Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The binding characteristics and localization of bosentan, an orally active endothelin-1 (ET-1) antagonist, were studied on sections of human coronary artery by in vitro autoradiography. Competition studies were performed to determine the ability of bosentan to prevent [125I]ET-1 binding to the coronary vasculature. The effects of bosentan on ET-1-induced contraction of the coronary artery were also studied in vitro. [3H]Bosentan bound to the tunica media of the human coronary artery. Unlabeled bosentan prevented [125I]ET-1 binding to this vessel in a concentration-dependent manner, and functional studies indicated that bosentan antagonizes ET-1--induced constriction. These data show that bosentan is able to reduce ET-1 binding to the human coronary artery and ET-1 constrictor effects in vitro. Bosentan is an orally active ET-1 antagonist, and these results suggest that this compound might be used to block the effects of locally released ET-1 in pathologic conditions, such as atherosclerosis, angina, and myocardial ischemia.
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PMID:[3H]bosentan binding to human coronary artery: functional correlates. 858 20

The contribution of endothelin to the genesis of neointimal development in collared rabbit carotid arteries, a widely accepted model of atherosclerosis, was investigated. Three sets of rabbits were studied. In the first group, a non-occlusive, biologically inert silastic collar was positioned around the right carotid artery of the rabbit. In another group, the application of the collar was accompanied by endothelial denudation via a Fogarty arterial balloon catheter, while the third group of animals underwent only endothelial denudation. After two weeks, intimal hyperplasia of a similar degree was observed in all groups. The administration of the nonselective ET(A)/ET(B) receptor antagonist Bosentan, significantly reduced both the neointimal area and the intima/media area ratio in all groups. However, the beneficial effects of Bosentan were less pronounced in balloon injured vessels than in collared ones. The results of the present study indicate that i) endothelin has a key role in the development of intimal hyperplasia following arterial collaring, ii) the contribution of endothelin to intimal hyperplasia is greater in collared arteries that in balloon injured ones, and iii) the nonselective ET(A)/ET(B) receptor antagonists are potential tools for the prevention of intimal hyperplasia.
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PMID:ET(A)/ET(B) receptor antagonist bosentan inhibits neointimal development in collared carotid arteries of rabbits. 980 21

Endothelins (ETs) are potent vasoconstrictor peptides and are associated with several disease states like pulmonary hypertension, systemic hypertension and heart failure. Endothelin-1 (ET-1) is the first member of the family and it has the receptor subtypes known as ETA and ETB. The receptors ETA and ETB are attractive new therapeutic targets for diseases associated with elevated ET-1 levels. Several studies have thus led to the discovery of selective ETA receptor antagonists as well as non-selective ETA/ETB antagonists. The preclinical and clinical studies have clearly established that these antagonists are effective in the treatment of essential hypertension, pulmonary hypertension, heart failure and atherosclerosis. The advances in this area have resulted in the FDA approval of the orally active dual antagonist Bosentan for pulmonary hypertension in 2001. This review highlights the synthesis and structure-activity of the endothelin receptor antagonists and covers the literature in this area up to 2001.
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PMID:Endothelin receptor antagonists: an overview of their synthesis and structure-activity relationship. 1585 28

In humans, the endothelins (ETs) comprise a family of three 21-amino-acid peptides, ET-1, ET-2 and ET-3. ET-1 is synthesised from a biologically inactive precursor, Big ET-1, by an unusual hydrolysis of the Trp21 -Val22 bond by the endothelin converting enzyme (ECE-1). In humans, there are four isoforms (ECE-1a-d) derived from a single gene by the action of alternative promoters. Structurally, they differ only in the amino acid sequence of the extreme N-terminus. A second enzyme, ECE-2, also exists as four isoforms and differs from ECE-1 in requiring an acidic pH for optimal activity. Human chymase can also cleave Big ET-1 to ET-1, which is cleaved, in turn, to the mature peptide as an alternative pathway. ET-1 is the principal isoform in the human cardiovascular system and remains one of the most potent constrictors of human vessels discovered. ET-1 is unusual in being released from a dual secretory pathway. The peptide is continuously released from vascular endothelial cells by the constitutive pathway, producing intense constriction of the underlying smooth muscle and contributing to the maintenance of endogenous vascular tone. ET-1 is also released from endothelial cell-specific storage granules (Weibel-Palade bodies) in response to external stimuli. ETs mediate their action by activating two G protein-coupled receptor sub-types, ETA and ET(B). Two therapeutic strategies have emerged to oppose the actions of ET-1, namely inhibition of the synthetic enzyme by combined ECE/neutral endopeptidase inhibitors such as SLV306, and receptor antagonists such as bosentan. The ET system is up-regulated in atherosclerosis, and ET antagonists may be of benefit in reducing blood pressure in essential hypertension. Bosentan, the first ET antagonist approved for clinical use, represents a significant new therapeutic strategy in the treatment of pulmonary arterial hypertension (PAH).
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PMID:Endothelin. 1699 23

Pulmonary hypertension in systemic sclerosis appears in up to 35% of patients, is characterized by increased pulmonary artery resistance, and carries a poorer prognosis than in patients with other causes of pulmonary hypertension. The recommended therapy for stage III disease, based on clinical trials and by the Israeli Ministry of Health for 2006, includes bosentan (Tracleer), an endothelin-1 antagonist. This is a case report of a patient with severe pulmonary hypertension secondary to systemic sclerosis where therapy with prostacyclins was contraindicated due to the development of congestive heart failure and severe atherosclerosis. The patient responded well to bosentan monotherapy for 4 years until his death.
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PMID:[Long-term therapy with endothelin-1 antagonist for pulmonary hypertension secondary to systemic sclerosis]. 1868 6