TY - JOUR

T1 - Endothelin Receptor Antagonists

T2 - Status Quo and Future Perspectives for Targeted Therapy

AU - Enevoldsen, Frederik C

AU - Sahana, Jayashree

AU - Wehland, Markus

AU - Grimm, Daniela

AU - Infanger, Manfred

AU - Krüger, Marcus

PY - 2020/3

Y1 - 2020/3

N2 - The endothelin axis, recognized for its vasoconstrictive action, plays a central role in the pathology of pulmonary arterial hypertension (PAH). Treatment with approved endothelin receptor antagonists (ERAs), such as bosentan, ambrisentan, or macitentan, slow down PAH progression and relieves symptoms. Several findings have indicated that endothelin is further involved in the pathogenesis of certain other diseases, making ERAs potentially beneficial in the treatment of various conditions. In addition to PAH, this review summarizes the use and perspectives of ERAs in cancer, renal disease, fibrotic disorders, systemic scleroderma, vasospasm, and pain management. Bosentan has proven to be effective in systemic sclerosis PAH and in decreasing the development of vasospasm-related digital ulcers. The selective ERA clazosentan has been shown to be effective in preventing cerebral vasospasm and delaying ischemic neurological deficits and new infarcts. Furthermore, in the SONAR (Study Of Diabetic Nephropathy With Atrasentan) trial, the selective ERA atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease. These data suggest atrasentan as a new therapy in the treatment of diabetic nephropathy and possibly other renal diseases. Preclinical studies regarding heart failure, cancer, and fibrotic diseases have demonstrated promising effects, but clinical trials have not yet produced measurable results. Nevertheless, the potential benefits of ERAs may not be fully realized.

AB - The endothelin axis, recognized for its vasoconstrictive action, plays a central role in the pathology of pulmonary arterial hypertension (PAH). Treatment with approved endothelin receptor antagonists (ERAs), such as bosentan, ambrisentan, or macitentan, slow down PAH progression and relieves symptoms. Several findings have indicated that endothelin is further involved in the pathogenesis of certain other diseases, making ERAs potentially beneficial in the treatment of various conditions. In addition to PAH, this review summarizes the use and perspectives of ERAs in cancer, renal disease, fibrotic disorders, systemic scleroderma, vasospasm, and pain management. Bosentan has proven to be effective in systemic sclerosis PAH and in decreasing the development of vasospasm-related digital ulcers. The selective ERA clazosentan has been shown to be effective in preventing cerebral vasospasm and delaying ischemic neurological deficits and new infarcts. Furthermore, in the SONAR (Study Of Diabetic Nephropathy With Atrasentan) trial, the selective ERA atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease. These data suggest atrasentan as a new therapy in the treatment of diabetic nephropathy and possibly other renal diseases. Preclinical studies regarding heart failure, cancer, and fibrotic diseases have demonstrated promising effects, but clinical trials have not yet produced measurable results. Nevertheless, the potential benefits of ERAs may not be fully realized.

KW - A-RECEPTOR

KW - B-RECEPTOR

KW - CONTROLLED-TRIAL

KW - ETA-RECEPTOR

KW - GROWTH-FACTOR EXPRESSION

KW - HUMAN BREAST-CANCER

KW - PULMONARY ARTERIAL-HYPERTENSION

KW - RENAL-CELL CARCINOMA

KW - SYSTEMIC-SCLEROSIS

KW - ZIBOTENTAN ZD4054

KW - ambrisentan

KW - atrasentan

KW - bosentan

KW - cancer

KW - cerebral vasospasm

KW - clazosentan

KW - fibrotic disorders

KW - macitentan

KW - pain management

KW - pulmonary arterial hypertension

KW - renal disease

KW - systemic scleroderma

KW - zibotentan

U2 - 10.3390/jcm9030824

DO - 10.3390/jcm9030824

M3 - Review

C2 - 32197449

VL - 9

JO - Journal of Clinical Medicine

JF - Journal of Clinical Medicine

SN - 2077-0383

IS - 3

M1 - 824

ER -