Heart failure, animal models

R563 R. Tian and J. S. Ingwall, The Molecular Energetics of the Failing Heart from Animal Models - Small Animal Models , Heart Failure Rev., 1999, 4, 245... 

The disturbance of balance between superoxide and nitric oxide occurs in a variety of common disease states. For example, altered endothelium-dependent vascular relaxation due to a decrease in NO formation has been shown in animal models of hypertension, diabetes, cigarette smoking, and heart failure [21]. Miller et al. [22] suggested that a chronic animal model atherosclerosis closely resembles the severity of atherosclerosis in patients. On the whole, the results obtained in humans, for example, in hypertensive patients [23] correspond well to animal experiments. It is important that endothelium-dependent vascular relaxation in patients may be improved by ascorbic acid probably through the reaction with superoxide. 

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. 

Recently developed vasopeptidase inhibitors include omapatrilat, sampatrilat, and fasidotrilat. Omapatrilat, which has received the most attention, lowers blood pressure in animal models of hypertension as well as in hypertensive patients, and improves cardiac function in patients with heart failure. Unfortunately, omapatrilat causes a significant incidence of angioedema in addition to cough and dizziness and has not been approved for clinical use. 

Penney DG. Acute carbon monoxide poisoning animal model A review. Toxicology 1990 62 123. Penny DG. A review Hemodynamic response to carbon monoxide. Environ Health Perspect 1988 77 121. Rocco TP, Fang JC. Pharmacological treatment of heart failure. In Brunton L, Lazo J, Parker K, eds. 

There are four gel protein databases of cardiac proteins, established by three independent groups, that can be accessed via the World Wide Web (Table 16.1). These databases facilitate proteomic research into heart diseases containing information on several hundred cardiac proteins that have been identified by protein chemical methods. They all conform to the rules for federated 2-D protein databases (Appel et al., 1996). In addition, 2-D protein databases for other mammals, such as the mouse, rat (li et al., 1999), dog (Dimn et al., 1997), pig and cow, are also under construction to support work on animal models of heart disease and heart failure. 

Antagonistic effects of cyclo-oxygenase inhibitors (indo-metacin or aspirin) have been repeatedly reported both in hypertension and in heart failure, strongly suggesting that there may be prostaglandin participation in the clinical response to ACE inhibitors (103,104). In animals, although not in all experimental models, aspirin can attenuate the beneficial effects of ACE inhibitors on ventricular remodelling after myocardial infarction. 

PrARs couple to the stimulatory Gs protein in both adult and neonatal myocytes, which leads to activation of adenylyl cyclase and production of cAMP (Fig. 1). In adult myocytes, the cAMP-dependent PKA phosphorylates various substrates, including the L-type Ca2+ channel, which increases Ca2+ entry into cells. PKA-mediated phosphorylation of phospholamban accelerates Ca2+ sequestration into the sarcoplasmic reticulum, resulting in accelerated cardiac relaxation (17). PKA-mediated phosphorylation of troponin I and C proteins reduces myofilament sensitivity to Ca2+ (17). The ryanodine receptor is also a substrate for PKA ryanodine receptor hyperphosphorylation has been observed in the failing human heart and in animal models of heart failure (58,59). Both in vivo and in vitro assays showed that the prAR plays the predominant role in modulating the rate and force of myocyte contraction in the mouse (24,30,55). 

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