Animal models cardiovascular systems

Comparative Toxicokinetics. In humans, the targets for trichloroethylene toxicity are the liver, kidney, cardiovascular system, and nervous system. Experimental animal studies support this conclusion, although the susceptibilities of some targets, such as the liver, appear to differ between rats and mice. The fact that these two species could exhibit such different effects allows us to question which species is an appropriate model for humans. A similar situation occurred in the cancer studies, where results in rats and mice had different outcomes. The critical issue appears to be differences in metabolism of trichloroethylene across species (Andersen et al. 1980 Buben and O Flaherty 1985 Filser and Bolt 1979 Prout et al. 1985 Stott et al. 1982). Further studies relating the metabolism of humans to those of rats and mice are needed to confirm the basis for differences in species and sex susceptibility to trichloroethylene s toxic effects and in estimating human heath effects from animal data. Development and validation of PBPK models is one approach to interspecies comparisons of data. 

Ospemifene is a novel third-generation SERM that in animal models has been shown to have agonistic effects on bone and the cardiovascular system and antagonistic effects in uterus and breast. 

Comparative Toxicokinetics. The metabolism and excretion of orally administered phenol in 18 animal species have been compared to metabolism and excretion in humans (Capel et al. 1972). The rat was the most similar to the human with respect to the fraction of administered dose excreted in urine in 24 hours (95%) and the number and relative abundance of the 4 principal metabolites excreted in urine (sulfate and glucuronide conjugates of phenol and 1,4-dihydroxybenzene). The rat excreted a larger fraction of the orally administered dose than the guinea pig or the rabbit (Capel et al. 1972) and appears to be the least susceptible of the three species to respiratory, cardiovascular, hepatic, renal, and neurological effects of inhaled phenol (Deichmann et al. 1944). More rapid metabolism and excretion of absorbed phenol may account for the lower sensitivity of the rat to systemic effects of phenol. More information on the relative rates of metabolism of phenol in various species is needed to identify the most appropriate animal model for studying potential health effects in humans. 

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. 

The hemodynamic effects of compounds supposed to affect the cardiovascular system are evaluated by measuring preload and afterload of the heart, contractility, heart rate, cardiac output and peripheral or coronary flow. To measure these cardiovascular parameters accurately, the use of larger animals such as dogs or pigs is necessary. This experimental model allows the classification of test drugs according to their action as having ... 

Symptoms of toxicity are related to the cardiovascular, gastrointestinal, and neurological systems. These include bradycardia, ventricular tachycardia, nausea, and vomiting. Paresthesias of the extremities and generalized weakness have been reported. Rarely, seizures may occur in humans. This symptom is more commonly seen in animal models. 

Interestingly, many more lycopene-based studies have been conducted in animal models or in human subjects rather than in cell culture. The explanation for this may be seen as two-fold. Firstly, because of the high lipophilic nature of lycopene, it is most commonly solubilized in tetrahydrofuran, which, in itself, is toxic to cells. Second, since lycopene, a phytochemical, is a natural product and, in most studies, was either supplied to subjects in its natural form (tomato juice, etc.) rather than supplements or indirectly deduced from dietary questioimaires, ethical committee approval was relatively easy to obtain. Substantial evidence has been produced relating the consumption of lycopene to a decreased risk of acquiring degenerative diseases, such as certain kinds of cancers and cardiovascular disease. In addition, the usefulness of lycopene has, on several accounts, been shown in the treatment of cancers. Thus it becomes increasingly important to understand in detail the molecular mechanism of action of lycopene in varions model cell systems. 

In our opinion, the model of choice to study a genetic defrciency is a knockout model. This implies that the model animal has to be a mouse, since only in murine embryonic stem cells it has been possible to efficiently create tiie desired genetic alterations while pertaining fliese cells pluripotent, a prerequisite for proper embryonic development. Thus, in contrast to transgenic model systems, which in principle can be generated in any mammalian qrecies by means of oocyte microinjection, tbe choice of animal for knockout studies is limited to the mouse. Techniques to analyse cardiovascular function are well developed for larger animal models, and some of these are now modified for the small size of the mouse heart and for the animal s rapid cardiac cycle. ... 

To study CAVD in a controlled system, animal models of valvular dysfunction are utilized in the laboratory setting. The same principles used to diagnose AS in humans may be applied in the study of the progression of this disease in a wide array of animal models. Valvular cells extracted from bovine sources have been widely used due to the ease of extraction and because the structure of the bovine aortic valve is similar to the human aortic valve [65-67]. Porcine models have been utilized to a large extent for studies of the aortic valve, since the heart and cardiovascular system are nearer in size to the human equivalents [68-70]. A relevant porcine model for aortic valve calcification has been developed by Balachandran et al [71] in which the effects of cyclic stretch were studied using porcine aortic valve leaflets in a unidirectional stretch bioreactor. Calcification was significantly... 

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