Date of Award
Doctor of Philosophy in Pharmaceutical Sciences
Pharmacy and Toxicology
Pharmacology and Toxicology
Robert L. Rogers
Both clinical and experimental evidence suggest that diabetes mellitus impairs cardiac performance to a greater extent in the presence of hypertension than it does in the absence of hypertension. There is also indirect evidence to suggest that a low thyroid state, which often coincides with experimental and clinical diabetes, may contribute to this impairment. The following study was designed in the hypertensive rat, and to determine whether involvement of attendant hypothyroidism is functionally significant. The hypothesis of this study can be summarized as follows: 1? The marked depression in cardiac performance cause by diabetes in hypertensive rats is associated with impairments in sarcoplasmic reticular (SR) calcium uptake and with prolongations in the duration of ventricular muscle action potentials; and 2) Demonstrated disturbances in cardiac performance, SR calcium uptake, and action potential duration caused by diabetes could then be altered by either thyroid hormone or insulin treatment in vivo. To test these hypotheses, spontaneously hypertensive rates (SHR) were made diabetic with a single injection of streptozotocin (STZ; 45 mg/kg). Subgroups of diabetic animals were treated with either thyroid hormone (T3; 8-10 mh/kg/day) or insulin (10-20 U/kg/day). After 8 weeks of untrated and treated diabetes, the following measurements were taken: 1) Indices of performance (contraction and relaxation) of perfused, working hearts ex vivo; 2) Rate and extent of calcium uptake by microsomal preparations of ventricular homogenates in vitro; and 3) Action potential profiles of papillary muscle in vitro. Control groups for various studies included nonhypertensive Wistar Kyoto (WKY) rats, and renovascular hyptertensive (RVH) rats, to rule out strain-dependent effects in the SHR model, food-restricted nondiabetic rats to control primarily for reductions in heart size, and rats pretreated with 3-0-methylgucose to protext against the diabetogenic effects of STZ (as a control for nonselective STZ-induced cardiotoxicity). The results showed, first, that indices of left ventricular (LV) performance ex vivo (e.g., LV pressure generation and rates of contraction and relaxation) of SHR, but not WKY rats, were depressed by diabetes. Diabetes-induced LV mechanical deficits of SHR were ameliorated by either insulin or T3 treatment. The adverse effects of diabetes on mechanical function of SHR hearts were independent of coronary macrolesions, as evidenced by normal coronary flow rates, myocardial oxygen consumption and coronary vascular resistance in the diabetic SHR group. These data provide additional evidence that a “diabetic cardiomyopathy” at least partially contributes to depressed function in the SHR and that thyroid hormone treatment can prevent at least a portion of the mechanical deficits. Second, the results showed that diabetes impaired LV relaxation and depressed rates of SR calcium uptake in the SHR left ventricle without affecting either measurement in the WKY group. Thyroid hormone treatment completely prevented these mechanical and biochemical changes in the diabetic SHR heart. The third component of the results indicated that diabetes prolonged the ventricular action potential to the same extent in the SHR as it did in the WKY. Either insulin or T3 treatment of diabetic SHR completely prevented the prolongation of the action potential. As it did in the SHR strain, diabetes also caused a marked depression in the performance in hearts of RVH rats. Similarly, T3 treatment of diabetic RVH, like T3 treatment of diabetic SHR, prevented the impairment of cardiac performance. Collectively, these results suggested that left ventricular hypertrophy, as a common element of SHR and RVH models of hypertension, predisposes the myocardium to the adverse effects of diabetes. The thyroid hormone deficit associated with diabetes, in both the SHR and RVH models of hypertension, may contribute to this myocardial dysfunction. Furthermore, since thyroid hormone treatment of diabetic SHR prevents impaired SR calcium uptake and action potential prolongation, attendant hypothyroidism may play a significant role in the etiology of diabetic cardiomyopathy in hypertrophic left ventricle.
Davidoff, Amy Jane, "CHANGES IN CARDIAC FUNCTION DUE TO THE INTERACTIONS OF DIABETES AND HYPERTENSION IN THE RAT" (1989). Open Access Dissertations. Paper 340.