or with BQ-788 brachial infusion)