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

Status

Completed

Phases

Early Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01100736

Enrollment

Registered

2010-04-09

Start date

2009-01-31

Completion date

2010-01-31

Last updated

2015-07-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pulmonary Arterial Hypertension, Vasoconstriction, Vasodilation

Keywords

Forearm Blood Flow, Vasodilation, Vasoconstriction, Endothelin System, Endothelin-1, Endothelin-3, Endothelin antagonists, Bosentan, Sitaxsentan, Endothelin, Regional Blood Flow

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.

Interventions

DRUGBosentan

Bosentan 125mg tablets, orally, twice daily for 7 days

DRUGSitaxsentan

Sitaxsentan 100mg tablets, orally, once daily for 7 days

DRUGPlacebo

Placebo tablets taken twice daily, orally, for 7 days (placebo arm) or once daily for 7 days (sitaxsentan arm)

BIOLOGICALEndothelin-3

5 minute local intra-arterial infusion of endothelin-3 at a rate of rate of 60 pmol/min, during forearm blood flow studies

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

BASIC_SCIENCE

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Yes

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

Design outcomes

Primary

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

Countries

United Kingdom

Outcome results

None listed

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026