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

Early Phase 1

Completed

• Conditions: Vasoconstriction; Pulmonary Arterial Hypertension; Vasodilation
• Interventions: Drug: Placebo; Drug: Sitaxsentan; Drug: Bosentan; Biological: Endothelin-3

• Registration Number: NCT01100736
• Lead Sponsor: University of Edinburgh

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2009-01
• Primary Completion: 2009-09
• Study Completion: 2010-01
• Study First Submitted: 2010-03-30
• Study First Submitted QC: 2010-04-08
• Study First Posted: 2010-04-09
• Status Verified: 2015-07
• Last Update Submitted: 2015-07-20
• Last Update Posted: 2015-07-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Bosentan	Endothelin-3	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
Placebo	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
Sitaxsentan	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
Sitaxsentan	Placebo	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
Placebo	Endothelin-3	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
Sitaxsentan	Endothelin-3	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
Bosentan	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

Primary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (1)

Clinical Research Centre, Western General Hospital; 🇬🇧 Edinburgh, Scotland, United Kingdom