Endothelin and subarachnoid hemorrhage-induced cerebral vasospasm: pathogenesis and treatment.
Endothelin (ET)-mediated vasoconstriction has been implicated in the pathophysiology of various disorders, e.g. hypertension, chronic heart failure, acute renal failure, pulmonary hypertension, and subarachnoid hemorrhage (SAH)-induced cerebral vasospasm. The potential involvement of ETs in cerebral vasospasm following SAH has triggered considerable interest in designing therapeutic strategies to inhibit biological effects of ET. Major approaches include: (a) reducing the levels of circulating ET- 1 by the the specific anti- ET- 1 antibodies, (b) antagonizing the ET receptors, and (c) suppressing the biosynthesis of ET-1. To date, numerous antagonists of ET(A) and/or ET(B) receptors have been discovered, and some are under clinical evaluation. Inhibitors of endothelin-converting enzymes (ECEs), which catalyze the biosynthesis of ET-1, have also been synthesized. Two types of ECE-1 inhibitors have been evaluated in various animal disease models: dual ECE-1/neutral endopeptidase 24.11 (NEP) inhibitors and selective ECE-1 inhibitors. In this article, the effects of ET receptor antagonists and ECE-1 inhibitors on the prevention and reversal of SAH-induced cerebral vasospasm in preclinical animal models are reviewed.
Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University, Taiwan, Republic of China.
Chih-Lung
CL
Lin
Arco Y
AY
Jeng
Shen-Long
SL
Howng
Aij-Lie
AL
Kwan
D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D008666:Metalloendopeptidases; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology*
D018663:Adrenergic Agents; D019332:Endothelin-1; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes