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

University of Edinburgh

Status and phase: Completed; Early Phase 1

Conditions: Vasodilation; Vasoconstriction; Pulmonary Arterial Hypertension

Treatments: Drug: Placebo; Biological: Endothelin-3; Drug: Bosentan; Drug: Sitaxsentan

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT01100736

08/S1102/1

2008/W/CRC/01

Details and patient eligibility

About

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.

Enrollment: 10 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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10 participants in 3 patient groups, including a placebo group

Bosentan

Experimental group

Description:

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

Treatment:

Biological: Endothelin-3

Drug: Bosentan

Sitaxsentan

Experimental group

Description:

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

Treatment:

Biological: Endothelin-3

Drug: Placebo

Drug: Sitaxsentan

Placebo

Placebo Comparator group

Description:

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

Treatment:

Biological: Endothelin-3

Drug: Placebo