Role of Endothelin-A (ETA) and Endothelin-B (ETB) Receptors in the Vasodilatory Response to Endothelin-3 (ET-3)

Characterisation of the Role of ETA and ETB Receptors in Regulating Plasma ET-1 and the Vasodilator Response to ET-3 in Man

Endothelin-1 (ET-1) has been linked to a number of conditions including pulmonary arterial hypertension (PAH). ET-1 acts via 2 receptors, ETA and ETB. The ET-1 receptor blockers bosentan and sitaxsentan have been shown to be beneficial in patients with PAH. Bosentan blocks both ETA and ETB receptors. Sitaxsentan selectively blocks ETA receptors. Theoretically, selective ETA blockade may be associated with greater vasodilation and clearance of ET-1 by leaving the ETB receptor unblocked. This has not been directly studied in humans.

We aim to investigate the endothelial ETB-mediated vascular responses between bosentan and sitaxsentan by using a ETB selective agonist (ET-3). We hypothesise that at clinically relevant doses:

• Bosentan will show evidence of ETB receptor blockade compared to sitaxsentan and placebo.
• These effects will be confirmed by 2 functional markers of ETB receptor antagonism: plasma ET-1 (a very sensitive, but not necessarily clinically relevant marker), and the forearm vasodilator response to ET-3.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension; Vasodilation; Vasoconstriction
• Intervention / Treatment: Drug: Bosentan; Biological: Endothelin-3; Drug: Sitaxsentan; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Scotland
    • Edinburgh, Scotland, United Kingdom, EH4 2XU
      • Clinical Research Centre, Western General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy men and post-menopausal women
• Age 18-70 years
• BMI 18-35 kg/m2

Exclusion Criteria:

• Are mentally or legally incapacitated
• Have donated blood within the last 4 weeks
• Have a history of past or present drug or alcohol abuse
• Have participated in another clinical trial within 1 month
• Are considered to be at a high risk of HIV or Hepatitis B
• Are taking routine medicines
• Are women taking hormone replacement therapy
• Have significant medical or psychiatric illness

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bosentan; Bosentan 125mg twice daily will be taken for 7 days, before ET-1 plasma sample taken. ET-3 infusion (5mins) and associated forearm blood flow study (60 mins) will also occur after 7 days of bosentan therapy	Drug: Bosentan; Bosentan 125mg tablets, orally, twice daily for 7 days; Other Names: Tracleer; Biological: Endothelin-3; 5 minute local intra-arterial infusion of endothelin-3 at a rate of rate of 60 pmol/min, during forearm blood flow studies
Experimental: Sitaxsentan; Sitaxsentan 100mg once daily + placebo tablet will be taken for 7 days, before ET-1 plasma sample taken. ET-3 infusion (5mins) and associated forearm blood flow study (60 mins) will also occur after 7 days of sitaxsentan therapy	Biological: Endothelin-3; 5 minute local intra-arterial infusion of endothelin-3 at a rate of rate of 60 pmol/min, during forearm blood flow studies; Drug: Sitaxsentan; Sitaxsentan 100mg tablets, orally, once daily for 7 days; Other Names: Thelin; Drug: Placebo; Placebo tablets taken twice daily, orally, for 7 days (placebo arm) or once daily for 7 days (sitaxsentan arm)
Placebo Comparator: Placebo; Placebo tablet twice daily will be taken for 7 days, before ET-1 plasma sample taken. ET-3 infusion (5mins) and associated forearm blood flow study (60 mins) will also occur after 7 days of placebo therapy	Biological: Endothelin-3; 5 minute local intra-arterial infusion of endothelin-3 at a rate of rate of 60 pmol/min, during forearm blood flow studies; Drug: Placebo; Placebo tablets taken twice daily, orally, for 7 days (placebo arm) or once daily for 7 days (sitaxsentan arm)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Plasma ET-1 after 7-day administration of bosentan, sitaxsentan and placebo	7 days
Responses to ET-3 (maximum vasodilation after ET-3 administration and area under the curve of vasodilation) after bosentan compared with the results from sitaxsentan and placebo.	60 mins

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: Encysive Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: March 30, 2010
• First Submitted That Met QC Criteria: April 8, 2010
• First Posted (Estimate): April 9, 2010

Study Record Updates

• Last Update Posted (Estimate): July 21, 2015
• Last Update Submitted That Met QC Criteria: July 20, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: Bosentan; Forearm Blood Flow; Vasodilation; Sitaxsentan; Endothelin-1; Endothelin; Vasoconstriction; Regional Blood Flow; Endothelin System; Endothelin-3; Endothelin antagonists
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan; Sitaxsentan
• Other Study ID Numbers: 2008/W/CRC/01; 08/S1102/1