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.

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