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Cardiovascular Pharmacology Concepts

Richard E. Klabunde, PhD

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Endothelin Receptor Antagonists

General Pharmacology

Endothelin-1 formation, receptors and mechanisms of action in blood vessels

Endothelin-1 (ET-1) is a 21 amino acid peptide that is produced by the vascular endothelium (click here for details). It is a very potent vasoconstrictor that binds to smooth muscle endothelin receptors, of which there are two subtypes: ETA and ETB receptors. These receptors are coupled to a Gq-protein and receptor activation leads to the formation of IP3, which causes the release of calcium by the sarcoplasmic reticulum (SR) and increased smooth muscle contraction and vasoconstriction. There are also ETB receptors located on the endothelium that stimulate the formation of nitric oxide, which produces vasodilation in the absence of smooth muscle ETA and ETB receptor activation. This receptor distribution helps to explain the phenomenon that ET-1 administration causes transient vasodilation (initial endothelial ETB activation) and hypotension, followed by prolong vasoconstriction (smooth muscle ETA and ETB activation) and hypertension.

ET-1 receptors in the heart are also linked to the Gq-protein and IP3 signal transduction pathway (click here for details). Therefore, ET-1 in the heart causes SR release of calcium, which increases contractility. ET-1 also increases heart rate.

Therapeutic Indications

Because of its powerful vasoconstrictor properties, and its effects on intracellular calcium, ET-1 has been implicated in the pathogenesis of hypertension, coronary vasospasm, and heart failure. A number of studies suggest a role for ET-1 in pulmonary hypertension, as well as in systemic hypertension. ET-1 has been shown to be released by the failing myocardium where it can contribute to cardiac calcium overload and hypertrophy.

Endothelin receptor antagonists, by blocking the vasoconstrictor and cardiotonic effects of ET-1, produce vasodilation and cardiac inhibition. Endothelin receptor antagonists have been shown to decrease mortality and improve hemodynamics in experimental models of heart failure.

At present, the one approved indication for endothelin antagonists is pulmonary hypertension.

Specific Drugs

One endothelin receptor antagonist has been approved. Bosentan, a non-selective ET-1 receptor antagonist (blocks ETA and ETB receptors) is currently used in the treatment of pulmonary hypertension. (Go to www.rxlist.com for detailed information on bosentan)

Side Effects and Contraindications

Some of bosentan's side effects are common to most vasodilators; namely, headache, cutaneous flushing, and edema formation. Bosentan may cause birth defects and therefore is contraindicated in pregnancy. It also can cause liver injury.

Revised 03/15/07

DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.