Chloral hydrate cardiotoxicity in adult and neonatal rabbit hearts
| dc.contributor.committeeMember | Hindmarsch, Kenneth | en_US |
| dc.creator | Fandrey, Sheri Lynne | en_US |
| dc.date.accessioned | 2004-10-21T00:02:49Z | en_US |
| dc.date.accessioned | 2013-01-04T05:02:47Z | |
| dc.date.available | 1997-01-01T08:00:00Z | en_US |
| dc.date.available | 2013-01-04T05:02:47Z | |
| dc.date.created | 1997-01 | en_US |
| dc.date.issued | 1997-01-01 | en_US |
| dc.date.submitted | January 1997 | en_US |
| dc.description.abstract | Chloral hydrate (CH) is one of the most commonly used sedative-hypnotic agents in pediatric patients. Previous investigations led to the concern that accumulation of chloral hydrate metabolites trichloroethanol (TCE) or trichloroacetic acid (TCA) in neonatal patients may have toxic potential. Of particular concern is the possibility that CH, TCE and/or TCA may contribute to the development of cardiac arrhythmias in this population. The present investigation has focused, using an in vitro rabbit heart model, on the mechanism and developmental aspects of cardiotoxicity of clinically relevant concentrations of CH, TCE and TCA. The results show that CH, TCE and TCA are general cardiac depressants in the isolated perfused adult rabbit heart. In the adult rabbit heart, all three compounds depressed coronary flow, contractility, and myocardial oxygen consumption over the range of concentrations tested. CH and its metabolites also caused conduction defects which are consistent with atrio-ventricular and intra-ventricular conduction delays. This type of phenomenon is involved in the development of re-entrant cardiac arrhythmias. A number of arrhythmias, including atrial and ventricular fibrillation, were observed in the hearts treated with TCE and TCA. The cardiac depressant effects were much less pronounced in the isolated perfused neonatal rabbit heart. CH, TCE and TCA had minimal and unpredictable effects on left ventricular contractility and oxygen consumption. Of particular importance was the observation that CH, TCE and TCA produced essentially no conduction delays in the neonatal heart. Few serious arrhythmias could be attributed to factors other than incidental conduction delays in the neonatal rabbit heart. Biochemical and pharmacological data suggest the involvement of free radicals in lipid peroxidation of phospholipid components of the cell membrane in the adult heart preparations. CH and TCA produced increases in thiobarbituric acid reactive substances (TBARS) in adult cardiac tissue, suggesting that lipid peroxidation is initiated by these compounds. TBARS levels were also increased following TCE and TCA treatment in juvenile cardiac tissue. Neonatal myocardium appeared to be protected from the peroxidative effects of CH and its metabolites, with TBARS levels significantly reduced in the treated tissue. The reduced lipid peroxidation in neonatal hearts may be related to significantly increased activities of three antioxidant enzymes--catalase, glutathione peroxidase and superoxide dismutase--in the neonatal myocardium. It was demonstrated that the heart is a site of metabolism and accumulation of chloral hydrate and its two primary metabolites in both neonatal and adult hearts. It is axiomatic that the effects of chemically reactive intermediates tend to be limited to the tissues in which they are formed. Also, very low concentrations of reactive intermediates have demonstrated significant toxicity in vivo. Therefore, the heart appears to be capable of producing reactive metabolites of chloral hydrate which may be involved in lipid peroxidation and subsequent cardiotoxic effects. In conclusion, the present investigation has shown that the cardiotoxic effects of chloral hydrate and its metabolites may be related to myocardial lipid peroxidation. Myocardial accumulation and metabolism of CH, TCE and TCA may contribute to the cardiotoxic effects of these compounds. The resistance of the neonatal heart to cardiotoxic effects of CH and its metabolites may be due to high levels of antioxidant enzymes in immature versus adult hearts. | en_US |
| dc.identifier.uri | http://hdl.handle.net/10388/etd-10212004-000249 | en_US |
| dc.language.iso | en_US | en_US |
| dc.title | Chloral hydrate cardiotoxicity in adult and neonatal rabbit hearts | en_US |
| dc.type.genre | Thesis | en_US |
| dc.type.material | text | en_US |
| thesis.degree.department | Pharmacy | en_US |
| thesis.degree.discipline | Pharmacy | en_US |
| thesis.degree.grantor | University of Saskatchewan | en_US |
| thesis.degree.level | Doctoral | en_US |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) | en_US |