We hypothesize that altered lipoprotein metabolism produces changes in cardiovascular functions through modification of vascular smooth muscle contractility, Ca2+ flux and autonomic receptor characteristics. This is based on the fact that hyperlipoproteinemia, particularly elevated low density lipoprotein (LDL) cholesterol, has been shown to correlate with increased incidence of hypertension and atherosclerotic heart disease, cholesterol crystals and Ca2+ deposit are major components of atherosclerotic plaques and the ensuing vascular rigidity accounts, in part, for the elevated blood pressure. Hypothyroidism is associated with increased plasma LDL cholesterol and atherosclerotic cardiac disease, whereas the opposite is observed for hyperthyroidism. Therefore we propose to produce altered lipoprotein metabolism in rats by inducing hypo- and hyperthyroidism. Some of our objectives are to: 1) demonstrate that hyper-and hypothyroidism alter blood pressure in rats in a way that correlated with the changes in lipoprotein metabolism; 2) examine how various lipoprotein levels produced by eu- hypo- and hyperthyroid states alter vascular smooth muscle responsiveness to Ca2+ and other vasoactive agents; and 3) examine how altered thyroid status affect autonomic receptor characteristics in vascular smooth muscle relative to those in nonvascular smooth muscles. In adult rats, mild and severe hyperthyroidism will be induced by i.p. administration for 14 days of T3 via osmotic minipumps. Hypothyroidism will be induced by subcutaneously implanted osmotic minipumps for administration of propylthiouracil for 14 days or 28 days. During and after completion of the treatment periods, blood lipoprotein profiles will be measured and cardiovascular parameters computed. The rats will then be decapitated and spiral strips of aortic smooth muscles will be prepared for in vitro studies. Similar studies will be carried out in the presence of high cholesterol (hyperlipidemic serum) in the incubating medium. Data from our investigations are expected to provide evidence to enhance our understanding of how: 1) alteration in lipid metabolism lead to cardiovascular complications through changes in the contractility of vascular smooth muscles; 2) prevention of atheroma formation by Ca2+ antagonists correlate with the way vascular smooth muscles responded to vasoactive agents; and 3) impairment of cardio- vascular functions by different thyroid status, coupled with high fat-high cholesterol (HF-HC) diet is a function of altered lipid metabolism.
| Olubadewo, J O; Wingard, M; Washington, B et al. (1994) The effects of stress on lipoproteins and catecholamines in rats. Cell Mol Biol (Noisy-le-grand) 40:1201-6 |
