Endothelin animal models

Since the early 1980s, much effort has focused on animal models of acute and chronic neurodegeneration in search of therapeutics for stroke. Neuronal cell death follows strokes, acute ischemic insults, and chronic neurodegeneration, such as Parkinson s disease, Alzheimer s disease (AD), epilepsy, and Huntington s disease. Up to 80% of all strokes result from focal infarcts and ischemia in the middle cerebral artery (MCA), so the commonly used animal models for neuroprotection are produced by temporary or permanent occlusion of the MCA.5 Lesions of the MCA include occlusion by electrocoagulation, intraluminal monofilaments, photochemical effects, thrombosis, and endothelin-1, but all of these models necessitate studying reperfusion events and validating MCA occlusion by behavioral assessments. 

Bosentan and tezosentan, orally active competitive inhibitors of endothelin (see Chapter 17), have been shown to have some benefits in experimental animal models with heart failure, but results in human trials have been disappointing. Bosentan is approved for use in pulmonary hypertension (see Chapter 11). It has significant teratogenic and hepatotoxic effects. 

Studies in animal models using endothelin antibodies are now being reported. Miyamori et al. demonstrated in rabbits [163] that endothelin antibody administration failed to show any appreciable changes in systemic or renal haemodynamic parameters suggesting that endothelin in the circulation may not contribute to blood pressure maintenance under normal conditions. However, its role as a local modulator is as yet not defined. 

Endothelin may also have a role in ischaemic stroke. Endothelin, released after ischaemia caused by thrombo-embolic occlusion of a cerebral vessel, could propagate further infarction by constricting the collateral circulation. Much less information is available on endothelin in ischaemic stroke but endothelin levels are raised in animal models of focal ischaemia [183] and in ischaemic stroke patients [184]. 

A variety of vasoactive substances may modulate the CM-induced vasoconstriction, including prostaglandins, ANF, adenosine, endothelin, vasopressin, noradrenahne and angiotensin [53A, 55]. Of particular interest has been the possible role of superoxide radicals in the pathogenesis of CMIN. Not only do they induce renal vasoconstriction, but, as noted above, they also cause direct renal cell injury. Superoxide dismutase prevents the fall in GFR associated with CM, while in a dehydrated animal model, renal levels of superoxide dismutase is diminished which may account for the demonstrated increased susceptibility to... 

BQ 123 is a cyclic pentapeptide, which acts as a subtype-selective (ETa) endothelin receptor antagonist. It shows cardioprotective effects in an animal model of nryocardial infarction. It is used as a pharmacological tool. 

Restenosis occurring after balloon angioplasty and coronary artery stent implantation is characterized by an extensive neoin-timal proliferation of vascular smooth muscle cells and the formation of extracellular matrix [38, 39]. This change in smooth muscle cell phenotype from a contractile to a synthetic state was shown to be correlated with an increased synthesis of the potent mitogen endothelin-1 (ET-1) in the vessel wall [40]. Increased synthesis of ET-1 has been demonstrated to occur after pressure trauma to the vessel wall in experimental animal models and in hu-... 

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