Endothelin+receptor+antagonists

__General Pharmacology__ 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 for 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.
 * Endothelin Receptor Antagonists**