Inhibitors of Endothelin Synthesis & Action

INHIBITORS OF ENDOTHELIN SYNTHESIS & ACTION

The endothelin system can be blocked with receptor antagonists and drugs that block endothelin-converting enzyme. Endothelin ET_A or ET_B receptors can be blocked selectively, or both can be blocked with nonselective ET_A-ET_B antagonists.

Bosentan is a nonselective receptor blocker. It is active orally,and blocks both the initial transient depressor (ET_B) and the pro-longed pressor (ET_A) responses to intravenous endothelin. Many orally active endothelin receptor antagonists with increased selec-tivity have been developed and are available for research use. Examples include the selective ET_A antagonists ambrisentan, which has been approved by the Food and Drug Administration to treat pulmonary artery hypertension, and sitaxsentan.

The formation of endothelins can be blocked by inhibiting endothelin-converting enzyme with phosphoramidon. Phospho-ramidon is not specific for endothelin-converting enzyme, but more selective inhibitors including CGS35066 are now available for research. Although the therapeutic potential of these drugs appeared similar to that of the endothelin receptor antagonists , their use has been eclipsed by endothelin antagonists.

Physiologic & Pathologic Roles of Endothelin: Effects of Endothelin

Antagonists

Systemic administration of endothelin receptor antagonists or endothelin-converting enzyme inhibitors causes vasodilation and decreases arterial pressure in humans and experimental animals. Intra-arterial administration of the drugs also causes slow-onset forearm vasodilation in humans. These observations provide evidence that the endothelin system participates in the regulation of vascular tone, even under resting conditions. The activity of the system is higher in males than in females. It increases with age, an effect that can be counteracted by regular aerobic exercise.

Increased production of ET-1 has been implicated in a variety of cardiovascular diseases, including hypertension, cardiac hyper-trophy, heart failure, atherosclerosis, coronary artery disease, and myocardial infarction. ET-1 also participates in pulmonary dis-eases, including asthma and pulmonary hypertension; renal dis-eases; and several malignancies, including ovarian cancer.

Endothelin antagonists have considerable potential for the treatment of these diseases. Indeed, endothelin antagonism with bosentan, sitaxsentan, and ambrisentan has proved to be a moderately effective and generally well-tolerated treatment for patients with pulmonary arterial hypertension, an important condition with few effective treatments. Other promising targets for these drugs are resistant hypertension, chronic renal disease, connective tissue disease, and subarachnoid hemorrhage. On the other hand, clinical trials of the drugs in the treatment of congestive heart failure have been disappointing.

Endothelin antagonists occasionally cause systemic hypotension, increased heart rate, facial flushing or edema, and headaches. Potential gastrointestinal effects include nausea, vomiting, andconstipation. Because of their teratogenic effects, endothelin antag-onists are contraindicated in pregnancy. Bosentan has been associated with fatal hepatotoxicity, and patients taking this drug must have monthly liver function tests. Negative pregnancy test results are required for women of child-bearing age to take this drug.