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

Early Phase 1CompletedNCT01100736

University of Edinburgh10 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

TRIPLE

Enrollment

Conditions

Pulmonary Arterial Hypertension Vasodilation Vasoconstriction

Interventions

BosentanDRUG

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

SitaxsentanDRUG

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

PlaceboDRUG

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

Endothelin-3BIOLOGICAL

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

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Plasma ET-1 after 7-day administration of bosentan, sitaxsentan and placebo

Time frame: 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.

Time frame: 60 mins