Cardiovascular disease animal models

Phytochemicals have been the subject of many studies evaluating their effects in relation to common chronic human illnesses such as cancer and cardiovascular diseases. These studies encounter difficulties in using this information to influence the dietary patterns of consumers because in the past they have used models or experiments with animals. However, in the last decade, researchers have moved away from animal studies in favour of human cell models or human intervention studies. Scientists still need to determine the likely incidence of illness from exposure to known amounts of a given natural compound in the diet and specifically in relation to the complex matrices of whole foods. Therefore, it is inevitable that some animal studies have to be continued for toxicological studies. 

As in the case of other cardiovascular diseases, the possibility of antioxidant treatment of diabetes mellitus has been studied in both animal models and diabetic patients. The treatment of streptozotocin-induced diabetic rats with a-lipoic acid reduced superoxide production by aorta and superoxide and peroxynitrite formation by arterioles providing circulation to the region of the sciatic nerve, suppressed lipid peroxidation in serum, and improved lens glutathione level [131]. In contrast, hydroxyethyl starch desferrioxamine had no effect on the markers of oxidative stress in diabetic rats. Lipoic acid also suppressed hyperglycemia and mitochondrial superoxide generation in hearts of glucose-treated rats [132],... 

Whole animal studies are generally necessary to determine the effect of the drug on organ systems and disease models. Cardiovascular and renal function studies of all new drugs are generally first performed in normal animals. Where appropriate, studies on disease models are performed. For a candidate antihypertensive drug, animals with hypertension would be treated to see whether blood pressure was lowered in a dose-related manner and to characterize other effects of the compound. Evidence would be collected on duration of action and efficacy after oral and parenteral administration. 

Selective B2 agonists are under study and have been shown to be effective in some animal models of human cardiovascular disease. 

Although they remain less effective than inhaled corticosteroids, a 5-LOX inhibitor (zileuton) and selective antagonists of the CysLTl receptor for leukotrienes (zafirlukast, montelukast, and pranlukast see Chapter 20) are used clinically in mild to moderate asthma. Growing evidence for a role of the leukotrienes in cardiovascular disease has expanded the potential clinical applications of leukotriene modifiers. Conflicting data have been reported in animal studies depending on the disease model used and the molecular target (5-LOX versus FLAP). Human genetic studies have demonstrated a link between cardiovascular disease and polymorphisms in the leukotriene biosynthetic enzymes, in particular FLAP, in some populations. 

There is evidence that by acting on B2 receptors, bradykinin may play a beneficial, protective role in cardiovascular disease. Selective B2 agonists are available and have been shown to be effective in some animal models of human cardiovascular disease. These drugs may have potential for the treatment of hypertension and myocardial hypertrophy. 

Of these, omapatrilat is at the most advanced stage of clinical development. It 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. Nevertheless, combined inhibition of neutral endopeptidase NEP 24.11 and ACE with this new class of drugs may be a promising approach to treat cardiovascular disease and further clinical trials are underway. 

Elevated TAFI levels have been found in men with symptomatic coronary artery disease (142). TAFI is also reported to be a risk factor for deep venous thrombosis, A recent report on the high levels of TAFI in the acute phase of ischemic stroke revealed not only elevated levels but also an incremental increase in TAFI with the degree of neurologic deterioration (143). Therefore, the observation by Boffa et al. on the acute phase nature of this protein requires further validation, In addition, Juhan-Vague et al, stated that there is a correlation between TAFI levels and cardiovascular risk factors (144). Animal models may be needed to truly validate studies on TAFI upregulation and its relation to thrombosis. 

Candidate genes can be selected using a variety of approaches such as literature searches, genes resulting from experiments in animal models, homology searches, and gene expression experiments. Studies testing even dozens of candidates at once exist for many complex diseases cardiovascular disease (83), osteoarthritis (84), and asthma (85) to name a few. 

Angiogenesis for cardiovascular disease. Angiogenesis represents an excellent therapeutic target for the treatment of cardiovascular disease, namely the production of new collateral vessels to overcome the ischaemic insult. However, despite the large number of pre-clinical trials in animal models of cardiac ischaemia, no therapy designed to stimulate angiogenesis in underperfused tissue has yet become viable in man. 

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